bluuebunny/crossref_metadata_2025 huggingface dataset:
Cryo-Focused Ion Beam-Induced Deposition of Tungsten–Carbon Nanostructures Using a Thermoelectric Plate
Authors: Orús Pablo , Sigloch Fabian , Sangiao Soraya , De Teresa José María
Published: October 2021

Focused Ion Beam-Induced Deposition (FIBID) is a single-step nanopatterning technique that applies a focused beam of ions to induce the decomposition of a gaseous precursor. The processing rate of FIBID increases by two orders of magnitude when the process is performed at cryogenic temperatures (Cryo-FIBID): the precursor forms a condensed layer on the surface of the cooled substrate, greatly enhancing the amount of material available for decomposition. Cryo-FIBID has been achieved so far by making use of liquid nitrogen-based cooling circuits, which require the passage of a flowing gas as a cooling agent. Here, the Cryo-FIBID of the W(CO)6 precursor is performed using a coolant-free thermoelectric plate utilizing the Peltier effect. Performed at −60 ∘C, the procedure yields a W–C-based material with structural and electrical properties comparable to those of its counterpart grown in coolant-based Cryo-FIBID. The use of the thermoelectric plate significantly reduces the vibrations and sample drift induced by the flow of passing coolant gas and allows for the fabrication of similar nanostructures. In summary, the reported process represents a further step towards the practical implementation of the Cryo-FIBID technique, and it will facilitate its use by a broader research community.
Design of a Remote Monitoring System Based on Optical Sensors to Prevent Medical Accidents during Fluid Treatment
Authors: Lee Jae-Kyeong , Yoon Ki-Cheol , Kim Kwang Gi
Published: October 2021

It is essential to measure and monitor the intravenous (IV) infusion rate of inpatients. Medical staff monitor the IV infusion rate continually to ensure that a constant value is maintained. Developing an IV infusion monitoring system can help alleviate the workload of medical staff. Therefore, this paper proposes a method based on optical sensors, in conjunction with the Internet of Things, to overcome the challenges of IV therapy. To increase the sensitivity of the system, both optical sensors and load cells are used to compensate for their disadvantages. Our system yielded accuracies of 87.9% and 89.9% under horizontal and vertical motion conditions, respectively. The proposed system can send notifications to nursing stations regarding the residual IV fluid, current infusion rate, and expected end time, which can be monitored remotely by medical staff. Furthermore, this system can help prevent possible medical accidents during fluid treatment.
Cost-Aware Design and Fabrication of New Support Structures in Laser Powder Bed Fusion: Microstructure and Metallurgical Properties
Authors: Ravichander Bharath Bhushan , Thakare Sourabh , Ganesh-Ram Aditya , Farhang Behzad , Hanumantha Manjunath , Yang Yiran , Shayesteh Moghaddam Narges , Amerinatanzi Amirhesam
Published: October 2021

This study investigates the effect of support structures on the properties of Inconel 718 (i.e., IN718) parts produced by the laser powder bed fusion (LPBF) additive manufacturing process. Specifically, the effects of support structure shape (i.e., pin-type, angled-type, cone-type) and geometry (i.e., support wall thickness, and gap) on their composition, hardness, microstructure, and material/time consumption are investigated and compared to the conventionally fabricated Inconel 718. From the microstructural analysis, the deepest melt pools appeared to be formed in the sample fabricated on top of the pin-type support structure having a relatively low wall thickness. The XRD results conveyed that a proper selection of geometrical variables for designing support structure results in elevated levels of the strengthening phases of IN718. The sample fabricated on top of the pin-type support structure showed the highest Vickers hardness value of 460.5 HV, which was even higher than what was reported for the heat-treated wrought Inconel 718 (355–385 HV). Moreover, for the thinner support wall thickness, an improvement in the hardness value of the fabricated samples was observed. This study urges a reconsideration of the common approach of selecting supports for additive manufacturing of samples when a higher quality of the as-fabricated parts is desired.
Layout Design and Die Casting Using CAE Simulation for Household Appliances
Authors: Kwon Hong-Kyu
Published: October 2021

Due to the development and industrialization of science and technology, aluminum alloys have been developed in various fields. Recently, the government has been pursuing ways to decrease the weight and increase the recyclability of various components in order to conserve resources, energy, and the environmental. In keeping with this trend, cast iron products are being replaced by aluminum products in the foundry industry by using high-pressure die casting (HPDC). Casting layout design, relies on the experience and knowledge of mold designers in the casting industry, which proves insufficient to respond to the rapidly changing needs of the era and to increasing production costs. Designing and producing casting layouts using CAD/CAM/CAE technology has become a critical issue. Computer-Aided Engineering (CAE) technology is rapidly increasing with the development of computer software and hardware. CAE technology not only predicts defects in mass production but also performs filling or solidification analysis during the mold design stage before production, enabling optimal mold design methods. New technologies that combine the emerging casting processes of filling and solidification analysis using computer simulation with existing technology and practical experience in the field are rapidly increasing in the foundry industry. Based on empirical knowledge, the layout and design of casting products has traditionally progressed through trial and error. The solutions achieved through scientific calculation and analysis using CAE technology can save a great deal of money and time in the building of die-casting molds and in their design and fabrication. In this study, numerical analysis of household appliances (cooking grills) quickly and accurately predicts problems arising from the filling and solidification of the melted metal in the casting process, thereby ensuring the quality of the final cast product. These results can be used to quickly establish a sound casting layout with reduced production costs.
Prescribed Performance Non-Singular Fast Terminal Sliding Mode Control Based on Extended State Observer for a Deep-Sea Electric Oil-Filled Joint Actuator
Authors: Liao Lihui , Li Baoren , Wang Yuanyuan , Tang Tengfei , Zhang Dijia , Yang Gang
Published: October 2021

