bluuebunny/crossref_metadata_2025 huggingface dataset:
Proposal on Miniaturization of Distributed Sensing System Based on Optical Frequency Domain Reflectometry
Authors: Shishkin Victor , Tanaka Kenji , Murayama Hideaki
Published: October 2021

The main goal of our research is to develop an integrated photonics circuit for sensing system based on Optical Frequency Domain Reflectometry in order to reduce size, weight and cost of current system. In this work we designed, simulated and fabricated Michelson interferometer integrating components such as adiabatic splitter, loop back mirrors, grating couplers and waveguides on total area 150x410 μm of silicon-on-insulator chip. According to simulation results free spectral range of the interferometer is 0.55 nm. Manufacturing variability was taken into account by performing corner analysis.
Simulation Model for Project Duration Estimation with Parameters Extraction Method from Accumulated Data
Authors: Hiekata Kazuo , Wang Rujia , Mitsuyuki Taiga
Published: October 2021

A framework combining project simulation model with extracted uncertainty parameters from past data is proposed in this paper. In the existing simulation models which take uncertainty elements into consideration, a large number of input parameters are requested. However, most of these parameters are difficult or time-consuming to state. The aim of this paper is to provide a possible solution proposing a new simulation model based on extracted parameters and setting up a protocol to extract uncertainty parameters from past log data. The output of the simulation model will be the project duration, giving feedback to the design of human resource. The proposed protocol includes a definition of necessary past data and how to calculate minimum work amount, delay probability and rework probability. On the other hand, the proposed simulation model includes basic model describing project structures such as task dependency and resource skills, delay model describing variation of task work amount, and rework model describing transition among different tasks. Besides, in the case study, we test the program of the proposed framework constructed of the parameter extracting protocol and the simulation model. After that, we apply the framework on a project introduced in existing research. Two human resource strategies are considered of, on the basis of the duration estimation results. The conclusion of this study is that the proposed framework is able to conduct duration estimation and support the decision-making process around human resource at the early stage of a project.
Apply Machine Learning to Improve Fault Detection and Classification in Cyber Physical System
Authors: Tsai Chien-De , Chiu Ming-Chuan
Published: October 2021

Cyber Physical System (CPS) is one of the key technologies of industry 4.0. CPS is an integrated system that combines computing, sensors and actuators. CPS is controlled by computer-based algorithms that integrates people and internet. However, the performance of CPS is limited by its computational complexity. How to implement CPS with less computational complexity in a real time performance remains an important issue. Therefore, the study attempts to establish a CPS based on machine learning to reduce its complexity and improve applicability. This study applies a Fault Detection and Classification system (FDC) with machine learning method in the virtual subsystem of CPS. This study consists of two steps. Based on the data collected from sensors of CPS, Random Forest (RF) is used to figure out key factors that reduces the data dimension for less computational complexity. The process engineers will know which factors are causing the machine fails. The second step is to establish a time series model which bases on Long Short-Term Memory (LSTM) network to achieve real time monitoring of the machine. Before the machine fails, FDC will alarm that allow the engineer to adjust parameters of machines to avoid machine fails. The study in order to achieve the goals of predicting machines fails, figuring out key factors, predicting maintenance and increasing the productivity.
SIMULATION OF THE ROTATIVE-TRANSLATIVE MOTION OF THE DUMBBELL, WHEN THE CENTER OF ITS MASS MOVES IN A CIRCLE
Authors: Leonid Kutsenko  , Andrii Kalynovskyi  , Oleksandr Polivanov  , Andrii Cherniavskyi  , Leonid Zapolskyi
Published: October 2021

