This paper presents a passivity-based control (PBC) design methodology for three-phase voltage source inverters (VSI) for uninterruptable power supply (UPS) systems where reduced harmonic distortions for the nonlinear load, reduced output voltage overshoot, and a restricted settling time are required. The output filter design and modification for efficient control and existing challenges with the assignment of scaling coefficients of the output voltage, load, and inductor currents are addressed and analyzed. Notably, special attention is given to the modulator saturation issue through implementing an accurate converter model. Applications of the two versions of PBC in three-phase voltage source inverters using stationary αβ and rotating dq frames for a constant frequency of the output voltage are presented. Furthermore, the influence of the PBC parameters on the power converter performance is investigated. A comparative simulation and the experimental results validate the effectiveness of the presented passivity-based control design methodology. Full article

Intra-striatal transplantation of fetal ventral mesencephalic (VM) tissue has a therapeutic effect on patients with Parkinson’s disease (PD). Sertoli cells (SCs) possess immune-modulatory properties that benefit transplantation. We hypothesized that co-graft of SCs with VM tissue can attenuate rejection. Hemi-parkinsonian rats were generated by injecting 6-hydroxydopamine into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats or pigs (rVM or pVM), with/without a co-graft of SCs (rVM+SCs or pVM+SCs). Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small animal-positron emission tomography (PET) coupled with [¹⁸F] DOPA or [¹⁸F] FE-PE2I, respectively. Immunohistochemistry (IHC) examination was used to determine the survival of the grafted dopaminergic neurons in the striatum and to investigate immune-modulatory effects of SCs. The results showed that the rVM+SCs and pVM+SCs groups had significantly improved drug-induced rotational behavior compared with the VM alone groups. PET revealed a significant increase in specific uptake ratios (SURs) of [¹⁸F] DOPA and [¹⁸F] FE-PE2I in the grafted striatum of the rVM+SCs and pVM+SCs groups as compared to that of the rVM and pVM groups. SC and VM tissue co-graft led to better dopaminergic (DA) cell survival. The co-grafted groups exhibited lower populations of T-cells and activated microglia compared to the groups without SCs. Our results suggest that co-graft of SCs benefit both xeno- and allo-transplantation of VM tissue in a PD rat model. Use of SCs enhanced the survival of the grafted dopaminergic neurons and improved functional recovery. The enhancement may in part be attributable to the immune-modulatory properties of SCs. In addition, [¹⁸F]DOPA and [¹⁸F]FE-PE2I coupled with PET may provide a feasible method for in vivo evaluation of the functional integrity of the grafted DA cell in parkinsonian rats. Full article

(1) Background: Metallo-β-lactamases (MBLs) have raised concerns due to their ability to inactivate carbapenems and newer generation cephalosporins and the absence of clinically available MBL inhibitors. Their genes are often transferred horizontally, and the number of MBL variants has grown exponentially, with many newer variants showing enhanced enzyme activity or stability. In this study, we investigated a closely related group of variants from the IMP family that all contain the combination of mutations S115T and S119G relative to IMP-1. (2) Methods: The effects of each individual mutation and their combination in the IMP-1 sequence background in comparison to IMP-1 were investigated. Their ability to confer resistance and their in-cell expression levels were determined. All enzymes were purified, and their secondary structure and thermal stability were determined with circular dichroism. Their Zn(II) content and kinetic constants with a panel of β-lactam antibiotics were determined. (3) Results: All four enzymes were viable and conferred resistance to all antibiotics tested except aztreonam. However, the single-mutant enzymes were slightly deficient, IMP-1S115T due to decreased enzyme activity and IMP-1-S119G due to decreased thermal stability and expression, while the double mutant did not show these defects. (4) Conclusions: These observations suggest that S119G was acquired due to its increased enzyme activity and S115T to suppress the thermal stability and expression defect introduced by S119G. Full article

In mobile ad-hoc networks (MANETs), nodes are mobility naturally which renders a great challenge in topology controls. Connected dominating set (CDS) has been considered as an efficient solution to solve such a problem by constructing a virtual backbone network to achieve the scalability and efficiency of wireless networks. In this paper, we propose an efficient connected dominating set clustering based routing protocol with dynamic channel selection (CRD) in multi-channel cognitive radio MANETs to obtain high packet delivery ratio (PDR), low control overheads, low delay and low energy consumption when node is moving in high speed. Moreover, CRD protocol can apply for Vehicular Ad Hoc Network, IoT and 5G. The proposed CRD protocol includes clustering and routing phases under multi-channel cognitive radio approach. In the clustering phase, we propose CDS selection, CDS size reduction and CDS based clustering algorithms to formulate clusters and provide a set of intermediate nodes which is latter used as a route searching space for the routing phase. In the routing phase, a sending channel based focus region selection (CFS) algorithm is adopted dynamically to establish an efficient route from a set of intermediate nodes that avoids the affected region of a primary user. The CRD routing protocol is then implemented in environmental conditions close to reality (OMNET++ platform) to demonstrate its superiority over the conventional AODV protocol in terms of PDR, control overhead, delay and energy consumption. Full article

Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed. Full article

This study aims to explore how family firms pursue strategies that promote strategic flexibility and knowledge-management (KM) practices to respond to strategic-renewal goals. Specifically, based on a knowledge-based view of the firm, the following research question is proposed: Are there heterogeneous groups of family firms in terms of knowledge management, strategic flexibility and strategic renewal goals? To answer this question, an exploratory study using a two-step cluster analysis is developed. It reveals natural groupings from a sample of 288 small and medium-sized Spanish family enterprises (SMEs). The results obtained identified three distinctive clusters of family firms, namely proactive family firms, transitional or adaptive family firms, and rigid family firms. After two-step cluster analysis, we also conducted analysis of variance (ANOVA) to confirm that significant differences amongst the three clusters exist. After heterogeneity been confirmed, a further profile of the cluster solution was provided by using CEO and board characteristics, as well as the generational stage of the company. The findings offer some counterbalance for those studies that tend to study family businesses as a homogeneous entity, thus permitting researchers to access more information, providing rich explanations for renewal managerial decision-making purposes in family firm contexts. Full article

Direct antiviral agents (DAAs) have excellent efficacy against chronic hepatitis C virus (HCV) infection. Despite this strength, recent studies raised concerns about an unexpected hepatocellular carcinoma (HCC) occurrence rate after DAA therapy. In this exploratory case-control study, we evaluated the potential use of miRNAs as serum biomarkers for the detection of early HCC in DAA-treated patients. In the discovery phase, the circulating miRNome was assessed in 10 matched patients with (HCC+) or without HCC (HCC−) occurrence. Microarray analysis was performed before (T0) and after one month of the DAA therapy (T1). MiRNAs discriminating HCC+ and HCC− patients were validated in 60 samples by means of RT-qPCR. We estimated the time-averaged difference of a given miRNA between HCC+ and HCC− patients using a bootstrapped random-effect generalized least square regression model (RE-GLS). At T0, miR-1207-5p, miR-1275, miR-3197, miR-4443, miR-3178, miR-483-5p, miR-4706, miR-4793-3p and miR-1246 discriminated HCC+ from HCC− patients (p < 0.05). At T1, only miR-1180-3p, miR-1228-3p, miR-4329 and miR-4484 (p < 0.05) discriminated HCC+ from HCC− patients. The subsequent validation phase identified miR-3197 as changing with both disease and time. Our results suggest that patients might be already committed to HCC occurrence before DAA therapy. MiR-3197 shows some potential for the identification of patients at risk of HCC during DAA treatments. Full article

Nature-based health interventions (NBIs) for the treatment of poor mental health are becoming increasingly common, yet evidence to support their effectiveness is lacking. We conduct a pilot study of a six-week intervention, aiming to engage individuals with wetland nature for the treatment of anxiety and/or depression. We employed a mixed methods design, using questionnaires, focus groups and semi-structured interviews to evaluate the intervention from the perspective of participants (n = 16) and healthcare professionals (n = 2). Results demonstrate significant improvements in mental health across a range of indicators, including mental wellbeing (Warwick and Edinburgh Mental Wellbeing Scale), anxiety (Generalised Anxiety Disorder-7), stress (Perceived Stress Scale) and emotional wellbeing (Positive and Negative Affect Schedule). Participants and healthcare professionals cited additional outcomes including improved physical health and reduced social isolation. The wetland site provided a sense of escape from participants’ everyday environments, facilitating relaxation and reductions in stress. Wetland staff knowledge of the natural world, transportation and group organisation also played a considerable role in the intervention’s success. These aspects should be considered in future and existing NBIs to maximise benefits to participants. We propose NBIs based in wetlands are an effective therapy option for individuals diagnosed with anxiety and/or depression. Full article

This study investigates Italian consumer knowledge and use of nutrition and health claims (NHCs). Six specific claims are examined on the basis of a web survey carried out on a sample of 504 consumers. Our results show that there is little attention to NHCs and their use is not widespread; objective knowledge of the selected claims is fairly scant, generating misinterpretation and confusion about their real meaning. K-means cluster analysis allowed us to identify three segments of consumers, characterized by different levels in attention and use frequency of NHCs, with a specific profile in terms of motivation and nutritional knowledge. Our results suggest the advisability of policy interventions and communication efforts which target the three segments with a view to achieving greater attention to NHCs. In conclusion, to boost knowledge concerning the actual meaning of the claims and their relation with a healthy diet, especially to reach non-users, information should be provided both simply and clearly, avoiding the use of complex scientific terminology. Full article