High dynamic performance of a deep-sea electric oil-filled joint actuator is an important premise to guarantee the working performance of an electric underwater manipulator. However, the unfavorable factors (i.e., extremely high water pressure, near freezing temperature) brought by the deep-sea working environment seriously affect the characteristic and dynamic performance of the electric oil-filled joint actuator, which mainly includes oil stirring viscos loss, output shaft dynamic seal loss, and core loss. In this paper, a novel observer-based robust control method named prescribed performance non-singular fast-terminal sliding-mode control (PP-NFTSMC-ESO) was synthesized for improving the dynamic performance of a deep-sea electric oil-filled joint actuator. The extended state observer (ESO) was employed to observe the unmeasured joint velocity signal and estimate the lumped uncertainties, while the prescribed performance function (PPF) was applied to constrain the instantaneous and steady-state performance of the trajectory-tracking error. The robust NFTSMC control method was then established by integrating the function of ESO and PPF through backstepping methodology. The stability of the proposed PP-NFTSMC-ESO strategy was analyzed and proved by the Lyapunov’s stability theory. It was proven that under the proposed controller, all the closed-loop signals are bounded and the trajectory tracking errors will converge to a small neighborhood of the origin with appropriate design parameters. The effectiveness of the proposed control scheme was illustrated by comparative simulation studies.
AWEU-Net: An Attention-Aware Weight Excitation U-Net for Lung Nodule Segmentation
Authors: Banu Syeda Furruka , Sarker Md. Mostafa Kamal , Abdel-Nasser Mohamed , Puig Domenec , Raswan Hatem A.
Published: October 2021

Lung cancer is a deadly cancer that causes millions of deaths every year around the world. Accurate lung nodule detection and segmentation in computed tomography (CT) images is a vital step for diagnosing lung cancer early. Most existing systems face several challenges, such as the heterogeneity in CT images and variation in nodule size, shape, and location, which limit their accuracy. In an attempt to handle these challenges, this article proposes a fully automated deep learning framework that consists of lung nodule detection and segmentation models. Our proposed system comprises two cascaded stages: (1) nodule detection based on fine-tuned Faster R-CNN to localize the nodules in CT images, and (2) nodule segmentation based on the U-Net architecture with two effective blocks, namely position attention-aware weight excitation (PAWE) and channel attention-aware weight excitation (CAWE), to enhance the ability to discriminate between nodule and non-nodule feature representations. The experimental results demonstrate that the proposed system yields a Dice score of 89.79% and 90.35%, and an intersection over union (IoU) of 82.34% and 83.21% on the publicly available LUNA16 and LIDC-IDRI datasets, respectively.
Analysis of Inductive Displacement Sensors with Large Range and Nanoscale Resolution
Authors: He Qiang , Fan Shixun , Chen Ning , Tan Ruoyu , Chen Fan , Fan Dapeng
Published: October 2021

With the advantages of high resolution, structural simplicity, reliability, compact size, and high sensitivity, inductive sensors have been widely used in nanopositioning systems. However, the measuring range of traditional inductive sensors are usually limited to 0.2 mm. A novel analysis and design methodology of the miniaturized inductive sensor with large measuring range and nanoscale resolution is proposed. Firstly, an accurate leakage inductance model is established. Secondly, a design rule of armature size is proposed by considering the fringing effect. Then, the error terms introduced by the measurement circuit of differential inductive sensors are analyzed and the corresponding error suppression methods are illustrated. Moreover, A design rule of selecting the optimal excitation frequency is proposed to meet the requirements of high Q value and high bandwidth, and to minimize the impact of core loss resistance on the performance of the sensor. Validated by the experiments, the proposed analysis and design method can effectively guide the design of the miniaturized inductive sensor with nanoscale resolution in the measuring range of ±0.5 mm. The overall size of the fabricated sensor prototypes is less than 6 mm × 6 mm × 3 mm. Combined with large range, high resolution and ideal miniaturization, this inductive sensor can be well suitable for compact and large stroke nanopositioning systems.
Tensile Capacity of Adhesive Anchors in Damaged Masonry
Authors: Cattaneo Sara , Vafa Navid
Published: October 2021

