bluuebunny/crossref_metadata_2025 huggingface dataset:
Analyzing and Controlling Inter-Head Diversity in Multi-Head Attention
Authors: Yun Hyeongu , Kang Taegwan , Jung Kyomin
Published: February 2021

Multi-head attention, a powerful strategy for Transformer, is assumed to utilize information from diverse representation subspaces. However, measuring diversity between heads’ representations or exploiting the diversity has been rarely studied. In this paper, we quantitatively analyze inter-head diversity of multi-head attention by applying recently developed similarity measures between two deep representations: Singular Vector Canonical Correlation Analysis (SVCCA) and Centered Kernel Alignment (CKA). By doing so, we empirically show that multi-head attention does diversify representation subspaces of each head as the number of heads increases. Based on our analysis, we hypothesize that there exists an optimal inter-head diversity with which a model can achieve better performance. To examine our hypothesis, we deeply inspect three techniques to control the inter-head diversity; (1) Hilbert-Schmidt Independence Criterion regularizer among representation subspaces, (2) Orthogonality regularizer, and (3) Drophead as zero-outing each head randomly in every training step. In our experiments on various machine translation and language modeling tasks, we show that controlling inter-head diversity leads to the best performance among baselines.
Using Recognizable Fuzzy Analysis for Non-Destructive Detection of Residual Stress in White Light Elements
Authors: Chang Han-Jui , Mao Zhong-Fa , Su Zhi-Ming , Zhang Guang-Yi
Published: February 2021

The phenomenon of residual stress in optical lens injection molding affects the quality of optical devices, with the refractive errors that are caused by geometric errors being the most serious, followed by the reduced accuracy and function of optical components; it is very important to ensure that the lens geometry remains intact and that the refractive index is reduced. This paper uses a photoelastic stress compensation method for measurement verification along with fuzzy theory to reorganize a set of processes that can be used to evaluate the residual stress of a product, whereby the use of corresponding theoretical formulas can effectively quantify and measure the residual stress of the product. A mold flow simulation is used to analyze the molded optical components and determine the feasibility of evaluating the quality of the lens. Through the measurement of the refractive stress value of the optical components, the molding quality of the lens can be improved, and its force distribution effects can be investigated. Geometric analysis and shear stress affect the performance of optical components, and these errors may also cause irreparable problems during secondary processing. Therefore, it is crucial to reduce the residual stress of optical components. When the stress distribution is uniform and the internal melting pressure is reasonably configured, the product’s shrinkage rate can be controlled; the method for determining the residual stress is the core theme of this research.
Shaking Table Test on the Response of a Cross Interchange Metro Station under Harmonic Excitations Refers to a Single Two-Storey Metro Station
Authors: Ge Shiping , Wu Weifeng , Ding Wenqi , Yuan Yong
Published: February 2021

Interchange is essential in a metro network. Regarding the seismic performance, a series of large-scale shaking table tests were performed on an interchange station. The interchange station was composed of a two-story section rigidly connected to a perpendicular three-story section, leading to an abrupt change of stiffness in the conjunction area. Synthetic model soil (a mixture of sand and sawdust) and granular concrete with galvanized steel wires were used to model the soil–structure system. The seismic motion was input along the transversal direction of the two-story structure, including white noise and sinusoidal seismic excitations. Parallel tests of a single two-story station were correspondingly carried out as a contrast. Test data recorded by accelerometers and strain gauges are presented. The bending strains of the columns measured in the interchange station were found to be smaller than those in the single station. The concentration of the longitudinal strain was observed near the conjunction. Insights on the seismic response of the interchange station are provided.
Air Concentrations of Gaseous Elemental Mercury and Vegetation–Air Fluxes within Saltmarshes of the Tagus Estuary, Portugal
Authors: Cesário Rute , O’Driscoll Nelson J. , Justino Sara , Wilson Claire E. , Monteiro Carlos E. , Zilhão Henrique , Canário João
Published: February 2021

In situ air concentrations of gaseous elemental mercury (Hg(0)) and vegetation–atmosphere fluxes were quantified in both high (Cala Norte, CN) and low-to-moderate (Alcochete, ALC) Hg-contaminated saltmarsh areas of the Tagus estuary colonized by plant species Halimione portulacoides (Hp) and Sarcocornia fruticosa (Sf). Atmospheric Hg(0) ranged between 1.08–18.15 ng m−3 in CN and 1.18–3.53 ng m−3 in ALC. In CN, most of the high Hg(0) levels occurred during nighttime, while the opposite was observed at ALC, suggesting that photoreduction was not driving the air Hg(0) concentrations at the contaminated site. Vegetation–air Hg(0) fluxes were low in ALC and ranged from −0.76 to 1.52 ng m−2 (leaf area) h−1 for Hp and from −0.40 to 1.28 ng m−2 (leaf area) h−1 for Sf. In CN, higher Hg fluxes were observed for both plants, ranging from −9.90 to 15.45 ng m−2 (leaf area) h−1 for Hp and from −8.93 to 12.58 ng m−2 (leaf area) h−1 for Sf. Mercury flux results at CN were considered less reliable due to large and fast variations in the ambient air concentrations of Hg(0), which may have been influenced by emissions from the nearby chlor-alkali plant, or historical contamination. Improved experimental setup, the influence of high local Hg concentrations and the seasonal activity of the plants must be considered when assessing vegetation–air Hg(0) fluxes in Hg-contaminated areas.
Investigation of Aeolian Dust Deposition Rates in Different Climate Zones of Southwestern Iran
Authors: Ahmadi Foroushani Mansour , Opp Christian , Groll Michael
Published: February 2021

