The deleterious variants of N-acetylgalactosamine-6-sulfatase (GalN6S) enzyme trigger Morquio a syndrome by disrupting protein foldings.

Lysosomal enzymes degrade cellular macromolecules, while their inactivation causes human hereditary metabolic disorders. Mucopolysaccharidosis IVA (MPS IVA; Moquio A syndrome) is one of the lysosomal storage disorders caused by a defective Galactosamine-6-sulfatase (GalN6S) enzyme. In several populations, disease incidence is elevated due to missense mutations brought on by non-synonymous allelic variation in the GalN6S enzyme. Here, we studied the effect of non-synonymous single nucleotide polymorphism (nsSNPs) on the structural dynamics of the GalN6S enzyme and its binding with N-acetylgalactosamine (GalNAc) using all-atom molecular dynamics simulation and an essential dynamics approach. Consequently, in this study, we have identified three functionally disruptive mutations in domain-I and domain-II, that is, S80L, R90W, and S162F, which presumably contribute to post-translational modifications. The study delineated that both domains work cooperatively, and alteration in domain II (S80L, R90W) leads to conformational changes in the catalytic site in domain-I, while mutation S162F mainly provokes higher residual flexibility of domain II. These results show that these mutations impair the hydrophobic core, implying that Morquio A syndrome is caused by misfolding of the GalN6S enzyme. The results also show the instability of the GalN6S-GalNAc complex upon substitution. Overall, the structural dynamics resulting from point mutations give the molecular rationale for Moquio A syndrome and, more importantly, the Mucopolysaccharidoses (MPS) family of diseases, re-establishing MPS IVA as a protein-folding disease.Communicated by Ramaswamy H. Sarma.

Novel 2D MXene Cobalt Ferrite (CoF@Ti3C2) Composite: A Promising Photothermal Anticancer In Vitro Study.

In search of materials with superior capability of light-to-heat (photothermal) conversion, biocompatibility, and confinement of active photothermal materials within the cells, novel magnetic MXene-based nanocomposites are found to possess all of these criteria. The CoF@Ti3C2 composite is fabricated by a simple two-step method, including an exfoliation strategy followed by sonochemical method. MXene composite has been modified with polyvinylpyrrolidone (PVP) to improve the stability in physiological conditions. The synthesized composite was characterized with multiple analytical tools. In vitro photothermal conversion efficiency of composite was determined by the time constant method and achieved η = 34.2% with an NIR 808 nm laser. In vitro, cytotoxicity studies conducted on human malignant melanoma (Ht144) and cells validated the photothermal property of the CoF@Ti3C2-PVP composite in the presence of an NIR laser (808 nm, 1.0 W cm-2), with significantly increased cytotoxicity. Calculated IC50 values were 86 µg/mL with laser, compared to 226 µg/mL without the presence of NIR laser. Microscopic results demonstrated increased apoptosis in the presence of NIR laser. Additionally, hemolysis assay confirmed biocompatibility of CoF@Ti3C2-PVP composite for intravenous applications at the IC50 concentration. The research described in this work expands the potential applications of MXene-based nanoplatforms in the biomedical field, particularly in photothermal therapy (PTT). Furthermore, the addition of cobalt ferrite serves as a magnetic nanocomposite, which eventually helps to confine therapeutic photothermal materials inside the cells, provides enhanced photothermal conversion efficiency, and creates externally controlled theranostic nanoplatforms for cancer therapy.

RSSI Fingerprint Height Based Empirical Model Prediction for Smart Indoor Localization.