In Europe, the qualification of injection anchors in masonry under static and quasi-static actions is based on an assessment of tests performed in undamaged masonry. Nevertheless, in seismic prone countries like Italy the influences deriving from earthquake actions cannot be disregarded. Masonry elements are very sensitive to cyclic/seismic action and research on the behavior of anchors in damaged masonry is rather limited. The paper presents the results of an experimental campaign aimed at evaluating the residual tensile strength of adhesive anchors installed into undamaged walls that were subsequently subjected to cyclic in-plane loading to simulate seismic actions before. Consequently, the anchors experienced different stresses depending on their location within the walls. Overall, 29 tests were performed with anchors placed both, in undamaged and damaged areas. The results showed that there is a correlation between residual tensile strength and masonry initial conditions, and therefore the installation of anchors in masonry elements should be carefully planned avoiding areas that could be heavily damaged during seismic events or considering redundant connections in critical areas. In particular, it seems that the width of the crack (created by cyclic actions) that passes nearby/into the anchor borehole is the main parameter that affects the ultimate resistance of the anchors.
Dust Criteria Derived from Long-Term Filter and Online Observations at Gosan in South Korea
Authors: Shang Xiaona , Lee Meehye , Lim Saehee , Gustafsson Örjan , Lee Gangwoong , Chang Limseok
Published: October 2021

Dust and pollution are frequently mixed together in East Asia, causing large uncertainties in assessing climate change and environmental influence and in relevant policymaking. To discern the dust effect on particle mass, we carried out long-term measurements of the mass and key chemical compositions of PM10, PM2.5, and PM1 from August 2007 to February 2012 and collected hourly data of PM10 and PM2.5 concentrations from January 2012 to October 2020 at Gosan, South Korea. The principal component analysis of measured species reveals two dominant factors, pollution and dust, accounting for 46% and 16% of the total variance, respectively. The mode distribution of PM10, PM2.5, and PM1 mass in addition to the dust events helps to provide a robust criterion of the dust impact. Dust can be identified by the mean + standard deviation (σ) of PM10, while the threshold is down to the mean concentration when dust particles experience precipitation. High PM2.5 concentration also presents dust impact; however, the criterion decreases from mean + σ in 2007–2012 to mean in 2012–2020. It indicates that dust is no longer a high-concentration event of PM2.5, but its influence gradually appears in low-concentration particles. Therefore, the dust criterion obtained from long-term PM10 concentration data is robust; however, the standard is based on PM2.5 changes over time and still needs to be determined by follow-up long-term observations.
Stress-Induced Apparent Resistivity Variations at the Kalpin Observatory and the Correlation with the 2020 Mw 6.0 Jiashi Earthquake
Authors: Wang Yali , Yu Chen , Yu Huaizhong , Yue Chong , Jia Donghui , Ma Yuchuan , Zhang Zhiguang , Yang Wen
Published: October 2021

Stress may induce apparent resistivity changes. Clarifying the deformation process of the source media is critical for determining the correlations between resistivity variations and earthquake occurrence. In this study, the stress state of a medium was analyzed by integrating GPS measurements, the spatiotemporal evolution of the load/unload response ratio (LURR), geochemical monitoring, and synchronous apparent resistivity changes preceding the 2020 Mw 6.0 Jiashi earthquake. The medium hosting the Kalpin Observatory underwent elastic deformation before 2019, and the synchronous decreases in the E–W and N–S apparent resistivities from 2015 can be attributed to N–S-dominated compressive stress. The microdamage stage occurred in 2019, with subsequent E–W apparent resistivity variation amplitudes that were ~0.4 Ωm higher than those in previous years. This difference is a result of microdamage to the medium owing to tensile stress during the seismogenic process. The spatiotemporal evolution of the LURR and gas seepage monitoring data also indicate that the medium was damaged prior to the earthquake. Variations in the apparent resistivity measured at the Kalpin Observatory indicate that the medium underwent elastic deformation, followed by microdamage, until stress triggered the earthquake.
Significance of Absorbing Fraction of Coating on Absorption Enhancement of Partially Coated Black Carbon Aerosols
Authors: Zhang Xiaolin , Wang Yuanzhi , Zhou Yu , Wang Junyao , Mao Mao
Published: October 2021

Black carbon (BC), particularly internally mixed and aged BC, exerts a significant influence on the environment and climate. Black carbon coated by non-absorbing materials shows an enhancement of BC absorption, whereas absorptive coatings on BC can reduce the BC absorption enhancement. In this paper we use the multiple-sphere T-matrix method to accurately model the influence of the absorbing volume fraction of absorbing coatings on the reduction of the absorption enhancement of partially coated BC. The reduction of the absorption enhancement due to the absorbing coating exhibited a strong sensitivity to the absorbing volume fraction of the coating, and no reduction of BC absorption enhancement was seen for BC particles with non-absorbing coatings. We found that coatings with higher absorbing volume fraction, greater coated volume fraction of BC, higher shell/core ratio, and larger coated BC particle size caused stronger reductions of the BC absorption enhancement, whereas the impact of the BC’s fractal dimension was negligible. Moreover, the sensitivity of the reduction of absorption enhancement resulting from the ratio of the absorbing coating shell to the BC core increased for coatings with higher absorbing volume fractions, higher coated volume fractions of BC, or larger particle sizes, although this effect was weaker than the sensitivities to size distribution, absorbing volume fraction of coating, and coated volume fraction of BC. Reductions in the absorption enhancements resulting from the absorbing coating for partially coated BC with various size distributions typically varied in the range of 0.0–0.24 for thin coatings with shell/core ratio of 1.5 and between 0.0 and 0.43 for thick coatings with shell/core ratio of 2.7. In addition, we propose an empirical formula relating the reduction of BC absorption enhancement to the absorbing volume fraction of the coating, which could inform a quantitative understanding and further applications. Our study indicates the significance of the absorbing volume fraction of coatings on the absorption properties of BC.
Spatio-Temporal Variations in the Temperature and Precipitation Extremes in Yangtze River Basin, China during 1961–2020
Authors: Yuan Zhe , Yin Jun , Wei Mengru , Yuan Yong
Published: October 2021