Dust and atmospheric particles have been described in southwestern Iran primarily in terms of load, concentration and transport. The passive deposition, however, has been discussed inadequately. Therefore, the relationships between different climate zones in southwestern Iran and dust deposition rates were quantified between 2014 and 2017 using both space- (second modern-era retrospective analysis for research and applications, version 2 reanalysis model) and ground-based (eolian ground deposition rate) tools. In addition, the surface meteorological records, including the wind patterns favoring the occurrence of dust events, were examined. A hot desert climate (BWh), hot semi-arid climate (BSh), and temperate hot and dry summer climate (Csa) were identified as the three dominant climate regions in the study area, exhibiting the highest average dust deposition rates. In this study, correlations between the most relevant climate patterns and deposition rate weather parameters were found to describe a region’s deposition rate when a dust event occurred. Based on these results, the BSh and Csa regions were found to be associated with the seasonal cycle of dust events in March, April, and May, revealing that in the long run meteorological conditions were responsible for the varying dust deposition rates. Relatively, precipitation and temperature were the two major factors influencing dust deposition rates, not wind speed. Moreover, the peak seasonal deposition rates in the spring and summer were 8.40 t km−2 month−1, 6.06 t km−2 month−1, and 3.30 t km−2 month−1 for the BWh, BSh, and Csa climate regions, respectively. However, each of these climate types was directly related to the specific quantity of the dust deposition rates. Overall, the highest dust deposition rates were detected over the years studied were 100.80 t km−2 year−1, 79.27 t km−2 year−1, and 39.60 t km−2 year−1 for BWh, BSh, and Csa, respectively.
Projected Characteristic Changes of a Typical Tropical Cyclone under Climate Change in the South West Indian Ocean
Authors: Thompson Callum , Barthe Christelle , Bielli Soline , Tulet Pierre , Pianezze Joris
Published: February 2021

During 2 January 2014, Cyclone Bejisa passed near La Réunion in the southwestern Indian Ocean, bringing wind speeds of 41 m s−1, an ocean swell of 7 m, and rainfall accumulations of 1025 mm over 48 h. As a typical cyclone to impact La Réunion, we investigate how the characteristics of this cyclone could change in response to future warming via high-resolution, atmosphere–ocean coupled simulations of Bejisa-like cyclones in historical and future environments. Future environments are constructed using the pseudo global warming method whereby perturbations are added to historical analyses from six Coupled Model Intercomparison Project 5 (CMIP5) climate models. These models follow the Intergovernmental Panel for Climate Change’s (IPCC) Representative Concentration Pathways (RCP) RCP8.5 emissions scenario and project ocean surface warming of 1.1–4.2 °C by 2100. Under these conditions, we find that future Bejisa-like cyclones are 6.5% more intense on average and reach their lifetime maximum intensity 2 degrees further poleward. Additionally, future cyclones produce heavier rainfall, with a 33.8% average increase in the median rainrate, and are 9.2% smaller, as measured by the radius of 17.5 m s−1 winds. Furthermore, when surface wind output is used to run an ocean wave model in post, we find a 4.6% increase in the significant wave height.
An Investigation of the Quantitative Correlation between Urban Spatial Morphology Indicators and Block Wind Environment
Authors: Wei Di , Hu Xing , Chen Yangjun , Li Baofeng , Chen Hong
Published: February 2021

The research purpose of this work is guiding the spatial morphological design of blocks via relevant indicators to realize suitable wind environments. In doing so, it is necessary to find the most suitable indicator types and value ranges for each urban spatial morphology. At present, most of the relevant research has been based on the numerical simulation of ideal block shapes and rarely proposes results based on actual block types, which often tend to be complex environments. Therefore, this paper firstly presents a theoretical speculation on the main factors influencing indicator effectiveness via analyzing physical significance and formulating principles for each indicator. These speculations are verified via wind environment measurement and statistical analysis, indicating that porosity (P0) can be used as an important indicator to guide the design of block wind environments in the case of deep street canyons, while frontal area density (λF) can be used as a supplement in shallow street canyons with no height differences. Finally, computational fluid dynamics (CFD) is used to quantify the impact of block height difference and street canyon depth on λF and P0, thereby finding suitable types of urban form and value ranges for λF and P0. This paper provides a feasible wind environment index system for urban designers.
Modeling and Forecasting of COVID-19 Spreading by Delayed Stochastic Differential Equations
Authors: Mahrouf Marouane , Boukhouima Adnane , Zine Houssine , Lotfi El Mehdi , Torres Delfim F. M. , Yousfi Noura
Published: February 2021

