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Ali Riza Koksal,1,2 Paul Thevenot,3 Yucel Aydin,1 Kelley Nunez,3 Tyler Sandow,4 Kyle Widmer,5 Leela Nayak,5 John Scott,1 Molly Delk,2 Martin W Moehlen,2 Ari J Cohen,3,6 Srikanta Dash1,2,5 1Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA; 2Department of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA, USA; 3Department of Gastroenterology and Hepatology, Institute of Translational Research, Ochsner Health, New Orleans, LA, USA; 4Department of Radiology, Multi-Organ Transplant Institute, Ochsner Health, New Orleans, LA, USA; 5Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA; 6Department of General Surgery, Multi-Organ Transplant Institute, Ochsner Health, New Orleans, LA, USACorrespondence: Srikanta Dash, Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA, 70112, USA, Tel +1 504-988-2519, Fax +1 504-988-7389, Email sdash@tulane.eduBackground and Aim: HCC development in liver cirrhosis is associated with impaired autophagy leading to increased production of extracellular vesicles (EVs) including exosomes and microvesicles. The goal of the study is to determine which of these particles is primarily involved in releasing of HCC-specific biomarker glypican-3 (GPC3) when autophagy is impaired.Methods: Streptavidin-coated magnetic beads were coupled with either biotinylated CD63 or Annexin A1 antibodies. Coupled beads were incubated with EVs isolated from either HCC culture or serum. EVs captured by immuno-magnetic beads were then stained with FITC or PE fluorescent-conjugated antibodies targeting exosomes (CD81), and microvesicles (ARF6). The percentage of GPC3 enrichment in the microvesicles and exosomes was quantified by flow cytometry. The impact of autophagy modulation on GPC3 enrichment in exosomes and microvesicles was assessed by treating cells with Torin 1 and Bafilomycin A1. For clinical validation, GPC3 content was quantified in microvesicles, and exosomes were isolated from the serum of patients with a recent HCC diagnosis.Results: The immune-magnetic bead assay distinguishes membrane-derived microvesicles from endosome-derived exosomes. The GPC3 expression was only seen in the CD63 beads group but not in the Annexin A1 beads group, confirming that in HCC, GPC3 is preferentially released through exosomes. Furthermore, we found that autophagy induction by Torin1 decreased GPC3-positive exosome secretion and decreased microvesicle release. Conversely, autophagy inhibition by Bafilomycin A1 increased the secretion of GPC3-positive exosomes. Serum analysis showed CD81+ve EVs were detected in exosomes and ARF6+ve vesicles were detected in microvesicles, suggesting that immunoaffinity assay is specific. The exosomal GPC3 enrichment was confirmed in isolated EVs from the serum of patients with HCC. The frequency of GPC3-positive exosomes was higher in patients with HCC (12.4%) compared to exosomes isolated from non-cirrhotic and healthy controls (3.7% and 1.3% respectively, p< 0.001).Conclusion: Our results show that GPC3 is enriched in the endolysosomal compartment and released in exosome fractions when autophagy is impaired.Keywords: hepatocellular carcinoma, glypican 3, exosome, biomarker, magnetic beads

Internet of Things (IoT) networks are becoming a part of our daily lives, as the number of IoT devices around us are surging. The authentication of millions of connected things and the distribution and management of secret keys between these devices pose challenging research problems. Current one-to-one authentication schemes do not take the resource limitations of IoT devices into consideration. Nor do they address the scalability problem of massive machine type communication (mMTC) networks. Group authentication schemes (GAS), on the other hand, have emerged as novel approaches for many-to-many authentication problems. They can be used to simultaneously authenticate numerous resource-constrained devices. However, existing GAS are not energy efficient, and they do not provide enough security for widespread use. In this paper, we propose a lightweight GAS that significantly reduces energy consumption on devices, providing almost 80% energy savings when compared to the state-of-the-art solutions. Our approach is also resistant to the replay and man-in-the-middle attacks. The proposed approach also includes a solution for key agreement and key distribution problems in mMTC environments. Moreover, this approach can be used in both centralized and decentralized group authentication scenarios. The proposed approach has the potential to address the fast authentication requirements of the envisioned agile 6G networks, supported through aerial networking nodes., Comment: Published in IEEE Internet of Things Journal

Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFN-α) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.