Based on daily maximum temperature (Tmax), minimum temperature (Tmin), and precipitation of the Yangtze River Basin (YRB) from 1961 to 2020, we employed the trend analysis method and correlation analysis method to analyze spatiotemporal variations in 10 extreme indices and their associations with atmospheric and oceanic circulations. Results indicated that maximum Tmax (TXx), maximum Tmin (TNx), and minimum Tmin (TNn) all increased significantly, at rates of 0.19 °C, 0.19 °C, and 0.37 °C per decade, respectively, whereas minimum Tmax (TXn) did not show any significant trend. The diurnal temperature range (DTR) decreased by 0.09 °C per decade as minimum temperatures increased faster than maximum temperatures. TNx and TNn increased significantly in the majority of the YRB, but TXn showed no significant increases. TXn increased significantly in the upper reaches of the Yangtze River. The DTR increased significantly in the Jinsha River Basin and the lower reaches of the Yangtze River. Rx1day (maximum 1-day precipitation), SDII (Simple daily intensity index) and R99p (extremely wet-day precipitation) increased significantly, at rates of 1.12 mm, 0.09 mm, and 5.87 mm per decade, respectively, but the trends of Rx5day (maximum 5-day precipitation) and PRCPTOT (total wet-day precipitation) were not significant. However, the trends of precipitation extreme indices were not statistically significant in most of the YRB. In the future, maximum temperature and minimum temperature might increase while DTR might decrease. But, the trends of precipitation extremes in the future were ambiguous. Nearly all the extreme indices were related to the variability of Atlantic multidecadal oscillation (AMO) in the YRB. In addition, the correlations between extreme temperature indices and AMO are higher than that of extreme precipitation indices.
Smart Competence Management Using Business Analytics with Fuzzy Predicates
Authors: Luna Roberto , Rodríguez Gregorio , Ramos Liliana , Andrade Rafael , Figueredo Sandra , de-León-Gómez Victor
Published: October 2021

Organizations consider human capital as one of their most important assets. Experts in the field have focused on the research and development of human talent management skills. At present, companies are giving high importance to the management of this intangible resource. Management by competencies and skills is basic in the selection and development of the most valuable asset the organization has: its human capital. A conceptual framework of the intelligent management of human capital and some more advanced knowledge discovery techniques are presented in this paper. A methodology for smart detection of core competencies based on fuzzy logic predicates and business analytics is proposed. The proposed methodology allows: (1) the evaluation of the importance of competencies, (2) the identification of competencies achievement level of each employee, (3) the identification of competencies with difficulties, (4) the identification of competencies that have influence on others, and (5) a hierarchization of the competencies to select the most appropriated for the employee recruitment plan. Furthermore, an analysis is proposed using knowledge discovery, which allows one to identify which competences have influence on a specific one. All of the above is useful to build an ideal profile for a position. A case study was carried out in order to show the implementation and interpretation of our proposal.
Functional Interplay between P5 and PDI/ERp72 to Drive Protein Folding
Authors: Matsusaki Motonori , Okada Rina , Tanikawa Yuya , Kanemura Shingo , Ito Dai , Lin Yuxi , Watabe Mai , Yamaguchi Hiroshi , Saio Tomohide , Lee Young-Ho , Inaba Kenji , Okumura Masaki
Published: October 2021

P5 is one of protein disulfide isomerase family proteins (PDIs) involved in endoplasmic reticulum (ER) protein quality control that assists oxidative folding, inhibits protein aggregation, and regulates the unfolded protein response. P5 reportedly interacts with other PDIs via intermolecular disulfide bonds in cultured cells, but it remains unclear whether complex formation between P5 and other PDIs is involved in regulating enzymatic and chaperone functions. Herein, we established the far-western blot method to detect non-covalent interactions between P5 and other PDIs and found that PDI and ERp72 are partner proteins of P5. The enzymatic activity of P5-mediated oxidative folding is up-regulated by PDI, while the chaperone activity of P5 is stimulated by ERp72. These findings shed light on the mechanism by which the complex formations among PDIs drive to synergistically accelerate protein folding and prevents aggregation. This knowledge has implications for understanding misfolding-related pathology.
The Type III Effectome of the Symbiotic Bradyrhizobium vignae Strain ORS3257
Authors: Busset Nicolas , Gully Djamel , Teulet Albin , Fardoux Joël , Camuel Alicia , Cornu David , Severac Dany , Giraud Eric , Mergaert Peter
Published: October 2021