The novel coronavirus disease (COVID-19) pneumonia has posed a great threat to the world recent months by causing many deaths and enormous economic damage worldwide. The first case of COVID-19 in Morocco was reported on 2 March 2020, and the number of reported cases has increased day by day. In this work, we extend the well-known SIR compartmental model to deterministic and stochastic time-delayed models in order to predict the epidemiological trend of COVID-19 in Morocco and to assess the potential role of multiple preventive measures and strategies imposed by Moroccan authorities. The main features of the work include the well-posedness of the models and conditions under which the COVID-19 may become extinct or persist in the population. Parameter values have been estimated from real data and numerical simulations are presented for forecasting the COVID-19 spreading as well as verification of theoretical results.
Entropic Competition between Supercoiled and Torsionally Relaxed Chromatin Fibers Drives Loop Extrusion through Pseudo-Topologically Bound Cohesin
Authors: Rusková Renáta , Račko Dušan
Published: February 2021

We propose a model for cohesin-mediated loop extrusion, where the loop extrusion is driven entropically by the energy difference between supercoiled and torsionally relaxed chromatin fibers. Different levels of negative supercoiling are controlled by varying imposed friction between the cohesin ring and the chromatin fiber. The speed of generation of negative supercoiling by RNA polymerase associated with TOP1 is kept constant and corresponds to 10 rotations per second. The model was tested by coarse-grained molecular simulations for a wide range of frictions between 2 to 200 folds of that of generic fiber and the surrounding medium. The higher friction allowed for the accumulation of higher levels of supercoiling, while the resulting extrusion rate also increased. The obtained extrusion rates for the given range of investigated frictions were between 1 and 10 kbps, but also a saturation of the rate at high frictions was observed. The calculated contact maps indicate a qualitative improvement obtained at lower levels of supercoiling. The fits of mathematical equations qualitatively reproduce the loop sizes and levels of supercoiling obtained from simulations and support the proposed mechanism of entropically driven extrusion. The cohesin ring is bound on the fibers pseudo-topologically, and the model suggests that the topological binding is not necessary.
Increased Interleukin-11 and Stress-Related Gene Expression in Human Endothelial and Bronchial Epithelial Cells Exposed to Silver Nanoparticles
Authors: Jang Jiyoung , Park Sun , Choi In-Hong
Published: February 2021

This article aimed to identify and distinguish the various responses to silver nanoparticles (NPs) of endothelial and epithelial cells. We also assessed the significantly increased gene expression levels, as shown by microarray analysis. We evaluated the median lethal dose of NPs in each cell line and found that each value was different. We also confirmed the toxicity of 5 nm silver NPs. Meanwhile, cell death was not observed in cells exposed to 100 nm silver NPs at a high concentration. We verified that 5 nm silver NPs affected the variation in gene expression in cells through microarray analysis and observed a noticeable increase in interleukin (IL)-8 and IL-11 gene expression in early stages. This study showed noticeable variation in the expression of oxidative stress-related genes in early stages. Microarray results showed considerable variation in cell death-, apoptosis-, and cell survival-related gene expression. Of note, IL-11 gene expression was particularly increased following the exposure of endothelial and epithelial cells to 5 nm silver NPs. In conclusion, this study demonstrated that intracellular genes specifically responded to silver NPs in respiratory epithelial cells and endothelial cells. Among cytokine genes, IL-11 expression was noticeably increased. Additionally, we confirmed that NP toxicity was affected by NP size and dose.
The Ins and Outs of RAS Effector Complexes
Authors: Kiel Christina , Matallanas David , Kolch Walter
Published: February 2021

RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS-dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism-based therapies for RAS mutated cancers.
Arabidopsis Defense against the Pathogenic Fungus Drechslera gigantea Is Dependent on the Integrity of the Unfolded Protein Response
Authors: Samperna Simone , Boari Angela , Vurro Maurizio , Salzano Anna Maria , Reveglia Pierluigi , Evidente Antonio , Gismondi Angelo , Canini Antonella , Scaloni Andrea , Marra Mauro
Published: February 2021

Drechslera gigantea Heald & Wolf is a worldwide-spread necrotrophic fungus closely related to the Bipolaris genus, well-known because many member species provoke severe diseases in cereal crops and studied because they produce sesterpenoid phytoxins named ophiobolins which possess interesting biological properties. The unfolded protein response (UPR) is a conserved mechanism protecting eukaryotic cells from the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER). In plants, consolidated evidence supports the role of UPR in the tolerance to abiotic stress, whereas much less information is available concerning the induction of ER stress by pathogen infection and consequent UPR elicitation as part of the defense response. In this study, the infection process of D. gigantea in Arabidopsis thaliana wild type and UPR-defective bzip28 bzip60 double mutant plants was comparatively investigated, with the aim to address the role of UPR in the expression of resistance to the fungal pathogen. The results of confocal microscopy, as well as of qRT-PCR transcript level analysis of UPR genes, proteomics, microRNAs expression profile and HPLC-based hormone analyses demonstrated that ophiobolin produced by the fungus during infection compromised ER integrity and that impairment of the IRE1/bZIP60 pathway of UPR hampered the full expression of resistance, thereby enhancing plant susceptibility to the pathogen.
Signaling Nodes Associated with Endoplasmic Reticulum Stress during NAFLD Progression
Authors: Koo Ja Hyun , Han Chang Yeob
Published: February 2021