Smart indoor living advances in the recent decade, such as home indoor localization and positioning, has seen a significant need for low-cost localization systems based on freely available resources such as Received Signal Strength Indicator by the dense deployment of Wireless Local Area Networks (WLAN). The off-the-shelf user equipment (UE's) available at an affordable price across the globe are well equipped with the functionality to scan the radio access network for hearable single strength; in complex indoor environments, multiple signals can be received at a particular reference point with no consideration of the height of the transmitter and possible broadcasting coverage. Most effective fingerprinting algorithm solutions require specialized labor, are time-consuming to carry out site surveys, training of the data, big data analysis, and in most cases, additional hardware requirements relatively increase energy consumption and cost, not forgetting that in case of changes in the indoor environment will highly affect the fingerprint due to interferences. This paper experimentally evaluates and proposes a novel technique for Received Signal Indicator (RSSI) distance prediction, leveraging transceiver height, and Fresnel ranging in a complex indoor environment to better suit the path loss of RSSI at a particular Reference Point (RP) and time, which further contributes greatly to indoor localization. The experimentation in different complex indoor environments of the corridor and office lab during work hours to ascertain real-life and time feasibility shows that the technique's accuracy is greatly improved in the office room and the corridor, achieving lower average prediction errors at low-cost than the comparison prediction algorithms. Compared with the conventional prediction techniques, for example, with Access Point 1 (AP1), the proposed Height Dependence Path-Loss (HEM) model at 0 dBm error attains a confidence probability of 10.98%, higher than the 2.65% for the distance dependence of Path-Loss New Empirical Model (NEM), 4.2% for the Multi-Wall dependence on Path-Loss (MWM) model, and 0% for the Conventional one-slope Path-Loss (OSM) model, respectively. Online localization, amongst the hearable APs, it is seen the proposed HEM fingerprint localization based on the proposed HEM prediction model attains a confidence probability of 31% at 3 m, 55% at 6 m, 78% at 9 m, outperforming the NEM with 26%, 43%, 62%, 62%, the MWM with 23%, 43%, 66%, respectively. The robustness of the HEM fingerprint using diverse predicted test samples by the NEM and MWM models indicates better localization of 13% than comparison fingerprints.

Magnetoelectric core-shell CoFe2O4@BaTiO3 nanorods: their role in drug delivery and effect on multidrug resistance pump activity in vitro.

Nanoparticle mediated targeted drug delivery has become a widespread area of cancer research to address premature drug delivery problems. We report the synthesis of magneto-electric (ME) core-shell cobalt ferrite-barium titanate nanorods (CFO@BTO NRs) to achieve "on demand" drug release in vitro. Physical characterizations confirmed the formation of pure CFO@BTO NRs with appropriate magnetic and ferroelectric response, favorable for an externally controlled drug delivery system. Functionalization of NRs with doxorubicin (DOX) and methotrexate (MTX) achieved up to 98% drug release in 20 minutes, under a 4 mT magnetic field (MF). We observed strong MF and dose dependent cytotoxic response in HepG2 and HT144 cells and 3D spheroid models (p < 0.05). Cytotoxicity was characterized by enhanced oxidative stress, causing p53 mediated cell cycle arrest, DNA damage and cellular apoptosis via downregulation of Bcl-2 expression. In addition, MF and dose dependent inhibition of Multidrug Resistance (MDR) pump activity was also observed (p < 0.05) indicating effectivity in chemo-resistant cancers. Hence, CFO@BTO NRs represent an efficient carrier system for controlled drug delivery in cancer nanotherapeutics, where higher drug uptake is a prerequisite for effective treatment.

Two Cases of Interrupted Inferior Vena Cava with Azygos / Hemiazygos Continuation.

Interrupted inferior vena cava (IVC) is a rare disease, occurring either in isolation or in association with asplenia or polysplenia syndromes. Infrahepatic part of the IVC is absent representing the failure of fusion of the vitelline and subcardinal embryological portions of the IVC. It is replaced by an enlarged azygos or hemiazygos vein continuing into the thorax, either into the superior vena cava or into the brachiocephalic veins. We present two cases of interrupted IVC, one occurring in isolation with hemiazygos continuation and discovered incidentally, and the second one is a child with azygos continuation, associated with polysplenia syndrome. Key Words: Inferior vena cava, Polysplenia, Azygous vein, Hemiazygos vein.

Biocompatibility and cytotoxicity in vitro of surface-functionalized drug-loaded spinel ferrite nanoparticles.

