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Neuroblastoma is the most common extracranial solid tumor of childhood. While MYCN and mutant anaplastic lymphoma kinase (ALKF1174L) cooperate in tumorigenesis, how ALK contributes to tumor formation remains unclear. Here, we used a human stem cell-based model of neuroblastoma. Mis-expression of ALKF1174L and MYCN resulted in shorter latency compared to MYCN alone. MYCN tumors resembled adrenergic, while ALK/MYCN tumors resembled mesenchymal, neuroblastoma. Transcriptomic analysis revealed enrichment in focal adhesion signaling, particularly the extracellular matrix genes POSTN and FN1 in ALK/MYCN tumors. Patients with ALK-mutant tumors similarly demonstrated elevated levels of POSTN and FN1. Knockdown of POSTN, but not FN1, delayed adhesion and suppressed proliferation of ALK/MYCN tumors. Furthermore, loss of POSTN reduced ALK-dependent activation of WNT signaling. Reciprocally, inhibition of the WNT pathway reduced expression of POSTN and growth of ALK/MYCN tumor cells. Thus, ALK drives neuroblastoma in part through a feedforward loop between POSTN and WNT signaling.

Abstract The British Standards Institution's Publicly Available Specification 440 (PAS 440) provides a Responsible Innovation Framework (RIF) that companies can use to continuously monitor the societal, environmental and health benefits and risks of their innovations, as well as relevant changes to the supply chain and regulations. PAS 440 is intended to help companies achieve the benefits of innovation in a timely manner and avoid any potential harm or unintended misuse of a new product, process or service. Here, the authors have applied the PAS 440 RIF to a novel single‐cell protein (SCP) animal feed ingredient taking into consideration the perspectives of the value chain partners (VCPs), companies and laboratories involved in an Innovate UK research project. The authors’ findings show how VCPs can use PAS440 to demonstrate that they are innovating responsibly. Using this approach to responsible innovation along the value chain—from manufacturing scale‐up, through regulatory approval, to incorporation in animal feed and from there to food on supermarket shelves—can support the development of innovations that contribute to the economic and environmental sustainability of the animal feed sector. The authors conclude that the PAS 440 Guide can facilitate the progress of a new product throughout a value chain and contribute to coordinating responsible behaviour among companies involved in the value chain.

Capacitor banks (CBs) play a crucial role in energy storage and frequency control within autonomous microgrids. However, the impact of internal capacitor configurations, varying in terms of equivalent series resistance (ESR), capacitance, and rated voltage, on CB degradation, reliability, and peak current remains an understudied aspect. Moreover, the absence of a capacitance degradation coefficient in the standard MIL-HDBK-217 equations for predicting the reliability of electrolytic capacitors poses a significant challenge. To address these issues, this study examines a microgrid composed of diverse renewable energy systems, featuring nine distinct CB arrangements. The design of CBs considers both capacitance and peak output current individually. An evaluation is conducted to compare construction costs, lifetimes, and peak output currents across all layouts. Additionally, a novel formula is introduced to estimate the reliability and lifetime of CBs, while an existing formula for calculating CB peak output current is enhanced. The research explores the impact of ambient temperature and capacitor voltage on the reliability of various capacitor designs, proposing a novel framework for assessing CB reliability based on MIL-HDBK-338B, which accounts for both short-circuit and open-circuit faults. The practicality of these findings is confirmed through a comparison of experimental and simulation results. The inverter operation video, simulation, and all production data including PCB and processor codes are also attached.

Summary: Neuroblastoma is the most common extracranial solid tumor of childhood. While MYCN and mutant anaplastic lymphoma kinase (ALKF1174L) cooperate in tumorigenesis, how ALK contributes to tumor formation remains unclear. Here, we used a human stem cell-based model of neuroblastoma. Mis-expression of ALKF1174L and MYCN resulted in shorter latency compared to MYCN alone. MYCN tumors resembled adrenergic, while ALK/MYCN tumors resembled mesenchymal, neuroblastoma. Transcriptomic analysis revealed enrichment in focal adhesion signaling, particularly the extracellular matrix genes POSTN and FN1 in ALK/MYCN tumors. Patients with ALK-mutant tumors similarly demonstrated elevated levels of POSTN and FN1. Knockdown of POSTN, but not FN1, delayed adhesion and suppressed proliferation of ALK/MYCN tumors. Furthermore, loss of POSTN reduced ALK-dependent activation of WNT signaling. Reciprocally, inhibition of the WNT pathway reduced expression of POSTN and growth of ALK/MYCN tumor cells. Thus, ALK drives neuroblastoma in part through a feedforward loop between POSTN and WNT signaling.