A geometric model of the rotational-translational motion of a dumbbell in a central force field is proposed, provided that its center of mass moves in a circle of a given radius. The term dumbbell denotes a geometric object with two masses spaced apart at a certain distance, connected by a weightless rod (like a sports dumbbell). The idea of modeling is based on the compilation and solution of a system of Lagrange differential equations of the second kind. To compose the equations, the Lagrangian was used to describe the rotational-translational motion of a dumbbell in a central force field. The system of equations is formed with respect to five functions denoting five generalized coordinates. These coordinates connect the fixed and mobile coordinate systems that provide the rotational-translational movement of the dumbbell. The system of Lagrange differential equations of the second kind was solved numerically in the environment of the maple mathematical processor. The results obtained correspond to each of five different coordinate functions that can be plotted graphically. Also obtained are approximate descriptions of the derivatives of these functions depending on the parameters of the dumbbell and the initial conditions of its motion. These results made it possible to construct graphs of phase trajectories of functions of five coordinate coordinates, with the help of which it is possible to determine the nature of the dumbbell movement. The obtained time dependences for the functions of generalized coordinates make it possible to compose an algorithm for computer animation of the rotational-translational motion of the dumbbell. In this case, the parameters of the dumbbell and the initial conditions of its movement will be taken into account. Examples of modeling the trajectories of the centers of mass of the dumbbell weights are given.      It is advisable to use the results obtained to illustrate the position of the dumbbell in space when studying its orbital dynamics. Computer animations of a dumbbell movement in zero gravity will make it possible to analyze the influence of the angular velocities of rotation on its movement. At this stage of research, it is advisable to use the results obtained as the basis for laboratory or coursework of the departments of geometric modeling and computer graphics.
The yuraq haku, or plain mantle: A long tradition of north-central Perú
Authors: del Solar María Elena , Jara Crestina
Published: October 2021

The haku is a shawl indispensable for depicting the lives of women and men in several districts of the department of Hunuco, in north central Peru. It is used daily in rural tasks and domestic life, and it shines during public festivals as a clear representation of local identity. The skill of the spinners in achieving an exceptionally fine yarn makes the serene beauty of these handsome cloths of a single, even color stand out. Almost transparent, the four-selvage cloth is woven on a backstrap loom of native cotton or of sheep’s wool diverse in hue. The mark of the presence of Spanish obrajes in this region can be observed in tools and practices which, however, do not discard older technological traditions based in ancestral logics. The long history of textile production in the Andes still poses interesting questions. We look more closely to discern aspects of technological knowledge and design. In addition, we examine the significance of practices and functions of contemporary rituality, which provide rich information regarding the modification of socio-cultural contexts.

Today, the weaving community is experiencing new demands which give a new life to the mantle, symbolizing their identity to an outside consumer. This contributes to both spiritual and material satisfaction, confirming the space of their cultural values as a fundamental resource.
Ansiedad, depresión y estrés laboral asistencial en personal sanitario de un hospital de psiquiatría
Authors: Gómez Francisco Laura Alin , Ocampo Marín Santiago , Montoya Narváez Diana Elizabeth , Valtierra Contreras Carmen Guadalupe , Rentería Hernández Fabián Leonel , Vázquez Rincón Martha Anahí , Reyna García Aurora Saraí , Rodríguez Nava Víctor Federico
Published: October 2021

Introducción: El ambiente hospitalario de la salud mental requiere una especial atención por la prevalencia de cifras entorno al estrés laboral asistencial, sus principales consecuencias son: trastornos psicológicos (ansiedad-depresión), es necesario conocerse el estado mental de todas las profesiones. Objetivo: Establecer la fuerza de relación entre la ansiedad, depresión y estrés laboral asistencial en personal sanitario de un hospital de psiquiatría. Materiales y métodos: Se trata de una investigación con diseño no experimental, relacional, transversal y prospectivo, límites de espacio y tiempo en un hospital de psiquiatría Aguascalientes, en el año 2020. Resultados: Sobre un total de 86 participantes, la prevalencia fue de 2.3% en ansiedad severa, el 5.8% con menos que depresión mayor y el 3.5% con un estrés laboral asistencial alto; se correlacionaron las variables: depresión y estrés laboral (rho=.22:p=0.01), depresión y agotamiento emocional (rho=.569:p=0.00), depresión y despersonalización (rho=.407:p=0.00), depresión y realización personal (p=0.19), ansiedad y estrés laboral (r=.351:p=0.00), ansiedad y agotamiento emocional (rho=.483:p=0.00), ansiedad y despersonalización (rho=.30:p=0.00), ansiedad y realización personal (rho=-,247:p=0.01). Conclusión: A pesar de que en el hospital de psiquiatría se dé la prestación de acudir a terapia psicológica como método de desintoxicación por el trabajo, existe un nivel de estrés laboral del 36% bajo y 60.5% moderado, áreas que desencadenan falta de contacto con la realidad, baja realización en tareas laborales, auto concepto negativo y distanciamiento de actividades familiares/sociales. Existe una negación entorno a su propia salud mental, es necesario que se implemente un programa interno de atención hacia el personal sanitario.
Тrends and prospects of meat market development in Ukraine
Authors: Mamchur Liudmyla
Published: October 2021