In this study, poly(isobutylene-alt-maleic anhydride) (PMA)-coated spinel ferrite (MFe2O4, where M = Fe, Co, Ni, or Zn) nanoparticles (NPs) were developed as carriers of the anticancer drugs doxorubicin (DOX) and methotrexate (MTX). Physical characterizations confirmed the formation of pure cubic structures (14-22 nm) with magnetic properties. Drug-loaded NPs exhibited tumor specificity with significantly higher (p < 0.005) drug release in an acidic environment (pH 5.5). The nanoparticles were highly colloidal (zeta potential = -35 to -26 mV) in deionized water, phosphate buffer saline (PBS), and sodium borate buffer (SBB). They showed elevated and dose-dependent cytotoxicity in vitro compared to free drug controls. The IC50 values ranged from 0.81 to 3.97 µg/mL for HepG2 and HT144 cells, whereas IC50 values for normal lymphocytes were 10 to 35 times higher (18.35-43.04 µg/mL). Cobalt ferrite (CFO) and zinc ferrite (ZFO) NPs were highly genotoxic (p < 0.05) in cancer cell lines. The nanoparticles caused cytotoxicity via oxidative stress, causing DNA damage and activation of p53-mediated cell cycle arrest (significantly elevated expression, p < 0.005, majorly G1 and G2/M arrest) and apoptosis. Cytotoxicity testing in 3D spheroids showed significant (p < 0.05) reduction in spheroid diameter and up to 74 ± 8.9% of cell death after two weeks. In addition, they also inhibited multidrug resistance (MDR) pump activity in both cell lines suggesting effectivity in MDR cancers. Among the tested MFe2O4 NPs, CFO nanocarriers were the most favorable for targeted cancer therapy due to excellent magnetic, colloidal, cytotoxic, and biocompatible aspects. However, detailed mechanistic, in vivo cytotoxicity, and magnetic-field-assisted studies are required to fully exploit these nanocarriers in therapeutic applications.

Advanced Physical-Layer Technologies for Beyond 5G Wireless Communication Networks.

Fifth-generation (5G) networks will not satisfy the requirements of the latency, bandwidth, and traffic density in 2030 and beyond, and next-generation wireless communication networks with revolutionary enabling technologies will be required. Beyond 5G (B5G)/sixth-generation (6G) networks will achieve superior performance by providing advanced functions such as ultralow latency, ultrahigh reliability, global coverage, massive connectivity, and better intelligence and security levels. Important aspects of B5G/6G networks require the modification and exploitation of promising physical-layer technologies. This Special Issue (SI) presents research efforts to identify and discuss the novel techniques, technical challenges, and promising solution methods of physical-layer technologies with a vision of potential involvement in the B5G/6G era. In particular, this SI presents innovations and concepts, including nonorthogonal multiple access, massive multiple-input multiple-output (MIMO), energy harvesting, hybrid satellite terrestrial relays, Internet of Things-based home automation, millimeter-wave bands, device-to-device communication, and artificial-intelligence or machine-learning techniques. Further, this SI covers the proposed solutions, including MIMO antenna design, modulation detection, interference management, hybrid precoding, and statistical beamforming along with their performance improvements in terms of performance metrics, including bit error rate, outage probability, ergodic sum rate, spectrum efficiency, and energy efficiency.

Multifocus Thermal Strain Imaging Using a Curved Linear Array Transducer for Identification of Lipids in Deep Tissue.

Thermal strain imaging (TSI) is an ultrasound-based imaging technique intended primarily for diseases in which lipid accumulation is the main biomarker. The goal of the research described here was to successfully implement TSI on a single, commercially available curved linear array transducer for heating and imaging of organs at a deeper depth. For an effective temperature rise of the tissue over a large area, which is key to TSI performance, an innovative multifocus beamforming approach was applied. This yielded a heating area from 32 to 96 mm in the axial direction and -7 to +7 mm in the lateral direction. The pressure fields generated from simulation were in agreement with pressure fields measured with the hydrophone. TSI with safe acoustic power identified with high contrast a rubber inclusion and liposuction fat tissue embedded in a gelatin block.

Machine Learning for 5G MIMO Modulation Detection.