Excess and sustained endoplasmic reticulum (ER) stress, paired with a failure of initial adaptive responses, acts as a critical trigger of nonalcoholic fatty liver disease (NAFLD) progression. Unfortunately, there is no drug currently approved for treatment, and the molecular basis of pathogenesis by ER stress remains poorly understood. Classical ER stress pathway molecules have distinct but inter-connected functions and complicated effects at each phase of the disease. Identification of the specific molecular signal mediators of the ER stress-mediated pathogenesis is, therefore, a crucial step in the development of new treatments. These signaling nodes may be specific to the cell type and/or the phase of disease progression. In this review, we highlight the recent advancements in knowledge concerning signaling nodes associated with ER stress and NAFLD progression in various types of liver cells.
Viability Assessment in Liver Transplantation—What Is the Impact of Dynamic Organ Preservation?
Authors: Panconesi Rebecca , Flores Carvalho Mauricio , Mueller Matteo , Meierhofer David , Dutkowski Philipp , Muiesan Paolo , Schlegel Andrea
Published: February 2021

Based on the continuous increase of donor risk, with a majority of organs classified as marginal, quality assessment and prediction of liver function is of utmost importance. This is also caused by the notoriously lack of effective replacement of a failing liver by a device or intensive care treatment. While various parameters of liver function and injury are well-known from clinical practice, the majority of specific tests require prolonged diagnostic time and are more difficult to assess ex situ. In addition, viability assessment of procured organs needs time, because the development of the full picture of cellular injury and the initiation of repair processes depends on metabolic active tissue and reoxygenation with full blood over several hours or days. Measuring injury during cold storage preservation is therefore unlikely to predict the viability after transplantation. In contrast, dynamic organ preservation strategies offer a great opportunity to assess organs before implantation through analysis of recirculating perfusates, bile and perfused liver tissue. Accordingly, several parameters targeting hepatocyte or cholangiocyte function or metabolism have been recently suggested as potential viability tests before organ transplantation. We summarize here a current status of respective machine perfusion tests, and report their clinical relevance.
Current Promising Biomarkers and Methods in the Diagnostics of Antiphospholipid Syndrome: A Review
Authors: Bradacova Pavla , Slavik Ludek , Ulehlova Jana , Skoumalova Adela , Ullrychova Jana , Prochazkova Jana , Hlusi Antonin , Manukyan Gayane , Kriegova Eva
Published: February 2021

Antiphospholipid syndrome (APS) is a hypercoagulation condition associated with the incidence of heterogenic antiphospholipid antibodies (aPLs), which non-specifically affect hemostasis processes. APS is clinically manifested by recurrent arterial and venous thromboses and reproduction losses. The aPL antibodies, which may induce clinical manifestations of APS, include criteria antibodies anti-cardiolipin, anti-β2-glycoprotein-I, and lupus anticoagulant, but also non-criteria antibodies, for example anti-β2-glycoprotein-I domain I, anti-phosphatidylserine/prothrombin, anti-annexin V, and many others. APS occurs mostly in patients of younger and middle age, most frequently in females. Laboratory diagnostics of APS are quite difficult, as they include a wide spectrum of examining methods, which are based on various principles of detection and are performed using various laboratory techniques. The objective of the review is to describe the current state of potentially examined biomarkers and methods in APS diagnostics. The aforementioned biomarkers are lupus anticoagulant, anti-β2-glycoprotein-I, anti-cardiolipin, anti-β2-glycoprotein-I domain I, anti-phosphatidylserine/prothrombin, anti-β2-glycoprotein-I IgA, anti-cardiolipin IgA, anti-annexin V and II, anti-prothrombin, anti-cardiolipin/vimentin, anti-protein S/protein C, and antibodies against phospholipid antigens for whose diagnostics we may use some of the methods established for a long time and some of the modern methods—the coagulation method for the determination of lupus anticoagulant (LA), enzyme-linked imunosorbent assay (ELISA), chemiluminescence analysis (CLIA), multiplex fluorescence flow immunoassay (MFFIA), fluorescence enzyme immunoassay (EliA), line immunoassay (LIA), multiline dot assay (MLDA), and thin-layer chromatography (TLC). Conclusion: Antibodies against phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphatidylinositol, cardiolipin/vimentin complex, and annexin V are currently the most studied new markers. However, these assays have not been standardized until now, both from the laboratory and clinical point of view. In this review we summarize the evidence of the most studied aPL markers and their potential clinical significance in seronegative APS (SN-APS).
Netrin-1 in Atherosclerosis: Relationship between Human Macrophage Intracellular Levels and In Vivo Plaque Morphology
Authors: Fiorelli Susanna , Cosentino Nicola , Porro Benedetta , Fabbiocchi Franco , Niccoli Giampaolo , Fracassi Francesco , Capra Nicolò , Barbieri Simone , Crea Filippo , Marenzi Giancarlo , Cavalca Viviana , Tremoli Elena , Eligini Sonia
Published: February 2021