The purpose of the article is to analyse the main performance indicators of the functioning and development of the meat market and to assess the prospects for its development, from the standpoint of providing it with raw meat. The research uses the following methods: analysis and synthesis, analytical generalizations, graphic - in the analysis of the meat market; balance - in determining the market equilibrium of supply and demand, their changes and interactions, statistical, extrapolation, design, mathematical modelling, decomposition of the time series - in forecasting the development of the meat market. The main trends and features of the functioning and development of the meat market are determined, based on the analysis of component indicators, a slight but still increase in the total supply of meat and meat products, by increasing its own meat production by 5.2% which ensured an increase in domestic demand. Based on the current balance of supply and demand of meat and meat products in Ukraine as indicators of market efficiency, the level of consumer security of meat consumption in Ukraine is determined, and it is established that the level of income is the basic condition for consumption growth. In the framework of this study using the method of exponential smoothing with a damped trend, the calculation of forecast indicators of the balance of supply and demand of meat and meat products in Ukraine. Methodological approaches to forecasting the meat market have been further developed. The results of the study can be used by experts to assess the level of development of the meat market, government officials in choosing areas of regional and public policy, researchers to expand the scope of research.
Factores relacionados con los eventos adversos en enfermería
Authors: Heredia Barreto Sandy , Veloza Morales Martha Cecilia
Published: October 2021

Con el objetivo de identificar los factores relacionados con el evento adverso en enfermería, se realizó una investigación documental con enfoque cualitativo, presentando los hallazgos mediante una descripción narrativa. De la búsqueda en diferentes bases de datos se seleccionaron 24 artículos científicos que relacionaban diferentes factores con los eventos en enfermería, eventos adversos registrados, pacientes más vulnerables, y las intervenciones en presencia de un evento adverso. Se concluye que el reporte oportuno y la ejecución de buenas prácticas en seguridad del paciente son elementos claves para planes de mejora con el propósito de prevenir, minimizar y erradicar los eventos adversos, en donde juega un papel fundamental la enfermera(o).
Correlations and canonical variables applied to the distinction of soybean cultivars in a tropical environment
Authors: Ferreira Luiz Leonardo , Silva Ângelo José , Carvalho Ivan , Fernades Marilaine Sá , Lautenchleger Francine , Loro Murilo Vieira
Published: October 2021

The objective of this study was to evaluate the performance of soybean cultivars through their correlations and canonical variables in a tropical environment. The study was conducted in the municipality of Mineiros, GO, Brazil. The soil was classified as Quartzarenic Neosol (Entisol). The experimental design used was in randomized blocks consisting of 10 soybean cultivars (Bônus, Desafio, Flecha, Foco, ICS7019, M5917, M7110, Power, ST721 and ST797) in four replications. Before planting, pre-planting desiccation was performed. The fertilizer used was 450 kg ha-1 of fertilizer 05-25-15 applied in the furrow and in a single dose next to the seeding. During the conduct of the experiment, pest control was carried out respecting good practices and integrated management. At the end of the cycle of each cultivar, 10 plants were collected at random and then the agronomic attributes were taken. The data obtained were submitted to the assumptions of the statistical model, verifying the normality and homogeneity of the residual variances, as well as the additivity of the model. Univariate and multivariate models were used. The analyzes were performed on the Rbio and R interface, in addition to the Software Genes. According to the summary of analysis of variance, it was observed that all cultivars differed for all characteristics. It was concluded that the soybean cultivars Flecha and M5917 presented the highest yields among the others in a tropical environment; the cultivars differed, showing a strong correlation between the number of grains per plant and yield, with the other variables analyzed; the univariate and multivariate tools were efficient and complementary in data analysis.
Вплив регуляторів росту рослин на ріст і масу сіянців дуба звичайного у Південно-східному Лісостепу України
Authors: Danylenko O. M. , Vysotska N. Yu. , Tarnopilsky P. B. , Rumiantsev M. Н.
Published: October 2021