Abstract C–C motif chemokine ligand 2 (CCL2) is a monocyte chemoattractant that promotes metastatic disease and portends a poor prognosis in many cancers. To determine the potential of anti-CCL2 inhibition as a therapy for recurrent metastatic disease in neuroblastoma, a mouse model of minimal residual disease was utilized in which residual disease was treated with anti-CCL2 monoclonal antibody with etoposide. The effect of anti-CCL2 antibody on neuroblastoma cells was determined in vitro with cell proliferation, transwell migration, and 2-dimensional chemotaxis migration assays. The in vivo efficacy of anti-CCL2 antibody and etoposide against neuroblastoma was assessed following resection of primary tumors formed by two cell lines or a patient-derived xenograft (PDX) in immunodeficient NOD-scid gamma mice. In vitro, anti-CCL2 antibody did not affect cell proliferation but significantly inhibited neuroblastoma cell and monocyte migration towards an increasing CCL2 concentration gradient. Treatment of mice with anti-CCL2 antibody combined with etoposide significantly increased survival of mice after resection of primary tumors, compared to untreated mice.

The present paper aims to describe the structure, function, and goals of two of the oldest Mobile Mental Health Units in Greece, namely, the Mobile Mental Health Unit in Fokida (MMHU-F) and the Mobile Mental Health Unit in Thrace (Alexandroupolis, MMHU-T). Information about their historical background, catchment areas, and current staffing, as well as the services provided by each MMHU is discussed. The focus of the paper is slightly biased towards the MMHU-F because it is the only available mental health service in the whole Fokida prefecture. The major goals of the MMHUs are the diagnosis, treatment, and prevention of relapse of severe mental illness within the community. Other important goals of the MMHUs are psychoeducation, psychological support for the family/caregivers, as well as vocational training and support for patients with severe mental illness. Statistical data depicting the demographic characteristics and diagnostic profiles of patients in each MMHU is also provided, and the differences between the two MMHUs are briefly discussed.

We report a rare case of recurrent isolated internal ophthalmoplegia attributed to oculomotor nerve (CN III) compression by the posterior cerebral artery (PCA). A 30-year-old female patient presented with recurrent right-sided headaches, right periorbital pain, and slight anisocoria. Slit-lamp examination revealed normal anterior and posterior segments except for vermiform movements of the right pupil with a temporal hyporeactive flat area. Tonic pupils were ruled out with pilocarpine 0.1% testing. Suspecting an internal ophthalmoplegia, magnetic resonance imaging was ordered which demonstrated the right CN III indented by the PCA, fulfilling the criteria of a neurovascular conflict. The evaluation of unilateral mydriasis from internal ophthalmoplegia should prompt neuroimaging with exclusion of aneurysmal or compressive lesions. CN III palsy can rarely be caused by vascular anatomical variants because of the proximity of the posterior intracranial circulation and CN III. Newer, more precise imaging techniques will better help characterize neurovascular conflicts presenting as cranial nerve palsies.

In the modern technological era of sophisticated applications and high-quality communications, a platform of clever strategy and quickly updated systems is needed. It should be capable of withstanding the fastest emerging problems like signal attenuation and hostile actions intended to harm the whole network. The main contributions of this work are the production of an OFDM system (with low cost) that can sustain high-speed communications and be easily adjusted with new integrated code while exhibiting the feasibility of implementing a transmitter–receiver system in the same DSP and demonstrating the holistic approach with the qualitative integration of such an architecture in a warfare scenario. Specifically, in this research, the point of view is toward three facts. The first is to show a method of quick self-checking the operational status of a digital signal processor (DSP) platform and then the pedagogical issues of how to fast check and implement an updated code inside DSPs through simple schematics. The second point is to present the prototype system that can easily be programmed using a graphical user interface (GUI) and can change its properties (such as the transmitted modulated sinusoids—orthogonal frequency division multiplexing subcarriers). Alongside the presentation, the measurements are presented and discussed. These were acquired with the use of an oscilloscope and spectrum analyzer. The third point is to qualitatively show the application of such a system inside a modern warfare environment and to recommend various potential system responses according to the development of such a platform of reconfigurable implemented OFDM systems. The implementation was performed for two types of systems: (1) transmitter and (2) transmitter–receiver system. Notably, the system acts quickly with a delay of about 1 msec in the case of transmitting and receiving in the same DSP, suggesting excellent future results under real conditions.