Many Bradyrhizobium strains are able to establish a Nod factor-independent symbiosis with the leguminous plant Aeschynomene indica by the use of a type III secretion system (T3SS). Recently, an important advance in the understanding of the molecular factors supporting this symbiosis has been achieved by the in silico identification and functional characterization of 27 putative T3SS effectors (T3Es) of Bradyrhizobium vignae ORS3257. In the present study, we experimentally extend this catalog of T3Es by using a multi-omics approach. Transcriptome analysis under non-inducing and inducing conditions in the ORS3257 wild-type strain and the ttsI mutant revealed that the expression of 18 out of the 27 putative effectors previously identified, is under the control of TtsI, the global transcriptional regulator of T3SS and T3Es. Quantitative shotgun proteome analysis of culture supernatant in the wild type and T3SS mutant strains confirmed that 15 of the previously determined candidate T3Es are secreted by the T3SS. Moreover, the combined approaches identified nine additional putative T3Es and one of them was experimentally validated as a novel effector. Our study underscores the power of combined proteome and transcriptome analyses to complement in silico predictions and produce nearly complete effector catalogs. The establishment of the ORS3257 effectome will form the basis for a full appraisal of the symbiotic properties of this strain during its interaction with various host legumes via different processes.
Integrative Analysis of Multi-Omics and Genetic Approaches—A New Level in Atherosclerotic Cardiovascular Risk Prediction
Authors: Usova EIena I. , Alieva Asiiat S. , Yakovlev Alexey N. , Alieva Madina S. , Prokhorikhin Alexey A. , Konradi Alexandra O. , Shlyakhto Evgeny V. , Magni Paolo , Catapano Alberico L. , Baragetti Andrea
Published: October 2021

Genetics and environmental and lifestyle factors deeply affect cardiovascular diseases, with atherosclerosis as the etiopathological factor (ACVD) and their early recognition can significantly contribute to an efficient prevention and treatment of the disease. Due to the vast number of these factors, only the novel “omic” approaches are surmised. In addition to genomics, which extended the effective therapeutic potential for complex and rarer diseases, the use of “omics” presents a step-forward that can be harnessed for more accurate ACVD prediction and risk assessment in larger populations. The analysis of these data by artificial intelligence (AI)/machine learning (ML) strategies makes is possible to decipher the large amount of data that derives from such techniques, in order to provide an unbiased assessment of pathophysiological correlations and to develop a better understanding of the molecular background of ACVD. The predictive models implementing data from these “omics”, are based on consolidated AI best practices for classical ML and deep learning paradigms that employ methods (e.g., Integrative Network Fusion method, using an AI/ML supervised strategy and cross-validation) to validate the reproducibility of the results. Here, we highlight the proposed integrated approach for the prediction and diagnosis of ACVD with the presentation of the key elements of a joint scientific project of the University of Milan and the Almazov National Medical Research Centre.
Microglia and Astrocytes in Alzheimer’s Disease in the Context of the Aberrant Copper Homeostasis Hypothesis
Authors: Pal Amit , Rani Isha , Pawar Anil , Picozza Mario , Rongioletti Mauro , Squitti Rosanna
Published: October 2021

Evidence of copper’s (Cu) involvement in Alzheimer’s disease (AD) is available, but information on Cu involvement in microglia and astrocytes during the course of AD has yet to be structurally discussed. This review deals with this matter in an attempt to provide an updated discussion on the role of reactive glia challenged by excess labile Cu in a wide picture that embraces all the major processes identified as playing a role in toxicity induced by an imbalance of Cu in AD.
Pemphigus—The Crux of Clinics, Research, and Treatment during the COVID-19 Pandemic
Authors: Marinović Branka , Miše Joško , Jukić Ines Lakoš , Bukvić Mokos Zrinka
Published: October 2021

Pemphigus is a rare autoimmune disease characterised by the production of pathogenic autoantibodies in response to different desmosome proteins. The pathophysiological process leads to the development of blisters and erosions on mucosal and/or skin surfaces. The classical clinical variants of pemphigus are pemphigus vulgaris and pemphigus foliaceus. A diagnostic delay is very common in pemphigus, especially among patients with mucosal involvement. However, in recent years we have witnessed considerably fewer patients with extensive mucocutaneous manifestations, since patients with oral lesions are referred to dermatologists to start the treatment much sooner than they had been previously. Among non-classical variants of pemphigus, unusual cases with discrepancies between autoantibody profiles and clinics challenge the “desmoglein compensation theory”. The identification of several other autoantigens that perform a role in the pathogenesis of different variants of pemphigus will progress immunodermatology towards an approach that will determine personalized pemphigus subtypes for each patient. Comorbidities among patients are primarily associated with the prolonged use of corticosteroids and other immunosuppressive agents. The SARS-CoV-2 pandemic raised concerns regarding the immunosuppressive effects of treatment and the risk of a more complicated COVID-19 infection, as well as on the ability to develop an adequate vaccine response.
Predicting Serum Levels of Lithium-Treated Patients: A Supervised Machine Learning Approach
Authors: Hsu Chih-Wei , Tsai Shang-Ying , Wang Liang-Jen , Liang Chih-Sung , Carvalho Andre F. , Solmi Marco , Vieta Eduard , Lin Pao-Yen , Hu Chien-An , Kao Hung-Yu
Published: October 2021