Drones are begin used for various purposes such as border security, surveillance, cargo delivery, visual shows and it is not possible to overcome such intensive tasks with a single drone. In order to expedite performing such tasks, drone swarms are employed. The number of drones in a swarm can be high depending on the assigned duty. The current solution to authenticate a single drone using a 5G new radio (NR) network requires the execution of two steps. The first step covers the authentication between a drone and the 5G core network, and the second step is the authentication between the drone and the drone control station. It is not feasible to authenticate each drone in a swarm with the current solution without causing a significant latency. Authentication keys between a base station (BS) and a user equipment (UE) must be shared with the new BS while performing handover. The drone swarms are heavily mobile and require several handovers from BS to a new BS. Sharing authentication keys for each drone as explained in 5G NR is not scalable for the drone swarms. Also, the drones can be used as a UE or a radio access node on board unmanned aerial vehicle (UxNB). A UxNB may provide service to a drone swarm in a rural area or emergency. The number of handovers may increase and the process of sharing authentication keys between UxNB to new UxNB may be vulnerable to eavesdropping due to the wireless connectivity. In this work, we present a method where the time and the number of the communication for the authentication of a new drone joining the swarm are less than 5G NR. In addition, group-based handover solutions for the scenarios in which the base stations are terrestrial or mobile are proposed to overcome the scalability and latency issues in the 5G NR., Accepted for publication in IEEE Journal of Radio Frequency Identification

In parallel with the advances of aerial networks, the use of drones is quickly included in daily activities. According to the characteristics of the operations to be carried out using the drones, the need for simultaneous use of one or more drones has arisen. The use of a drone swarm is preferred rather than the use of a single drone to complete activities such as secure crowd monitoring systems, cargo delivery. Due to the limited airtime of the drones, new members may be included in the swarm, or there may be a unification of two or more drone swarms when needed. Authentication of the new drone that will take its place in the drone swarm and the rapid mutual-verification of two different swarms of drones are some of the security issues in the swarm structures. In this study, group authentication-based solutions have been put forward to solve the identified security issues. The proposed methods and 5G new radio (NR) authentication methods were compared in terms of time and a significant time difference was obtained. According to the 5G NR standard, it takes 22 ms for a user equipment (UE) to be verified by unified data management (UDM), while in the proposed method, this time varies according to the threshold value of the polynomial used and it is substantially lower than 22 ms for most threshold values., Published in IEEE International Conference on Wireless for Space and Extreme Environments (WiSEE)

Peptoids are highly biocompatible pseudopeptidic polyglycines with designable substituents on the nitrogen atoms. The therapeutic and drug-carrying potential of these materials requires a fundamental understanding of their interactions with lipid bilayers. In this work, we use amphiphilic polypeptoids with up to 100 monomeric units where a significant fraction (26%) of the nitrogen atoms are functionalized with decyl groups (hydrophobes) that insert into the lipid bilayer through the hydrophobic effect. These hydrophobically modified polypeptoids (HMPs) insert their hydrophobes into lipid bilayers creating instabilities that lead to the rupture of vesicles. At low HMP concentrations, such rupture leads to the creation of large fragments which remarkably anchor to intact vesicles through the hydrophobic effect. At high HMP concentrations, all vesicles rupture to smaller HMP-lipid fragments of the order of 10 nm. We show that the technique for such nanoscale polymer-lipid fragments can be exploited to sustain highly hydrophobic drug species in solution. Using the kinase inhibitor, Sorafenib as a model drug, it is shown that HMP-lipid fragments containing the drug can efficiently enter a hepatocellular carcinoma cell line (Huh 7.5), indicating the use of such fragments as drug delivery nanocarriers.