Netrin-1 is a laminin-like protein that plays a pivotal role in cell migration and, according to the site of its release, exerts both pro and anti-atherosclerotic functions. Macrophages, key cells in atherosclerosis, are heterogeneous in morphology and function and different subpopulations may support plaque progression, stabilization, and/or regression. Netrin-1 was evaluated in plasma and, together with its receptor UNC5b, in both spindle and round monocyte-derived macrophages (MDMs) morphotypes from coronary artery disease (CAD) patients and control subjects. In CAD patients, plaque features were detected in vivo by optical coherence tomography. CAD patients had lower plasma Netrin-1 levels and a higher MDMs expression of both protein and its receptor compared to controls. Specifically, a progressive increase in Netrin-1 and UNC5b was evidenced going from controls to stable angina (SA) and acute myocardial infarction (AMI) patients. Of note, spindle MDMs of AMI showed a marked increase of both Netrin-1 and its receptor compared to spindle MDMs of controls. UNC5b expression is always higher in spindle compared to round MDMs, regardless of the subgroup. Finally, CAD patients with higher intracellular Netrin-1 levels showed greater intraplaque macrophage accumulation in vivo. Our findings support the role of Netrin-1 and UNC5b in the atherosclerotic process.
Semi-Automatic MRI Muscle Volumetry to Diagnose and Monitor Hereditary and Acquired Polyneuropathies
Authors: Bähr Friederike , Gess Burkhard , Müller Madlaine , Romanzetti Sandro , Gadermayr Michael , Kuhl Christiane , Nebelung Sven , Schulz Jörg , Dohrn Maike
Published: February 2021

With emerging treatment approaches, it is crucial to correctly diagnose and monitor hereditary and acquired polyneuropathies. This study aimed to assess the validity and accuracy of magnet resonance imaging (MRI)-based muscle volumetry.Using semi-automatic segmentations of upper- and lower leg muscles based on whole-body MRI and axial T1-weighted turbo spin-echo sequences, we compared and correlated muscle volumes, and clinical and neurophysiological parameters in demyelinating Charcot-Marie-Tooth disease (CMT) (n = 13), chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 27), and other neuropathy (n = 17) patients.The muscle volumes of lower legs correlated with foot dorsiflexion strength (p < 0.0001), CMT Neuropathy Score 2 (p < 0.0001), early gait disorders (p = 0.0486), and in CIDP patients with tibial nerve conduction velocities (p = 0.0092). Lower (p = 0.0218) and upper (p = 0.0342) leg muscles were significantly larger in CIDP compared to CMT patients. At one-year follow-up (n = 15), leg muscle volumes showed no significant decrease.MRI muscle volumetry is a promising method to differentiate and characterize neuropathies in clinical practice.
Damage Detection in Multiple RC Structures Based on Embedded Ultrasonic Sensors and Wavelet Transform
Authors: Chakraborty Joyraj , Wang Xin , Stolinski Marek
Published: February 2021

This paper summarizes the results of research aimed at assessing cracks in reinforced concrete structures using embedded ultrasonic sensors. The diffuse ultrasonic waves were considered to evaluate the health status of the tested structures. There are different algorithms used to detect cracks in the structure, but most studies have been performed on benchmark reinforced concrete (RC) structures and in laboratory conditions. Since there were difficulties with the validity of damage detection in real structures in the presence of environmental changes and noises, the application of advanced signal processing methods was necessary. Therefore, the wavelet transform was applied to process ultrasonic signals acquired from multiple civil structures. It is shown that the ultrasonic sensors with an applied wavelet transform algorithm on collected signals can successfully detect cracks in the laboratory as well as in a real environment. Experimental results showed a perfect match for detecting damage and quasi-static load in the presence of environmental changes. The results were confirmed with other techniques. In addition, designing an extra filter for removing noises can be avoided by using the applied algorithms. The obtained results confirmed that diffuse ultrasonic sensor methodology with the proposed algorithm is useful and effective in monitoring real RC structures, and it is better than traditional techniques.
Effect of Masonry Infill Constitutive Law on the Global Response of Infilled RC Buildings
Authors: Gaetani d’Aragona Marco , Polese Maria , Prota Andrea
Published: February 2021

Masonry-infilled reinforced concrete frames represent a very common construction typology across the Mediterranean countries. The presence of infills substantially modifies the global seismic performances of buildings in terms of strength, stiffness, and energy dissipation. Although several research studies focused on the overall performances of infilled reinforced concrete frames, the modeling of infill panels remains an open issue due to the complex interaction between the infill and the frame and the uncertainties involved in the definition of the problem. In the present paper, an existing masonry-infilled RC frame designed according to obsolete seismic codes is chosen as a case study. A refined three-dimensional finite element model is built for performing nonlinear static and time-history analyses in order to investigate some significant aspects related to the modeling of infills. In particular, it is investigated the effect of different infill constitutive models on the seismic performance of infilled RC building expressed in terms of engineering demand parameters such as interstory drift ratios and peak floor accelerations, and on the generation of damage fragility curves.
Failure Analysis of Apennine Masonry Churches Severely Damaged during the 2016 Central Italy Seismic Sequence
Authors: Clementi Francesco
Published: February 2021