Наведено результати досліджень впливу регуляторів росту рослин на біометричні показники та масу однорічних сіянців дуба звичайного (Quercus robur L.) із закритою кореневою системою. Сіянці вирощено в контейнерах із агроволокна в умовах відкритого ґрунту. Виявлено, що під час передвисівної обробки жолудів найефективнішими є варіанти застосування «Агростимуліну» у концентрації 8 мл·л-1, «Чаркору» – 4 мл·л-1 та «Триману-1» – 150 мг·л-1. Найбільший позитивний вплив на біометричні показники та масу однорічних сіянців під час вирощування (трикратне підживлювання сіянців регуляторами росту рослин упродовж вегетаційного періоду) відзначено у варіантах, де застосовували «Мегафол» у концентрації 1 мл·л-1 та «Радіфарм» – 2,5 мл·л-1. Результати проведених досліджень свідчать про доцільність застосування досліджуваних регуляторів росту рослин під час вирощування сіянців дуба звичайного із закритою кореневою системою в умовах відкритого ґрунту та подальшого їхнього використання під час лісовідновлення й лісорозведення в Південно-східному Лісостепу України.
Intellectual property rights in research and development collaboration/ contract agreements between research institutions, universities and firms: part 1 — European Union, US
Authors: Kapitsa Yurii
Published: October 2021

Keywords: research and development contracts, research and development collaborationagreements, intellectual property rights, research organisations, universities

The practice of regulating intellectualproperty relations in R&D cooperation agreements / R&D contracts between researchinstitutions, universities (academic institutions) and companies in the EU, USA, aswell as in the recommendations of international organizations is studied.It is noted the significant role given in the EU, the USA to the settlement of IP issuesin R&D agreements. It is shown, that the development of model agreements inthe United States is carried out mainly at the university level. In the EU it is significantthe role of the European Commission, national government bodies in the developmentof the agreements.The principal provisions of IP regime in the R&D agreements are noted, which include:identification of Background IP and New IP. Granting Background IP rightsusually on the basis of a non-exclusive royalty license. Consolidation of New IP rightsfor academic institutions. Granting New IP rights on royalty-based licences or paidtransfer of rights.It is noted the importance of possibility of restitution of IP property rights to academicinstitution if the company does not commercialize the granted IP. Also, of the assignmentof IP rights to academic institutions for research and training purposes incases of granting exclusive licenses and transferring property rights.The principles of distribution of intellectual property rights and use of research resultsin R&D agreements are determined, which should be applied in the practice ofconcluding corresponding agreements in Ukraine. Amendments to the Law ofUkraine “On Scientific and Scientific-Technical Activity” are proposed to provide forthe indication of the types of R&D agreements, as well as the principles of using IP inagreements.
Platelets in Wound Healing: What Happens in Space?
Authors: Locatelli Laura , Colciago Alessandra , Castiglioni Sara , Maier Jeanette A.
Published: October 2021

Beyond their fundamental role in hemostasis, platelets importantly contribute to other processes aimed at maintaining homeostasis. Indeed, platelets are a natural source of growth factors and also release many other substances—such as fibronectin, vitronectin, sphingosine 1-phosphate—that are important in maintaining healthy tissues, and ensuring regeneration and repair. Despite rare thrombotic events have been documented in astronauts, somein vivoandin vitrostudies demonstrate that microgravity affects platelet’s number and function, thus increasing the risk of hemorrhages and contributing to retard wound healing. Here we provide an overview about events linking platelets to the impairment of wound healing in space, also considering, besides weightlessness, exposure to radiation and psychological stress. In the end we discuss the possibility of utilizing platelet rich plasma as a tool to treat skin injuries eventually occurring during space missions.
Manifesto for Digital Social Touch in Crisis
Authors: Jewitt Carey , Price Sara , Steimle Jürgen , Huisman Gijs , Golmohammadi Lili , Pourjafarian Narges , Frier William , Howard Thomas , Ipakchian Askari Sima , Ornati Michela , Panëels Sabrina , Weda Judith
Published: October 2021