Hepatitis C virus (HCV) infection promotes autophagic degradation of viral replicative intermediates for sustaining replication and spread. The excessive activation of autophagy can induce cell death and terminate infection without proper regulation. A prior publication from this laboratory showed that an adaptive cellular response to HCV microbial stress inhibits autophagy through beclin 1 degradation. The mechanisms of how secretory and degradative autophagy are regulated during persistent HCV infection is unknown. This study was performed to understand the mechanisms of viral persistence in the absence of degradative autophagy, which is essential for virus survival. Using HCV infection of a CD63-green fluorescence protein (CD63-GFP), labeled stable transfected Huh-7.5 cell, we found that autophagy induction at the early stage of HCV infection increased the degradation of CD63-GFP that favored virus replication. However, the late-stage of persistent HCV infection showed impaired autophagic degradation, leading to the accumulation of CD63-GFP. We found that impaired autophagic degradation promoted the release of extracellular vesicles and exosomes. The impact of blocking the release of extracellular vesicles (EVs) on virus survival was investigated in persistently infected cells and sub-genomic replicon cells. Our study illustrates that blocking EV and exosome release severely suppresses virus replication without effecting host cell viability. Furthermore, we found that blocking EV release triggers interferon lambda 1 secretion. These findings suggest that the release of EVs is an innate immune escape mechanism that promotes persistent HCV infection. We propose that inhibition of extracellular vesicle release can be explored as a potential antiviral strategy for the treatment of HCV and other emerging RNA viruses.

Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/β-catenin signaling activation due to the inhibition of GSK-3β activity via serine 9 phosphorylation (p-ser9-GSK-3β) leading to stable non-phosphorylated β-catenin. Immunohistochemical staining demonstrated the upregulation of both β-catenin and p-Ser9-GSK-3β in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of β-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/β-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3β-mediated β-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/β-catenin signaling for HCV-infected patients.

The widespread use of new technologies such as the Internet of things (IoT) and machine type communication(MTC) forces an increase on the number of user equipments(UEs) and MTC devices that are connecting to mobile networks. Inherently, as the number of UEs inside a base station's (BS) coverage area surges, the quality of service (QoS) tends to decline. The use of drone-mounted BS (UxNB) is a solution in places where UEs are densely populated, such as stadiums. UxNB emerges as a promising technology that can be used for capacity injection purposes in the future due to its fast deployment. However, this emerging technology introduces a new security issue. Mutual authentication, creating a communication channel between terrestrial BS and UxNB, and fast handover operations may cause security issues in the use of UxNB for capacity injection. This new protocol also suggests performing UE handover from terrestrial to UxNB as a group. To the best of the authors' knowledge, there is no authentication solution between BSs according to LTE and 5G standards. The proposed scheme provides a solution for the authentication of UxNB by the terrestrial BS. Additionally, a credential sharing phase for each UE in handover is not required in the proposed method. The absence of a credential sharing step saves resources by reducing the number of communications between BSs. Moreover, many UE handover operations are completed in concise time within the proposed group handover method., Published in IEEE Internet of Things Journal 2021

Liver cirrhosis is an independent risk factor for hepatocellular carcinoma (HCC). The mechanisms that contribute to HCC development in the cirrhotic microenvironment are unknown. We found that HCC grown in the highly stressed cirrhotic microenvironment undergoes autophagy switching from a protective state characterized by high macroautophagy with low chaperone-mediated autophagy (CMA) to an HCC-promoting state characterized by low macroautophagy with high CMA. This study examined how the stress response executes oncogenic cell programming through autophagy switching using hepatitis C virus cell culture. Protein kinase R–like endoplasmic reticulum kinase expression increased to high levels in hepatitis C virus culture. Protein kinase R–like endoplasmic reticulum kinase–dependent activation of nuclear factor erythroid 2–related factor (Nrf2) led to increased transcription of the cytoprotective genes: heat shock cognate 70 kDa protein and lysosome-associated membrane protein 2A (LAMP2A) and precipitated the induction of CMA. CMA selectively targeted beclin1 degradation, leading to accumulation of the autophagy flux protein p62 due to impaired autophagosome-endosome fusion. This impaired autophagosome-endosome fusion due to beclin1 degradation inhibited endocytosis and degradation of epidermal growth factor receptor. Silencing Nrf2 and LAMP2A reduced cell viability, suggesting that the stress response activates CMA as a compensatory mechanism of cell survival. We report a novel mechanism through which stress response triggers oncogenic Nrf2 signaling that promotes autophagy switching to favor cell survival.

The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2-mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-α based antiviral normalized the ER-stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation.