Modulation detection techniques have received much attention in recent years due to their importance in the military and commercial applications, such as software-defined radio and cognitive radios. Most of the existing modulation detection algorithms address the detection dedicated to the non-cooperative systems only. In this work, we propose the detection of modulations in the multi-relay cooperative multiple-input multiple-output (MIMO) systems for 5G communications in the presence of spatially correlated channels and imperfect channel state information (CSI). At the destination node, we extract the higher-order statistics of the received signals as the discriminating features. After applying the principal component analysis technique, we carry out a comparative study between the random committee and the AdaBoost machine learning techniques (MLTs) at low signal-to-noise ratio. The efficiency metrics, including the true positive rate, false positive rate, precision, recall, F-Measure, and the time taken to build the model, are used for the performance comparison. The simulation results show that the use of the random committee MLT, compared to the AdaBoost MLT, provides gain in terms of both the modulation detection and complexity.

Selective detection of preferential activity of Lanthanum ion at zinc oxide functionalized nanochannel.

A significant increase of rare earth transition metals concentration in water reservoirs caused by the dumping of household materials and petrol-producing industries is a potential threat to human and aquatic life. Here, we demonstrate a model nanofluidic channel for the Lanthanum (La3+) ions recognition. To this end, a single conical nanochannel is first modified with poly allylamine hydrochloride followed by immobilization of synthesized ZnO nanoparticles on the channel surface through electrostatic adsorption. A significant change in the nanopore electrical readout is noticed when the functionalized nanochannel is exposed to an electrolyte solution having La3+cations. The distinctive response by the nanofluidic system towards La3+ions is assumed to be due to ionic radii, hexagonal crystal structure, and associated basal plane interaction between anchored ZnO nanoparticles and La3+ions. We anticipate that this nanofluidic system can be used as a model to design highly sensitive metal ion detection devices.

Non-invasive Assessment of Liver Fat in ob/ob Mice Using Ultrasound-Induced Thermal Strain Imaging and Its Correlation with Hepatic Triglyceride Content.

Non-alcoholic fatty liver disease is the accumulation of triglycerides in liver. In its malignant form, it can proceed to steatohepatitis, fibrosis, cirrhosis, cancer and ultimately liver impairment, leading to liver transplantation. In a previous study, ultrasound-induced thermal strain imaging (US-TSI) was used to distinguish between excised fatty livers from obese mice and non-fatty livers from control mice. In this study, US-TSI was used to quantify lipid composition of fatty livers in ob/ob mice (n = 28) at various steatosis stages. A strong correlation coefficient was observed (R2 = 0.85) between lipid composition measured with US-TSI and hepatic triglyceride content. Hepatic triglyceride content is used to quantify adipose tissue in liver. The ob/ob mice were divided into three groups based on the degree of steatosis that is used in clinics: none, mild and moderate. A non-parametric Kruskal-Wallis test was conducted to determine if US-TSI can potentially differentiate among the steatosis grades in non-alcoholic fatty liver disease.

Field-controlled magnetoelectric core-shell CoFe2O4@BaTiO3 nanoparticles as effective drug carriers and drug release in vitro.

The targeted drug release at tumor cells while sparing normal cells is a huge challenge. Core-shell magnetoelectric (ME) nanoparticles have addressed this problem using shape-dependent magneto-electric attributes. The colloidally stable, core-shell cobalt ferrite@barium titanate (CFO@BTO) ME nanoparticles (NPs) used for in vitro study were synthesized using sonochemical method. The structural characteristics and core-shell morphology were analyzed by X-ray Diffraction (XRD) and Transmission Electron Microscopy (TEM) respectively. Further magnetic and exchange coupling between two phases of ME nanostructures were studied at room temperature. Colloidal stability was studied in different suspension solutions (Water, SBB, PBS, and DMEM) using dynamic light scattering. Subsequently, the synthesized nanoparticles were functionalized with anticancer drugs including doxorubicin and methotrexate up to 80% via (EDC) chemistry. In vitro cytotoxicity studies carried out on human hepatocellular carcinoma (HepG2) and human malignant melanoma (HT144), cells validated the magneto-electric property of CFO@BTO nano-carriers in the presence of external magnetic field (5 mT), with significantly enhanced cytotoxicity when compared to free drugs and without field replicates. The resulted IC50 values ranging from 5.3-7.3 µg/ml compared to 30.1-43.1 µg/ml in the absence of a magnetic field also confirmed the involved physical attributes of magnetoelectric nanostructures. The fluorescent microscopy results also indicated the increased apoptosis in magnetic field-assisted samples. Finally, hemolysis assay indicated the suitability of CFO@BTO nano-carriers for intravenous applications at IC50 concentration.