This paper presents a detailed study of the damages and collapses suffered by various masonry churches in the aftermath of the seismic sequence of Central Italy in 2016. The damages will first be analyzed and then compared with the numerical data obtained through 3D simulations with eigenfrequency and then nonlinear static analyses (i.e., pushover). The main purposes of this study are: (i) to create an adequately consistent sensitivity study on several definite case studies to obtain an insight into the role played by geometry—which is always unique when referred to churches—and by irregularities; (ii) validate or address the applicability limits of the more widespread nonlinear approach, widely recommended by the Italian Technical Regulations. Pushover analyses are conducted assuming that the masonry behaves as a nonlinear material with different tensile and compressive strengths. The consistent number of case studies investigated will show how conventional static approaches can identify, albeit in a qualitative way, the most critical macro-elements that usually trigger both global and local collapses, underlining once again how the phenomena are affected by the geometry of stones and bricks, the texture of the wall face, and irregularities in the plan and elevation and in addition to hypotheses made on the continuity between orthogonal walls.
Short and Long-Term Mortality Trends for Cancer Patients with Septic Shock Stratified by Cancer Type from 2009 to 2017: A Population-Based Cohort Study
Authors: Kim Youn-Jung , Kim Min-Ju , Kim Ye-Jee , Kim Won Young
Published: February 2021

There have been recent advances in both cancer and sepsis management. This study aimed to assess short and long-term mortality trends in cancer patients with septic shock from 2009 to 2017 by cancer type. This nationwide population-based cohort study using data from the National Health Insurance Service of Korea included adult cancer patients who presented to an emergency department (ED) with septic shock from 2009 to 2017. Among 43,466 adult cancer patients with septic shock (90% solid and 10% hematologic cancer cases), the 30-day and 1-year mortality rates were 52.1% and 81.3%, respectively. The overall 30-day mortality showed a marked decrease of 4.8% annually from 2013 to 2017, but the annual decrease in the 1-year mortality over the same period was only 1.9%. Pancreatic cancer cases showed the most significant improvement in 30-day mortality between 2014 and 2019 (11.0% decrease/year). Lung and stomach cancers showed a sustained decrease in 30-day mortality during the whole study period (1.7% and 2.0% decrease/year, respectively). The outcomes of cancer patients with septic shock have improved in recent years across most cancer types. Physicians should have expectations of an improved prognosis in cancer patients admitted to the ED with septic shock.
Curing Cancer: Lessons from a Prototype
Authors: Tu Shi-Ming , Pisters Louis L.
Published: February 2021

Germ cell tumor of the testis (TGCT) is a remarkably curable solid tumor even when it is widely metastatic and patently heterogeneous. It provides invaluable clues about the origin and nature of metastasis and heterogeneity, cancer dormancy and late recurrence, drug sensitivity and resistance, tumor immunity, and spontaneous remission that would enable us to enhance the cure and improve the care of patients with other currently intractable solid tumors. After all, germ cells are primeval stem cells and TGCT are a perfect stem cell tumor for us to investigate a stem cell versus genetic origin of cancer. In many respects, TGCT is a prototype stem cell tumor that will enable us to elucidate the role of differentiation versus dedifferentiation in the evolution of a complex mixed tumor. It will help us decipher relevance of the genome versus the epi-genome in a progenitor cancer stem cell versus a progeny differentiated cancer cell. Importantly, clarification of a cellular context versus the genetic makeup in cancer has immense clinical implications. We postulate a unified theory of cancer derived from seminal TGCT research to improve personalized cancer care. Contrary to current norms and conventional wisdom, we propose that when it concerns a complex rather than simple cancer and a mixed rather than pure tumor (which is practically all solid tumors) multimodal therapy trumps targeted therapy and integrated medicine overrides precision medicine.
Does Pathological Stage and Nodal Involvement Influence Long Term Oncological Outcomes after CROSS Regimen for Adenocarcinoma of the Esophagogastric Junction? A Multicenter Retrospective Analysis
Authors: de Pascale Stefano , Parise Paolo , Valmasoni Michele , Weindelmayer Jacopo , Terraneo Fabrizia , Cella Chiara , Giacopuzzi Simone , Cossu Andrea , Massaron Simonetta , Elmore Ugo , Merigliano Stefano , Fumagalli Romario Uberto ,   on behalf of the Italian Society for the Study of Esophageal Diseases (SISME)
Published: February 2021