We analyzed a large number (77) of low-to-medium-magnitude earthquakes (M3.5–M6.5) that occurred within a period of three years (2020–2022) in the Southern half of Greece in relation to the ELF activity in that region and time period. In most cases, characteristic ELF signals appear up to 20 days before the earthquakes. This observation may add an important new element to the Lithospheric–Atmospheric–Ionospheric scenario, thus contributing to a better prediction of incoming earthquakes. We discuss the role of ELF observations in reliable seismic forecasting. We conclude that the magnitude of an earthquake larger than M4.0 and the distance of the epicenter shorter than 300 km from the recording site is needed for typical pre-seismic signals to be observed. Finally, we remark that a reliable prediction of earthquakes could result from an integrated project of multi-instrumental observations, where all the known variety of precursors would be included, and the whole data set would be analyzed by advanced machine learning methods.

Assessing and controlling cyber risk is the cornerstone of information security management, but also a formidable challenge for organisations due to the uncertainties associated with attacks, the resulting risk exposure, and the availability of scarce resources for investment in mitigation measures. In this paper, we propose a cybersecurity decision-support framework, called CENSOR, for optimal cyber security investment. CENSOR accounts for the serial nature of a cyber attack, the uncertainty in the time required to exploit a vulnerability, and the optimisation of mitigation measures in the presence of a limited budget. First, we evaluate the cost that an organisation incurs due to a cyber security breach that progresses in stages and derive an analytical expression for the distribution of the present value of the cost. Second, we adopt a Set Covering and a Knapsack formulation to derive and compare optimal strategies for investment in mitigation measures. Third, we validate CENSOR via a case study of a small business (SB) based on: (i) the 2020 Common Weakness Enumeration (CWE) top 25 most dangerous software weaknesses; and (ii) the Center for Internet Security (CIS) Controls. Specifically, we demonstrate how the Knapsack formulation provides solutions that are both more affordable and entail lower risk compared to those of the Set Covering formulation. Interestingly, our results confirm that investing more in cybersecurity does not necessarily lead to an analogous cyber risk reduction, which indicates that the latter decelerates beyond a certain point of security investment intensity.

Purpose: We investigated intraoperative OCT (iOCT)—guided epiretinal membrane (ERM) and internal limiting membrane (ILM) removal using a novel forceps with a laser-ablated tip surface; it was designed to help prevent indentation force, shear stress, or tractional trauma when grasping very fine membranes. Patients and Methods: This retrospective study included patients who underwent 23- and 25-gauge pars plana vitrectomy (PPV) for vitreoretinal interface disorders. ERM and ILM peeling was performed under guidance with microscope-integrated iOCT using novel ILM forceps with laser-ablated tip surfaces. These forceps were engineered to enhance friction when grasping tissue. Evaluation of ERM/ILM manipulation included postoperative slow-motion video analysis of the number of grasping attempts, initial ILM mobilization, and observed damage to retinal tissue. Results: ERM/ILM removal was successfully performed in all patients, with an average of four grasp actions to initial membrane mobilization (91%). Additional use of a diamond-dusted membrane scraper was used in two cases (9%). Mean best-recorded visual acuity (BRVA) logMAR improved from 0.5 ± 0.34 to 0.33 ± 0.36 (p = 0.05) and mean central retinal thickness (CRT) improved from 462 ± 146 µm to 359 ± 78 µm (p = 0.002). Postoperative iOCT video analysis demonstrated hyper-reflectivity of the inner retinal layers associated with retinal hemorrhage in five eyes (22%), but no grasping-related retinal breaks. Conclusions: The texturized surface on the tips of the ILM forceps were found to be helpful for mobilizing ILM edges from the retinal surface. iOCT-guided ERM surgery also allowed for improved intraoperative tissue visualization. We believe that these two technologies helped reduce both unnecessary surgical maneuvers and retinal damage.

Abstract Since the turn of the century, metamaterials have gained a large amount of attention due to their potential for possessing highly nontrivial and exotic properties—such as cloaking or perfect lensing. There has been a great push to create reliable mathematical models that accurately describe the required material composition. Here, we consider a quantum graph approach to metamaterial design. An infinite square periodic quantum graph, constructed from vertices and edges, acts as a paradigm for a 2D metamaterial. Wave transport occurs along the edges with vertices acting as scatterers modelling sub-wavelength resonant elements. These resonant elements are constructed with the help of finite quantum graphs attached to each vertex of the lattice with customisable properties controlled by a unitary scattering matrix. The metamaterial properties are understood and engineered by manipulating the band diagram of the periodic structure. The engineered properties are then demonstrated in terms of the reflection and transmission behaviour of Gaussian beam solutions at an interface between two different metamaterials. We extend this treatment to N layered metamaterials using the Transfer Matrix Method. We demonstrate both positive and negative refraction and beam steering. Our proposed quantum graph modelling technique is very flexible and can be easily adjusted making it an ideal design tool for creating metamaterials with exotic band diagram properties or testing promising multi-layer set ups and wave steering effects.