By means of copper(I)-and ruthenium(II)-catalyzed click reactions of quinine- and quinidine-derived alkynes with azide-substituted chalcones a systematic series of novel cinchona-chalcone hybrid compounds, containing 1,4-disubstituted- and 1,5-disubstituted 1,2,3-triazole linkers, were synthesized and evaluated for their cytotoxic activity on four human malignant cell lines (PANC-1, COLO-205, A2058 and EBC-1). In most cases, the cyclization reactions were accompanied by the transition-metal-catalyzed epimerization of the C9-stereogenic centre in the cinchona fragment. The results of the in vitro assays disclosed that all the prepared hybrids exhibit marked cytotoxicity in concentrations of low micromolar range, while the C9-epimerized model comprising quinidine- and (E)-1-(4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl) fragments, connected by 1,5-disubstituted 1,2,3-triazole linker, and can be regarded as the most potent lead of which activity is probably associated with a limited conformational space allowing for the adoption of a relatively rigid well-defined conformation identified by DFT modelling. The mechanism of action of this hybrid along with that of a model with markedly decreased activity were approached by comparative cell-cycle analyses in PANC-1 cells. These studies disclosed that the hybrid of enhanced antiproliferative activity exerts significantly more extensive inhibitory effects in subG1, S and G2/M phases than does the less cytotoxic counterpart. Full article

Endemic freshwater fish from semiarid environments are among the most threated species in the world due to water overexploitation and habitat fragmentation problems. Stepped or pool-type fishways are used worldwide to reestablish longitudinal connectivity and mitigate fish migration problems. Many of them are being installed or planned in rivers of semiarid environments, however, very few studies about fish passage performance through pool-type fishways has been carried out to date on these regions. The present work focuses on the passage performance of two potamodromous cyprinids endemic of these regions, with different ecological and swimming behavior: southern Iberian barbel (Luciobarbus sclateri) and Iberian straight-mouth nase (Pseudochondrostoma polylepis). These are assessed in two of the most common types of stepped fishways: vertical slot and submerged notch with bottom orifice fishways. Experiments were carried out during the spawning season in the Segura River (southeastern Spain), using a passive integrated transponder (PIT) tag and antenna system. Ascent success was greater than 80%, with a median transit time lower than 17 minutes per meter of height in all trials, and for both species and fishway types. Results show that both types of fishways, if correctly designed and constructed, provide interesting alternatives for the restoration of fish migration pathways in these regions. Full article

Despite advances in diagnostic tools and therapeutic options, treatment resistance remains a challenge for many cancer patients. Recent studies have found evidence that autophagy, a cellular pathway that delivers cytoplasmic components to lysosomes for degradation and recycling, contributes to treatment resistance in different cancer types. A role for autophagy in resistance to chemotherapies and targeted therapies has been described based largely on associations with various signaling pathways, including MAPK and PI3K/AKT signaling. However, our current understanding of the molecular mechanisms underlying the role of autophagy in facilitating treatment resistance remains limited. Here we provide a comprehensive summary of the evidence linking autophagy to major signaling pathways in the context of treatment resistance and tumor progression, and then highlight recently emerged molecular mechanisms underlying autophagy and the p62/KEAP1/NRF2 and FOXO3A/PUMA axes in chemoresistance. Full article

This paper presents the control of a quadrotor with a cable-suspended payload. The proposed control structure is a hierarchical scheme consisting of an energy-based control (EBC) to stabilize the vehicle translational dynamics and to attenuate the payload oscillation, together with a nonlinear state feedback controller based on an linear matrix inequality (LMI) to control the quadrotor rotational dynamics. The payload swing control is based on an energy approach and the passivity properties of the system’s translational dynamics. The main advantage of the proposed EBC strategy is that it does not require excessive computations and complex partial differential equations (PDEs) for implementing the control algorithm. We present a new methodology for using an LMI to synthesize the controller gains for Lipschitz nonlinear systems with larger Lipschitz constants than other classical techniques based on LMIs. This theoretical approach is applied to the quadrotor rotational dynamics. Stability proofs based on the Lyapunov theory for the controller design are presented. The designed control scheme allows for the stabilization of the system in all its states for the three-dimensional case. Numerical simulations demonstrating the effectiveness of the controller are provided. Full article