Background:After the results reported by the “Chemoradiotherapy for esophageal Cancer Followed by Surgery Study” (CROSS) trial, neo-adjuvant chemoradiotherapy became the standard treatment for locally advanced cancers of esophagus and gastroesophageal junction (GEJ). Excellent results were reported for squamocellular carcinomas (SCCs). Since the advent of the CROSS regimen, the results of surgery for esophageal adenocarcinomas (EAC) have cast some doubts about its efficacy on overall survival (OS) even in the presence of local response. This study evaluated the relation between pathological (yp) stage after CROSS regimen followed by surgery for adenocarcinoma of cardia and overall (OS) and disease-free survival (DFS). Sites of relapse after surgery were also analyzed. Methods: Patients submitted to the CROSS regimen for locally advanced EAC of the cardia followed by transthoracic esophagectomy were analyzed. Actuarial OS and DFS were analyzed and stratified according to yp stage. The site of relapse, distal and local, was also analyzed. Results: The study included 132 patients. The 50-month OS and DFS were 45% and 6.7%, respectively. No differences emerged analyzing OS according to yp stage. Time to relapse was significantly longer for yp Stage I and II, and for yp N0, compared with yp N+. Recurrence occurred in 48 cases (36.3%) with a 9 months median time to relapse. Local and distal relapse were 10 (7.5%) and 38 (28.7%) cases, respectively (p ≦ 0.001). Conclusions: Pathological stage after CROSS regimen does not relate to OS and DFS. Time to recurrence is significantly longer for yp Stages I and II and ypN0. Chemoradiotherapy in a neoadjuvant setting may influence the site of relapse, significantly reducing local recurrences.
Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS
Authors: Janssen Jeroen , Löwenberg Bob , Manz Markus , Bargetzi Mario , Biemond Bart , Borne Peter von dem , Breems Dimitri , Brouwer Rolf , Chalandon Yves , Deeren Dries , Efthymiou Anna , Gjertsen Bjørn-Tore , Graux Carlos , Gregor Michael , Heim Dominik , Hess Urs , Hoogendoorn Mels , Jaspers Aurelie , Jie Asiong , Jongen-Lavrencic Mojca , Klein Saskia , Klift Marjolein van der , Kuball Jürgen , Lammeren-Venema Danielle van , Legdeur Marie-Cecile , Loosdrecht Arjan van de , Maertens Johan , Kooy Marinus van Marwijk , Moors Ine , Nijziel Marten , Obbergh Florence van , Oosterveld Margriet , Pabst Thomas , Poel Marjolein van der , Sinnige Harm , Spertini Olivier , Terpstra Wim , Tick Lidwine , Velden Walter van der , Vekemans Marie-Christiane , Vellenga Edo , Weerdt Okke de , Westerweel Peter , Stüssi Georg , Norden Yvette van , Ossenkoppele Gert
Published: February 2021

Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66–81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (n = 116), days 1–21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60–77%) vs 64% (55–73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (p = 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation was more common in the tosedostat arm as well. The results of the present study show that the addition of tosedostat to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients.
Photodynamic Therapy Using Hippo Pathway Inhibitor Verteporfin: A Potential Dual Mechanistic Approach in Treatment of Soft Tissue Sarcomas
Authors: Rytlewski Jeffrey D. , Scalora Nicholas , Garcia Keith , Tanas Munir , Toor Fatima , Miller Benjamin , Allen Bryan , Milhem Mohammed , Monga Varun
Published: February 2021

Sarcoma is a widely varied and devastating oncological subtype, with overall five-year survival of 65% that drops to 16% with the presence of metastatic disease at diagnosis. Standard of care for localized sarcomas is predicated on local control with wide-local resection and radiation therapy, or, less commonly, chemotherapy, depending on tumor subtype. Verteporfin has the potential to be incorporated into this standard of care due to its unique molecular properties: inhibition of the upregulated Hippo pathway that frequently drives soft tissue sarcoma and photodynamic therapy-mediated necrosis due to oxidative damage. The initial anti-proliferative effect of verteporfin is mediated via binding and dissociation of YAP/TEAD proteins from the nucleus, ultimately leading to decreased cell proliferation as demonstrated in multiple in vitro studies. This effect has the potential to be compounded with use of photodynamic therapy to directly induce cellular necrosis with use of a clinical laser. Photodynamic therapy has been incorporated into multiple malignancies and has the potential to be incorporated into sarcoma treatment.
The Role of Necroptosis: Biological Relevance and Its Involvement in Cancer
Authors: Della Torre Laura , Nebbioso Angela , Stunnenberg Hendrik G. , Martens Joost H. A. , Carafa Vincenzo , Altucci Lucia
Published: February 2021

Regulated cell death mechanisms are essential for the maintenance of cellular homeostasis. Evasion of cell death is one of the most important hallmarks of cancer. Necroptosis is a caspase independent form of regulated cell death, investigated as a novel therapeutic strategy to eradicate apoptosis resistant cancer cells. The process can be triggered by a variety of stimuli and is controlled by the activation of RIP kinases family as well as MLKL. The well-studied executor, RIPK1, is able to modulate key cellular events through the interaction with several proteins, acting as strategic crossroads of several molecular pathways. Little evidence is reported about its involvement in tumorigenesis. In this review, we summarize current studies on the biological relevance of necroptosis, its contradictory role in cancer and its function in cell fate control. Targeting necroptosis might be a novel therapeutic intervention strategy in anticancer therapies as a pharmacologically controllable event.
Highly Efficient Heterogeneous Pd@POPs Catalyst for the N-Formylation of Amine and CO2
Authors: Wang Guoqing , Jiang Miao , Ji Guangjun , Sun Zhao , Ma Lei , Li Cunyao , Du Hong , Yan Li , Ding Yunjie
Published: February 2021