Barrett's esophagus (BE) is one of the major complications of gastroesophageal reflux disease (GERD) commonly encountered in gastroenterology clinics. A consensus has not been achieved yet with respect to the definition of BE in published guidelines. It is advised to use the Prague classification and not to use the definition of short and long segments for the endoscopic standardization of BE. Undertaking biopsies with white-light endoscopy from each of the 4 quadrants at 2-cm intervals is the standard method for the diagnosis of BE. Because of the ability to perform targeted biopsies, the available data indicate that advanced endoscopic techniques may reduce the number of biopsies needed for diagnoses. In the presence of severe esophagitis along with BE, the biopsies should be taken after 8 weeks of PPI therapy. The evidence values of the suggestions about the surveillance requirements and surveillance frequencies are low because the available data mostly rely on retrospective studies. We suggest that all the patients with BE should be referred to specialized centers for surveillance in Turkey. Considering the additional risk factors of the patient, endoscopy surveillance intervals of the patients with BE without dysplasia should be in a range of 3-5 years and annual surveillance should be made in BE with low-grade dysplasia. In the presence of BE with high-grade dysplasia (HGD), the patients should be referred to specialized centers for treatment within 3 months at the latest.

This paper presents a study on optimized control for a magnetically levitated (MAGLEV) suspension system. Unstable magnetically levitated system is modelled and integer order PID (IOPID) and fractional order PID (FOPID) controller parameters are evaluated by using both Genetic Algorithm (GA) and Big Bang Big Crunch (BBBC) algorithm. Comparison between BBBC and GA based controllers are done. Responses for variable reference inputs are obtained. Results show that the performance of the BBBC based FOPID controller is better than GA optimized FOPID controller.

The mechanism why hepatitis C virus (HCV) clearance by direct-acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)-stress response. In this study, we examined whether HCV clearance by interferon-alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes. The unfolded protein response induces chaperone-mediated autophagy (CMA) in infected primary human hepatocytes and Huh-7.5 cells that results in degradation of p53 and induced expression of mouse double minute 2 (Mdm2). Inhibition of p53/Mdm2 interactions by small molecule (nutlin-3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway. Interestingly, we found that HCV infection degrades p53 in a lysosome-dependent mechanism because lysosome-associated membrane protein 2A silencing restored p53 degradation. Our results show that HCV clearance induced by interferon-alpha-based antiviral therapies normalizes the ER-stress response and restores p53, whereas HCV clearance by DAAs does neither. We show that decreased expression of p53 in HCV-infected cirrhotic liver is associated with expression of chaperones associated with ER stress and the CMA response. Conclusion: HCV-induced ER stress and CMA promote p53 degradation in advanced liver cirrhosis. HCV clearance by DAAs does not restore p53, which provides a potential explanation for why a viral cure by DAAs does not eliminate the HCC risk among patients with advanced liver disease. We propose that resolving the ER-stress response is an alternative approach to reducing HCC risk among patients with cirrhosis after viral cure. (Hepatology Communications 2017;1:256-269).

Hepatitis C virus (HCV) infection compromises the natural defense mechanisms of the liver leading to a progressive end stage disease such as cirrhosis and hepatocellular carcinoma (HCC). The hepatic stress response generated due to viral replication in the endoplasmic reticulum (ER) undergoes a stepwise transition from adaptive to pro-survival signaling to improve host cell survival and liver disease progression. The minute details of hepatic pro-survival unfolded protein response (UPR) signaling that contribute to HCC development in cirrhosis are unknown. This study shows that the UPR sensor, the protein kinase RNA-like ER kinase (PERK), mediates the pro-survival signaling through nuclear factor erythroid 2-related factor 2 (NRF2)-mediated signal transducer and activator of transcription 3 (STAT3) activation in a persistent HCV infection model of Huh-7.5 liver cells. The NRF2-mediated STAT3 activation in persistently infected HCV cell culture model resulted in the decreased expression of hepatocyte nuclear factor 4 alpha (HNF4A), a major liver-specific transcription factor. The stress-induced inhibition of HNF4A expression resulted in a significant reduction of liver-specific microRNA-122 (miR-122) transcription. It was found that the reversal of hepatic adaptive pro-survival signaling and restoration of miR-122 level was more efficient by interferon (IFN)-based antiviral treatment than direct-acting antivirals (DAAs). To test whether miR-122 levels could be utilized as a biomarker of hepatic adaptive stress response in HCV infection, serum miR-122 level was measured among healthy controls, and chronic HCV patients with or without cirrhosis. Our data show that serum miR-122 expression level remained undetectable in most of the patients with cirrhosis (stage IV fibrosis), suggesting that the pro-survival UPR signaling increases the risk of HCC through STAT3-mediated suppression of miR-122. In conclusion, our data indicate that hepatic pro-survival UPR signaling suppresses the liver-specific HNF4A and its downstream target miR-122 in cirrhosis. These results provide an explanation as to why cirrhosis is a risk factor for the development of HCC in chronic HCV infection.

Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFN-α) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.

The molecular mechanism(s) how liver damage during the chronic hepatitis C virus (HCV) infection evolve into cirrhosis and hepatocellular carcinoma (HCC) is unclear. HCV infects hepatocyte, the major cell types in the liver. During infection, large amounts of viral proteins and RNA replication intermediates accumulate in the endoplasmic reticulum (ER) of the infected hepatocyte, which creates a substantial amount of stress response. Infected hepatocyte activates a different type of stress adaptive mechanisms such as unfolded protein response (UPR), antioxidant response (AR), and the integrated stress response (ISR) to promote virus-host cell survival. The hepatic stress is also amplified by another layer of innate and inflammatory response associated with cellular sensing of virus infection through the production of interferon (IFN) and inflammatory cytokines. The interplay between various types of cellular stress signal leads to different forms of cell death such as apoptosis, necrosis, and autophagy depending on the intensity of the stress and nature of the adaptive cellular response. How do the adaptive cellular responses decode such death programs that promote host-microbe survival leading to the establishment of chronic liver disease? In this review, we discuss how the adaptive cellular response through the Nrf2 pathway that promotes virus and cell survival. Furthermore, we provide a glimpse of novel stress-induced Nrf2 mediated compensatory autophagy mechanisms in virus-cell survival that degrade tumor suppressor gene and activation of oncogenic signaling during HCV infection. Based on these facts, we hypothesize that the balance between hepatic stress, inflammation and different types of cell death determines liver disease progression outcomes. We propose that a more nuanced understanding of virus-host interactions under excessive cellular stress may provide an answer to the fundamental questions why some individuals with chronic HCV infection remain at risk of developing cirrhosis, cancer and some do not.

Hepatitis C virus (HCV) infection is frequently associated with the development of chronic liver disease, liver cirrhosis, and hepatocellular cancer. While antiviral therapies, such as interferon (IFN) and ribavirin (RBV), were initially widely accepted, these agents are not very effective against HCV, resulting in numerous deaths due to liver failure secondary to advanced cirrhosis and liver cancer. The recent development of IFN-free, direct-acting antiviral (DAA) drugs has drastically improved patient outcomes, clearing the infection in more than 90% of patients. Of the newly developed DAA drugs, the NS5B polymerase inhibitor sofosbuvir has become an integral part of an effective anti-HCV therapy regimen due to its broad spectrum of antiviral activity against all HCV genotypes and high genetic barrier to resistance. This review will summarize recent progress made in understanding the structure and function of NS5B polymerase and the development of targeted NS5B inhibitors widely used in the treatment of chronic HCV infection.

In this paper we will present on two methods for high performance active magnetic bearings (AMBs). These methods based on robust Variable Structure Control (VSC) with sliding mode in non-adaptive and adaptive cases. Our approach combines two simple architectures often referred to as Dynamic Feedback Linearization (DFL) and recent advances in robust control design techniques to form a new approach for AMB for two cases. The procedure enables the designer to explicitly define the desired closed loop dynamics and enables the design of a robust stabilizing controller that forces the system dynamics to the specified desired dynamics, despite gravitational and centrifugal disturbances, modeling uncertainties, and variations in mass, moments of inertia, radii of eccentricities and center of mass of the rotor. Our design hangs the magnetic bearing on gravitational parabolic sliding surface by switching electronics and sliding mode control components. Thus, electromagnets do not constitute cross forces on rotor shaft that affects against each other. This operation guarantees the lowest power losses, by considering low bias currents method that the currents affects against. The methods also guarante both stability and performance robustness and enable the design for other unstable magnetic levitation systems. When the methods are compared with each other, the results in adaptive case are more efficient about high speed and wide range of parameter uncertainties.