Routine monitoring of lithium levels is common clinical practice. This is because the lithium prediction strategies available developed by previous studies are still limited due to insufficient prediction performance. Thus, we used machine learning approaches to predict lithium concentration in a large real-world dataset. Real-world data from multicenter electronic medical records were used in different machine learning algorithms to predict: (1) whether the serum level was 0.6–1.2 mmol/L or 0.0–0.6 mmol/L (binary prediction), and (2) its concentration value (continuous prediction). We developed models from 1505 samples through 5-fold cross-validation and used 204 independent samples to test their performance by evaluating their accuracy. Moreover, we ranked the most important clinical features in different models and reconstructed three reduced models with fewer clinical features. For binary and continuous predictions, the average accuracy of these models was 0.70–0.73 and 0.68–0.75, respectively. Seven features were listed as important features related to serum lithium levels of 0.6–1.2 mmol/L or higher lithium concentration, namely older age, lower systolic blood pressure, higher daily and last doses of lithium prescription, concomitant psychotropic drugs with valproic acid and -pine drugs, and comorbid substance-related disorders. After reducing the features in the three new predictive models, the binary or continuous models still had an average accuracy of 0.67–0.74. Machine learning processes complex clinical data and provides a potential tool for predicting lithium concentration. This may help in clinical decision-making and reduce the frequency of serum level monitoring.
Dynamic Variations of 3′UTR Length Reprogram the mRNA Regulatory Landscape
Authors: Navarro Estanislao , Mallén Adrián , Hueso Miguel
Published: October 2021

This paper concerns 3′-untranslated regions (3′UTRs) of mRNAs, which are non-coding regulatory platforms that control stability, fate and the correct spatiotemporal translation of mRNAs. Many mRNAs have polymorphic 3′UTR regions. Controlling 3′UTR length and sequence facilitates the regulation of the accessibility of functional effectors (RNA binding proteins, miRNAs or other ncRNAs) to 3′UTR functional boxes and motifs and the establishment of different regulatory landscapes for mRNA function. In this context, shortening of 3′UTRs would loosen miRNA or protein-based mechanisms of mRNA degradation, while 3′UTR lengthening would strengthen accessibility to these effectors. Alterations in the mechanisms regulating 3′UTR length would result in widespread deregulation of gene expression that could eventually lead to diseases likely linked to the loss (or acquisition) of specific miRNA binding sites. Here, we will review the mechanisms that control 3′UTR length dynamics and their alterations in human disorders. We will discuss, from a mechanistic point of view centered on the molecular machineries involved, the generation of 3′UTR variability by the use of alternative polyadenylation and cleavage sites, of mutually exclusive terminal alternative exons (exon skipping) as well as by the process of exonization of Alu cassettes to generate new 3′UTRs with differential functional features.
Efficacy of DiscoGel in Treatment of Degenerative Disc Disease: A Prospective 1-Year Observation of 67 Patients
Authors: Latka Kajetan , Kozlowska Klaudia , Waligora Marek , Kolodziej Waldemar , Olbrycht Tomasz , Chowaniec Jacek , Hendryk Stanislaw , Latka Miroslaw , Latka Dariusz
Published: October 2021

Patients with degenerative disc disease may suffer from chronic lumbar discogenic (DP) or radicular leg (RLP) pain. Minimally invasive DiscoGel therapy involves the percutaneous injection of an ethanol gel into the degenerated disk’s nucleus pulposus. This paper compares the 1-year outcome of such treatment in DP and RLP patients. We operated on 67 patients (49 men and 18 women) aged 20–68 years (mean age 46 ± 11 years) with DP (n = 45) and RLP (n = 22), of at least 6–8 weeks duration, with no adverse effects. We evaluated the treatment outcome with Core Outcome Measures Index (COMI) and Visual Analog Scale (VAS). A year after the ethanol gel injection, in the DP cohort, COMI and VAS dropped by 66% (6.40 vs. 2.20) and 53% (6.33 vs. 2.97), respectively. For the RLP patients, the corresponding values dropped 48% (7.05 vs. 3.68) and 54% (6.77 vs. 3.13). There were no differences between the cohorts in COMI and VAS at the follow-up end. Six months into the study, 74% of DP and 81% of RLP patients did not use any analgesics. Ethanol gel therapy can be effective for many patients. Moreover, its potential failure does not exclude surgical treatment options.
Monitoring cfDNA in Plasma and in Other Liquid Biopsies of Advanced EGFR Mutated NSCLC Patients: A Pilot Study and a Review of the Literature
Authors: Verzè Michela , Minari Roberta , Gnetti Letizia , Bordi Paola , Leonetti Alessandro , Cosenza Agnese , Ferri Leonarda , Majori Maria , De Filippo Massimo , Buti Sebastiano , Gasparro Donatello , Nizzoli Rita , Azzoni Cinzia , Bottarelli Lorena , Squadrilli Anna , Mozzoni Paola , Tiseo Marcello
Published: October 2021