Utilization of CO2 for the production of fine chemicals has become a research hotspot for a long time. In order to make use of CO2, we developed a highly efficient heterogeneous catalyst (denoted as Pd@POPs) for the N-formylation reaction of amine and CO2 under mild conditions. The Pd catalyst was based on a porous organic polymer derived from the solvothermal polymerization of vinyl-functionalized PPh3. A series of characterizations and comparative experiments demonstrated that the Pd@POPs catalyst has high BET (Brunauer-Emmett-Teller) surface areas, hierarchical pore structure, and uniform dispersion of Pd active sites resulting from the formation of strong coordination bonds between Pd species and P atoms in the porous organic polymer (POP) support. In addition to the excellent activity, the Pd@POPs catalyst shows good stability for the N-formylation reaction of amine and CO2.
Eucalyptol: A Bio-Based Solvent for the Synthesis of O,S,N-Heterocycles. Application to Hiyama Coupling, Cyanation, and Multicomponent Reactions
Authors: Campos Joana F. , Ferreira Véronique , Berteina-Raboin Sabine
Published: February 2021

We report here the use of eucalyptol as a bio-based solvent for Hiyama coupling, cyanation, and multicomponent reactions on O,S,N-heterocycles. These heterocycles were chosen as targets or as starting materials given their biological potential; they play an important role in therapeutically active compounds. Once again, eucalyptol proved to be a credible and sustainable alternative to common solvents.
A Novel, LAT/Lck Double Deficient T Cell Subline J.CaM1.7 for Combined Analysis of Early TCR Signaling
Authors: Vico-Barranco Inmaculada , Arbulo-Echevarria Mikel M. , Serrano-García Isabel , Pérez-Linaza Alba , Miranda-Sayago José M. , Miazek Arkadiusz , Narbona-Sánchez Isaac , Aguado Enrique
Published: February 2021

Intracellular signaling through the T cell receptor (TCR) is essential for T cell development and function. Proper TCR signaling requires the sequential activities of Lck and ZAP-70 kinases, which result in the phosphorylation of tyrosine residues located in the CD3 ITAMs and the LAT adaptor, respectively. LAT, linker for the activation of T cells, is a transmembrane adaptor protein that acts as a scaffold coupling the early signals coming from the TCR with downstream signaling pathways leading to cellular responses. The leukemic T cell line Jurkat and its derivative mutants J.CaM1.6 (Lck deficient) and J.CaM2 (LAT deficient) have been widely used to study the first signaling events upon TCR triggering. In this work, we describe the loss of LAT adaptor expression found in a subline of J.CaM1.6 cells and analyze cis-elements responsible for the LAT expression defect. This new cell subline, which we have called J.CaM1.7, can re-express LAT adaptor after Protein Kinase C (PKC) activation, which suggests that activation-induced LAT expression is not affected in this new cell subline. Contrary to J.CaM1.6 cells, re-expression of Lck in J.CaM1.7 cells was not sufficient to recover TCR-associated signals, and both LAT and Lck had to be introduced to recover activatory intracellular signals triggered after CD3 crosslinking. Overall, our work shows that the new LAT negative J.CaM1.7 cell subline could represent a new model to study the functions of the tyrosine kinase Lck and the LAT adaptor in TCR signaling, and their mutual interaction, which seems to constitute an essential early signaling event associated with the TCR/CD3 complex.
Human Genetic Variation Influences Enteric Fever Progression
Authors: Ma Pei Yee , Tan Jing En , Hee Edd Wyn , Yong Dylan Wang Xi , Heng Yi Shuan , Low Wei Xiang , Wu Xun Hui , Cletus Christy , Kumar Chellappan Dinesh , Aung Kyan , Yong Chean Yeah , Liew Yun Khoon
Published: February 2021

In the 21st century, enteric fever is still causing a significant number of mortalities, especially in high-risk regions of the world. Genetic studies involving the genome and transcriptome have revealed a broad set of candidate genetic polymorphisms associated with susceptibility to and the severity of enteric fever. This review attempted to explain and discuss the past and the most recent findings on human genetic variants affecting the progression of Salmonella typhoidal species infection, particularly toll-like receptor (TLR) 4, TLR5, interleukin (IL-) 4, natural resistance-associated macrophage protein 1 (NRAMP1), VAC14, PARK2/PACRG, cystic fibrosis transmembrane conductance regulator (CFTR), major-histocompatibility-complex (MHC) class II and class III. These polymorphisms on disease susceptibility or progression in patients could be related to multiple mechanisms in eliminating both intracellular and extracellular Salmonella typhoidal species. Here, we also highlighted the limitations in the studies reported, which led to inconclusive results in association studies. Nevertheless, the knowledge obtained through this review may shed some light on the development of risk prediction tools, novel therapies as well as strategies towards developing a personalised typhoid vaccine.
NOD2 Mutation-Associated Case with Blau Syndrome Triggered by BCG Vaccination
Authors: Arakawa Akiko , Kambe Naotomo , Nishikomori Ryuta , Tanabe Akiyo , Ueda Masamichi , Nishigori Chikako , Miyachi Yoshiki , Kanazawa Nobuo
Published: February 2021

We describe a patient who developed multiple granulomatous skin lesions after Bacille de Calmette et Guérin (BCG) vaccination without significant effect by topical corticosteroid, followed by painless cystic tumors on the bilateral knees and hands and inflammatory changes on ophthalmologic examination. A functional mutation in NOD2 was detected by a genetic analysis, and he was diagnosed as sporadic Blau syndrome. Since NOD2 acts as a sensor for the BCG component, it is possible that BCG vaccination may trigger granuloma formation in Blau syndrome patients with such genetic background.