A method of designing adaptive controller for high performance active magnetic bearings (AMB) is represented. The approach combines two simple architectures often referred to as a Dynamic Feedback Linearization (DFL) and recent advances in adaptive control design techniques to form a new approach for AMB. The procedure enables the designer to explicitly define the desired closed loop dynamics. The result is a straight forward procedure that enables the design of a robust stabilizing adaptive controller that forces the system dynamics to the specified desired dynamics, despite disturbances, modelling uncertainties, and variations in AMB dynamics. This method also guarantees the robustness of both stability and system performance and enables the design for other unstable, magnetic levitation plants.

Disability is utmost important on an aging population's health. Obesity is associated with increased risk for disability. On-the-other-hand, higher-BMI is reported as associated with better functionality in older people in some reports defined as "obesity paradox". There is some evidence on differential relationship between body weight status and functionality by living setting gender, and different populations. We studied the relation between body mass index and functionality in Turkish community dwelling older males accounting for the most confounding factors: age, multimorbidity, polypharmacy and nutritional status. This is a cross-sectional study in a geriatric outpatient clinic of a university hospital. Functionality was assessed with evaluation of activities of daily living (ADL) and instrumental activities of daily living (IADL) scales. Nutrition was assessed by mini-nutritional assessment test. Two hundred seventy-four subjects comprised our study cohort. Mean age was 74.4 ± 7.1 years, BMI was 25.8 ± 4.4 kg/m(2). Linear regression analysis revealed significant and independent association of lower BMI with higher ADL and IADL scores (B = 0.047 and B = 0.128, respectively) (p 0.05) and better nutritional status (B = 1.94 and B = 3.05, respectively) (p 0.001) but not with the total number of medications. Higher IADL score was associated with younger age and lower total number of diseases (B = 0.121, B = 0.595, respectively) (p 0.05) while ADL was not. We suggest that lower BMI is associated with better functional status in Turkish community-dwelling male older people. Our study recommends longitudinal studies with higher participants from different populations, genders and living settings are needed to comment more.

Background Transient elastography (TE) has recently emerged as an accurate noninvasive imaging method for the diagnosis of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). Here, we tested whether adding serum measures of serum procollagen-III peptide (PIIIP) and caspase-cleaved cytokeratin 18 fragment (M30) to TE could improve its diagnostic accuracy in patients with biopsy-proven NAFLD. Patients and methods TE was performed in 87 patients with NAFLD. Serum PIIIP and M30 levels were determined by enzyme-linked immunosorbent assay. Liver histology was considered the gold standard. The diagnostic accuracies were assessed by measuring the area under the receiver operating curve. Results At histopathological examination, 34 patients (39.1%) had significant fibrosis (F2-F4) and 19 patients (21.8%) had advanced fibrosis (F3-F4). Both TE and serum M30 levels were independent predictors of fibrosis, whereas no association was found with PIIIP. No significant differences in terms of sensitivity and specificity for both significant and advanced fibrosis were evident for TE, serum M30, or their combination. Moreover, the area under the receiver operating curves of serum M30 combined with TE did not differ significantly from those of either test alone. Conclusion Both TE and serum M30 levels are accurate for the noninvasive diagnosis of fibrosis in NAFLD. However, their combination did not improve the overall diagnostic accuracy.

The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2-mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-α based antiviral normalized the ER-stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation.

A new approach based on discrete wavelet transform (DWT) and Walsh Hadamard transform (WHT) for improving carrier frequency offset (CFO) tracking performance of the multi carrier communication systems has been proposed in this paper. The proposed DWT-WHT technique has been applied to frequency domain channel equalizer (FDE) employed in orthogonal frequency division multiplexing (OFDM) systems. Computer simulations have been performed to verify the performance of the proposed method in stationary and non-stationary frequency selective Rayleigh fading channels. The obtained simulation results using HIPERLAN/2 (IEEE 802.11a) physical layer specifications have demonstrated that the proposed DWT-WHT-OFDM method is outperforming the CFO tracking performances of conventional OFDM, WHT-OFDM and DWT-OFDM techniques, and is removing the error floor.