In order to study alternatives at the tissue biopsy to study EGFR status in NSCLC patients, we evaluated three different liquid biopsy platforms (plasma, urine and exhaled breath condensate, EBC). We also reviewed the literature of the cfDNA biological sources other than plasma and compared our results with it about the sensitivity to EGFR mutation determination. Twenty-two EGFR T790M-mutated NSCLC patients in progression to first-line treatment were enrolled and candidate to osimertinib. Plasma, urine and EBC samples were collected at baseline and every two months until progression. Molecular analysis of cfDNA was performed by ddPCR and compared to tissue results. At progression NGS analysis was performed. The EGFR activating mutation detection reached a sensitivity of 58 and 11% and for the T790M mutation of 45 and 10%, in plasma and urine samples, respectively. Any DNA content was recovered from EBC samples. Considering the plasma monitoring study, the worst survival was associated with positive shedding status; both plasma and urine molecular progression anticipated the radiological worsening. Our results confirmed the role of plasma liquid biopsy in testing EGFR mutational status, but unfortunately, did not evidence any improvement from the combination with alternative sources, as urine and EBC.
Laser Immunotherapy: A Potential Treatment Modality for Keratinocyte Carcinoma
Authors: Omland Silje Haukali , Wenande Emily Cathrine , Svane Inge Marie , Tam Joshua , Olesen Uffe Høgh , Hædersdal Merete
Published: October 2021

The role of the immune system in cancer growth is well recognized and the development of immunotherapy represents a breakthrough in cancer treatment. Recently, the use of systemic immunotherapy was extended to keratinocyte carcinoma (KC), specifically locally advanced and metastasizing basal and squamous cell carcinoma. However, since most KC lesions are non-aggressive, systemic treatment with associated side effects is rarely justified. Conversely, topical immunotherapy with imiquimod remains restricted to premalignant and superficial lesions. Use of laser in the treatment of KC has evolved from physical tumor destruction and laser-assisted drug delivery to laser-mediated immune modulation. Evidence indicates that laser monotherapy can lead to immune cell infiltration, tumor reduction and resistance to tumor re-inoculation. Combining laser with immunotherapeutic agents, termed laser immunotherapy (LIT), may further potentiate immune activation and tumor response. Studies on LIT show not only direct anti-tumor effects but systemic adaptive immunity, illustrated by the prevention of tumor recurrence and regression in distant untreated tumors. These findings imply a therapeutic potential for both local and metastatic disease. This work provides rationales for immune-based treatment of KC and presents the current status of KC immunotherapy. Aiming to expand the field of KC immunotherapy, the review discusses the literature on immune activation following laser monotherapy and LIT.
Immune Checkpoint Inhibitors for Genitourinary Cancers: Treatment Indications, Investigational Approaches and Biomarkers
Authors: Labadie Brian W. , Balar Arjun V. , Luke Jason J.
Published: October 2021

Cancers of the genitourinary (GU) tract are common malignancies in both men and women and are a major source of morbidity and mortality. Immune checkpoint inhibitors (ICI) targeting CTLA-4, PD-1 or PD-L1 have provided clinical benefit, particularly in renal cell and urothelial carcinoma, and have been incorporated into standard of care treatment in both localized and metastatic settings. However, a large fraction of patients do not derive benefit. Identification of patient and tumor-derived factors which associate with response have led to insights into mechanisms of response and resistance to ICI. Herein, we review current approvals and clinical development of ICI in GU malignancies and discuss exploratory biomarkers which aid in personalized treatment selection.
A Combination of EPR, Microscopy, Electrophoresis and Theory to Elucidate the Chemistry of W- and N-Doped TiO2 Nanoparticle/Water Interfaces
Authors: Gorman Sam , Rickaby Kirstie , Lu Li , Kiely Christopher J. , Macphee Donald E. , Folli Andrea
Published: October 2021

The doping of TiO2-based nanomaterials for semiconductor-sensitised photoreactions has been a practice extensively studied and applied for many years. The main goal remains the improvement of light harvesting capabilities under passive solar irradiation, that in the case of undoped TiO2 is limited and restricted to relatively low latitudes. The activity and selectivity of doped TiO2 photocatalysts are generally discussed on the basis of the modified band structure; energetics of intrinsic or extrinsic band gaps including trapping states; redox potentials of band edges, including band bending at solid/fluid interfaces; and charge carriers scavenging/transfer by/to adsorbed species. Electron (and hole) transfer to adsorbates is often invoked to justify the formation of highly reactive species (e.g., HO. from water); however, a complete description of the nanoparticle surface chemistry dictating adsorption/desorption events is often missing or overlooked. Here, we show that by employing a surface electrochemical triple-layer (TLM) approach for the nanoparticles/water interface, in combination with electron paramagnetic resonance spectroscopy (EPR), transmission electron microscopy and electrophoretic measurements, we can elucidate the surface chemistry of doped TiO2 nanoparticles and link it to the nature of the dopants. Exemplifying it for the cases of undoped, as well as W- and N-doped and codoped TiO2 nanoparticles, we show how surface charge density; surface, Stern and ζ potentials; surface acidity constants; and speciation of surface sites are influenced by the nature of the dopants and their loading.
Kinetic and Structural Properties of a Robust Bacterial L-Amino Acid Oxidase
Authors: Savino Simone , Meijer J. Daniël-Moráh , Rozeboom Henriëtte J. , van Beek Hugo L. , Fraaije Marco W.
Published: October 2021