Residual Energy Analysis in Cognitive Radios with Energy Harvesting UAV under Reliability and Secrecy Constraints.

The integration of unmanned aerial vehicles (UAVs) with a cognitive radio (CR) technology can improve the spectrum utilization. However, UAV network services demand reliable and secure communications, along with energy efficiency to prolong battery life. We consider an energy harvesting UAV (e.g., surveillance drone) flying periodically in a circular track around a ground-mounted primary transmitter. The UAV, with limited-energy budget, harvests radio frequency energy and uses the primary spectrum band opportunistically. To obtain intuitive insight into the performance of energy-harvesting, and reliable and secure communications, the closed-form expressions of the residual energy, connection outage probability, and secrecy outage probability, respectively, are analytically derived. We construct the optimization problems of residual energy with reliable and secure communications, under scenarios without and with an eavesdropper, respectively, and the analytical solutions are obtained with the approximation of perfect sensing. The numerical simulations verify the analytical results and identify the requirements of length of sensing phase and transmit power for the maximum residual energy in both reliable and secure communication scenarios. Additionally, it is shown that the residual energy in secure communication is lower than that in reliable communication.

BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder characterized by development of high-flow arteriovenous malformations (AVMs) that can lead to stroke or high-output heart failure. HHT2 is caused by heterozygous mutations in ACVRL1, which encodes an endothelial cell bone morphogenetic protein (BMP) receptor, ALK1. BMP9 and BMP10 are established ALK1 ligands. However, the unique and overlapping roles of these ligands remain poorly understood. To define the physiologically relevant ALK1 ligand(s) required for vascular development and maintenance, we generated zebrafish harboring mutations in bmp9 and duplicate BMP10 paralogs, bmp10 and bmp10-like. bmp9 mutants survive to adulthood with no overt phenotype. In contrast, combined loss of bmp10 and bmp10-like results in embryonic lethal cranial AVMs indistinguishable from acvrl1 mutants. However, despite embryonic functional redundancy of bmp10 and bmp10-like, bmp10 encodes the only required Alk1 ligand in the juvenile-to-adult period. bmp10 mutants exhibit blood vessel abnormalities in anterior skin and liver, heart dysmorphology, and premature death, and vascular defects correlate with increased cardiac output. Together, our findings support a unique role for Bmp10 as a non-redundant Alk1 ligand required to maintain the post-embryonic vasculature and establish zebrafish bmp10 mutants as a model for AVM-associated high-output heart failure, which is an increasingly recognized complication of severe liver involvement in HHT2.

Spatial⁻Temporal Sensing and Utilization in Full Duplex Spectrum-Heterogeneous Cognitive Radio Networks for the Internet of Things.

The continuous growth of interconnected devices in the Internet of Things (IoT) presents a challenge in terms of network resources. Cognitive radio (CR) is a promising technology thatcan address the IoT spectral demands by enabling an opportunistic spectrum access (OSA) scheme. The application of full duplex (FD) radios in spectrum sensing enables secondary users (SUs) to perform sensing and transmission simultaneously, and improves the utilization of the spectrum. However, random and dense distributions of FD-enabled SU transmitters (FD-SU TXs) with sensing capabilities in small-cell CR-IoT environments poses new challenges, and creates heterogeneous environments with different spectral opportunities. In this paper, we propose a spatial and temporal spectral-hole sensing framework for FD-SU TXs deployed in CR-IoT spectrum-heterogeneous environment. Incorporating the proposed sensing model, we present the analytical formulation and an evaluation of a utilization of spectrum (UoS) scheme for FD-SU TXs present at different spatialpositions. The numerical results are evaluated under different network and sensing parameters to examine the sensitivities of different parameters. It is demonstrated that self-interference, primary user activity level, and the sensing outcomes in spatial and temporal domains have a significant influence on the utilization performance of spectrum.