Abstract Background Pacemaker implantation involves intraoperative testing of ventricular sensing using a device called a pacing system analyzer (PSA). The value obtained is expected to correspond to those taken by the pacemaker after its implantation. This study determined the latency period for sensing intracardiac electrogram (EGM) by the right ventricular (RV) lead. Methods Patients without significant heart disease and underlying intrinsic atrioventricular (AV) conduction underwent Medtronic or Abbott dual‐chamber pacemaker implantation with the RV lead positioned on the mid‐septum. Real‐time sensing data were obtained through PSA and after pacemaker implantation to evaluate latency as the time interval Q‐VS between the onset of QRS on surface electrocardiogram and the sensed EGM by the RV lead. Results Of 157 patients, 105 had narrow QRS (

Key Clinical Message CRAO is an ophthalmic and medical emergency. This case is a reminder that diagnosis and management of CRAO begins with ophthalmologists but immediately thereafter care involves emergency cardiovascular and neurological similar to cerebral stroke.

Abstract Background Osteoarthritis (ΟΑ) is characterized by cartilage breakdown and subchondral sclerosis. Micro‐fractures of the calcified tissues have been, also, detected, but their exact role has not been elucidated yet. This study was to examine the frequency of cracks during OA progression and to correlate them with the underlying cellular modifications and matrix metalloproteinase‐2 (MMP‐2) expression using histological/immunohistological methods. Methods Overall, 20 patients and 3 controls (9 specimens per patient), aged 60–89 years, diagnosed with hip/knee OA were included. The development of cracks was examined in 138 sections, whereas the expression of MMP‐2 was examined in 69 additional sections. Results Based on Mankin score, three groups of OA severity were analyzed: Group I (mild) was constituted of sections with score 1–5 while Groups II (moderate) and III (severe) with score 6–7 and greater or equal to 8, respectively. Demographic characteristics did not reveal any association between the number of microdefects and age or body mass index (BMI). Cartilage micro‐cracks were increased during moderate and severe OA, while bone cracks were increased during mild and severe OA. In knee OA, cartilage cracks were not correlated with Mankin score, whereas in hip OA they appeared association with severity score. Bone cracks were positively correlated with matrix apoptotic osteocytes and osteoblastic cells, but not with osteoclasts. MMP‐2 immunostaining was increasing by OA severity in the osteochondral unit. Similarly, MMP‐2 was expressed on the microcracks’ wall mainly in Group III. Conclusion Our data displayed that bone cracks during primary OA stages, represent an early adaptative mechanism aiming to maintain cartilage integrity. Accumulation of bone defects and concomitant increase of apoptotic osteocytes activated an abnormal remodeling due to osteoblastic activity, in which MMP‐2 played a pivotal role, leading to subchondral sclerosis promoting further osteochondral deformities.

This paper presents a compact multifrequency reconfigurable patch antenna in terms of design and fabrication for operating in the S and C bands of the RF spectrum, which are overwhelmed by wireless applications. Reconfiguration is achieved by using a single PIN diode on the ground plane. By varying the voltage applied to the diode, three modes can emerge, exhibiting main resonant frequencies at 2.07, 4.63, and 6.22 GHz. Resonance switching requires a voltage of less than 0.9 V. The antenna fabricated on an FR-4 substrate, with a volume of 70 × 60 × 1.5 mm3, has a radiating patch element of a rectangular ring shape. The proposed low-cost antenna is easily implemented in a typical university lab-based environment. The total bandwidth for the three modes is close to 1 GHz, while the voltage standing wave ratio (VSWR) of the fabricated version of the antenna does not exceed 1.02, and the return loss is well below −40 dB for the three primary resonant frequencies.

Abstract We present a numerical method for computing reflection and transmission coefficients at joints connecting composite laminated plates. The method is based on modelling joints with finite elements with boundary conditions given by the solutions of the wave finite element method for the plates in the infinite half-spaces connected to the joint. There are no restrictions on the number of plates, inter-plate angles, and material parameters of individual layers forming the composite. An L-shaped laminated plate junction is discussed in more detail. Comparisons of numerically predicted scattering coefficients with semi-analytical solutions for the selected structures are presented. The results obtained are essential for statistical energy analysis and dynamical energy analysis based calculations of the wave energy distribution in full built-up structure.