L-Amino acid oxidase (LAAO) is a flavin adenine dinucleotide (FAD)-dependent enzyme active on most proteinogenic L-amino acids, catalysing their conversion to α-keto acids by oxidative deamination of the substrate. For this oxidation reaction, molecular oxygen is used as the electron acceptor, generating hydrogen peroxide. LAAO can be used to detect L-amino acids, for the production of hydrogen peroxide as an oxidative agent or antimicrobial agent, and for the production of enantiopure amino acids from racemates. In this work, we characterised a previously reported LAAO from the bacterium Pseudoalteromonas luteoviolacea. The substrate scope and kinetic properties of the enzyme were determined, and the thermostability was evaluated. Additionally, we elucidated the crystal structure of this bacterial LAAO, enabling us to test the role of active site residues concerning their function in catalysis. The obtained insights and ease of expression of this thermostable LAAO provides a solid basis for the development of engineered LAAO variants tuned for biosensing and/or biocatalysis.
Relevance of Neutrophil Neprilysin in Heart Failure
Authors: Prausmüller Suriya , Spinka Georg , Arfsten Henrike , Stasek Stefanie , Rettl Rene , Bartko Philipp Emanuel , Goliasch Georg , Strunk Guido , Riebandt Julia , Mascherbauer Julia , Bonderman Diana , Hengstenberg Christian , Hülsmann Martin , Pavo Noemi
Published: October 2021

Significant expression of neprilysin (NEP) is found on neutrophils, which present the transmembrane integer form of the enzyme. This study aimed to investigate the relationship of neutrophil transmembrane neprilysin (mNEP) with disease severity, adverse remodeling, and outcome in HFrEF. In total, 228 HFrEF, 30 HFpEF patients, and 43 controls were enrolled. Neutrophil mNEP was measured by flow-cytometry. NEP activity in plasma and blood cells was determined for a subset of HFrEF patients using mass-spectrometry. Heart failure (HF) was characterized by reduced neutrophil mNEP compared to controls (p < 0.01). NEP activity on peripheral blood cells was almost 4-fold higher compared to plasma NEP activity (p = 0.031) and correlated with neutrophil mNEP (p = 0.006). Lower neutrophil mNEP was associated with increasing disease severity and markers of adverse remodeling. Higher neutrophil mNEP was associated with reduced risk for mortality, total cardiovascular hospitalizations, and the composite endpoint of both (p < 0.01 for all). This is the first report describing a significant role of neutrophil mNEP in HFrEF. The biological relevance of neutrophil mNEP and exact effects of angiotensin-converting-enzyme inhibitors (ARNi) at the neutrophil site have to be determined. However, the results may suggest early initiation of ARNi already in less severe HF disease, where effects of NEP inhibition may be more pronounced.
Exosomes in Ageing and Motor Neurone Disease: Biogenesis, Uptake Mechanisms, Modifications in Disease and Uses in the Development of Biomarkers and Therapeutics
Authors: Anakor Ekene , Le Gall Laura , Dumonceaux Julie , Duddy William John , Duguez Stephanie
Published: October 2021

Intercellular communication between neurons and their surrounding cells occurs through the secretion of soluble molecules or release of vesicles such as exosomes into the extracellular space, participating in brain homeostasis. Under neuro-degenerative conditions associated with ageing, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s or Parkinson’s disease, exosomes are suspected to propagate toxic proteins. The topic of this review is the role of exosomes in ageing conditions and more specifically in ALS. Our current understanding of exosomes and exosome-related mechanisms is first summarized in a general sense, including their biogenesis and secretion, heterogeneity, cellular interaction and intracellular fate. Their role in the Central Nervous System (CNS) and ageing of the neuromotor system is then considered in the context of exosome-induced signaling. The review then focuses on exosomes in age-associated neurodegenerative disease. The role of exosomes in ALS is highlighted, and their use as potential biomarkers to diagnose and prognose ALS is presented. The therapeutic implications of exosomes for ALS are considered, whether as delivery vehicles, neurotoxic targets or as corrective drugs in and of themselves. A diverse set of mechanisms underpin the functional roles, both confirmed and potential, of exosomes, generally in ageing and specifically in motor neurone disease. Aspects of their contents, biogenesis, uptake and modifications offer many plausible routes towards the development of novel biomarkers and therapeutics.
Hormonal Regulation of Oxidative Phosphorylation in the Brain in Health and Disease
Authors: Głombik Katarzyna , Detka Jan , Budziszewska Bogusława
Published: October 2021

The developing and adult brain is a target organ for the vast majority of hormones produced by the body, which are able to cross the blood–brain barrier and bind to their specific receptors on neurons and glial cells. Hormones ensure proper communication between the brain and the body by activating adaptive mechanisms necessary to withstand and react to changes in internal and external conditions by regulating neuronal and synaptic plasticity, neurogenesis and metabolic activity of the brain. The influence of hormones on energy metabolism and mitochondrial function in the brain has gained much attention since mitochondrial dysfunctions are observed in many different pathological conditions of the central nervous system. Moreover, excess or deficiency of hormones is associated with cell damage and loss of function in mitochondria. This review aims to expound on the impact of hormones (GLP-1, insulin, thyroid hormones, glucocorticoids) on metabolic processes in the brain with special emphasis on oxidative phosphorylation dysregulation, which may contribute to the formation of pathological changes. Since the brain concentrations of sex hormones and neurosteroids decrease with age as well as in neurodegenerative diseases, in parallel with the occurrence of mitochondrial dysfunction and the weakening of cognitive functions, their beneficial effects on oxidative phosphorylation and expression of antioxidant enzymes are also discussed.