Immobilization of quantum dots via conjugated self-assembled monolayers and their application as a light-controlled sensor for the detection of hydrogen peroxide.

A light-addressable gold electrode modified with CdS and FePt or with CdS@FePt nanoparticles via an interfacial dithiol linker layer is presented. XPS measurements reveal that trans-stilbenedithiol provides high-quality self-assembled monolayers compared to benzenedithiol and biphenyldithiol, in case they are formed at elevated temperatures. The CdS nanoparticles in good electrical contact with the electrode allow for current generation under illumination and appropriate polarization. FePt nanoparticles serve as catalytic sites for the reduction of hydrogen peroxide to water. Advantageously, both properties can be combined by the use of hybrid nanoparticles fixed on the electrode by means of the optimized stilbenedithiol layer. This allows a light-controlled analysis of different hydrogen peroxide concentrations.

Light triggered detection of aminophenyl phosphate with a quantum dot based enzyme electrode.

An electrochemical sensor for p-aminophenyl phosphate (pAPP) is reported. It is based on the electrochemical conversion of 4-aminophenol (4AP) at a quantum dot (QD) modified electrode under illumination. Without illumination no electron transfer and thus no oxidation of 4AP can occur. pAPP as substrate is converted by the enzyme alkaline phosphatase (ALP) to generate 4AP as a product. The QDs are coupled via 1,4-benzenedithiol (BDT) linkage to the surface of a gold electrode and thus allow potential-controlled photocurrent generation. The photocurrent is modified by the enzyme reaction providing access to the substrate detection. In order to develop a photobioelectrochemical sensor the enzyme is immobilized on top of the photo-switchable layer of the QDs. Immobilization of ALP is required for the potential possibility of spatially resolved measurements. Geometries with immobilized ALP are compared versus having the ALP in solution. Data indicate that functional immobilization with layer-by-layer assembly is possible. Enzymatic activity of ALP and thus the photocurrent can be described by Michaelis- Menten kinetics. pAPP is detected as proof of principle investigation within the range of 25 µM-1 mM.

Quantum-dot-modified electrode in combination with NADH-dependent dehydrogenase reactions for substrate analysis.

A quantum dot-electrode system was developed which allows the sensitive detection of NADH (nicotinamide adenine dinucleotide). The colloidal semiconductive CdSe/ZnS nanocrystals (quantum dots) are attached to gold by chemisorption via a dithiol compound. The current signal can be triggered by illumination of the quantum-dot-modified electrode surface. Because of photoexcitation, electron-hole pairs are generated in the quantum dots, which can be detected as anodic or cathodic photocurrent. The immobilization of the nanocrystals is verified by amperometric photocurrent and quartz crystal microbalance (QCM) measurements. This study shows that CdSe/ZnS quantum dot-modified electrodes allow concentration dependent NADH detection in the range of 20 microM to 2 mM already at rather low potentials (around 0 V vs. Ag/AgCl, 1 M KCl). Therefore such electrodes can be used in combination with NADH-producing enzyme reactions for the light-triggered analysis of the respective substrates of the biocatalyst. It can be shown that glucose detection is feasible with such an electrode system and photocurrent measurements.

Evaluation of quantum dots applied as switchable layer in a light-controlled electrochemical sensor.

Gold electrodes with switchable conductance are created by coating the gold surface with different colloidal quantum dots. For the quantum dot immobilization, a dithiol compound was used. By polarizing the electrode and applying a light pointer, local photocurrents were generated. The performance of this setup was characterized for a variety of different nanoparticle materials regarding drift and signal-to-noise ratio. We varied the following parameters: quantum dot materials and immobilization protocol. The results indicate that the performance of the sensor strongly depends on how the quantum dots are bound to the gold electrode. The best results were obtained by inclusion of an additional polyelectrolyte film, which had been fabricated using layer-by-layer assembly.