This qualitative exploratory research paper presents a Manifesto for Digital Social Touch in Crisis - a provocative call to action to designers, developers and researchers to rethink and reimagine social touch through a deeper engagement with the social and sensory aspects of touch. This call is motivated by concerns that social touch is in a crisis signaled by a decline in social touch over the past 2 decades, the problematics of inappropriate social touch, and the well documented impact of a lack of social touch on communication, relationships, and well-being and health. These concerns shape how social touch enters the digital realm and raise questions for how and when the complex space of social touch is mediated by technologies, as well the societal implications. The paper situates the manifesto in the key challenges facing haptic designers and developers identified through a series of interdisciplinary collaborative workshops with participants from computer science, design, engineering, HCI and social science from both within industry and academia, and the research literature on haptics. The features and purpose of the manifesto form are described, along with our rationale for its use, and the method of the manifesto development. The starting points, opportunities and challenges, dominant themes and tensions that shaped the manifesto statements are then elaborated on. The paper shows the potential of the manifesto form to bridge between HCI, computer science and engineers, and social scientists on the topic of social touch.
Hypertrophic Cardiomyopathy: From Phenotype and Pathogenesis to Treatment
Authors: Cheng Zeyi , Fang Tingting , Huang Jinglei , Guo Yingqiang , Alam Mahboob , Qian Hong
Published: October 2021

Hypertrophic cardiomyopathy (HCM) is a very common inherited cardiovascular disease (CAD) and the incidence is about 1/500 of the common population. It is caused by more than 1,400 mutations in 11 or more genes encoding the proteins of the cardiac sarcomere. HCM presents a heterogeneous clinical profile and complex pathophysiology and HCM is the most important cause of sudden cardiac death (SCD) in young people. HCM also contributes to functional disability from heart failure and stroke (caused by atrial fibrillation). Current treatments for HCM (medication, myectomy, and alcohol septal ablation) are geared toward slowing down the disease progression and symptom relief and implanted cardiac defibrillator (ICD) to prevent SCD. HCM is, however, entering a period of tight translational research that holds promise for the major advances in disease-specific therapy. Main insights into the genetic landscape of HCM have improved our understanding of molecular pathogenesis and pointed the potential targets for the development of therapeutic agents. We reviewed the critical discoveries about the treatments, mechanism of HCM, and their implications for future research.
Malnutrition and Risk of Procedural Complications in Patients With Atrial Fibrillation Undergoing Catheter Ablation
Authors: Kim Daehoon , Shim Jaemin , Kim Yun Gi , Yu Hee Tae , Kim Tae-Hoon , Uhm Jae-Sun , Choi Jong-Il , Joung Boyoung , Lee Moon-Hyoung , Kim Young-Hoon , Pak Hui-Nam
Published: October 2021

Background: Little is known about the prognostic value of nutritional status among patients undergoing atrial fibrillation (AF) catheter ablation (AFCA). We compared the risk of procedure-related complications and long-term rhythm outcomes of AFCA according to nutritional status.

Methods: We included 3,239 patients undergoing de novo AFCA in 2009-2020. Nutritional status was assessed using the controlling nutritional status (CONUT) score. The association between malnutrition and the risk of AFCA complications or long-term rhythm outcomes was evaluated. We validated the effects of malnutrition using an external cohort of 360 patients undergoing AFCA in 2013-2016.

Results: In the study population (26.8% women, median age: 58 years), 1,005 (31.0%) had malnutrition (CONUT scores ≥ 2); 991 (30.6%) had mild (CONUT 2–4) and 14 (0.4%) had moderate-to-severe (CONUT ≥ 5) malnutrition. The overall complication rates after AFCA were 3.3% for normal nutrition, 4.2% for mild malnutrition, and 21.4% for moderate-to-severe malnutrition. Moderate-to-severe malnutrition [odds ratio (OR) 6.456, 95% confidence interval (CI) 1.637-25.463, compared with normal nutrition], older age (OR 1.020 per 1-year increase, 95% CI 1.001-1.039), female sex (OR 1.915, 95% CI 1.302-2.817), and higher systolic blood pressure (OR 1.013 per 1-mmHg increase, 95% CI 1.000-1.026) were independent predictors for the occurrence of complications. In the validation cohort, malnutrition (CONUT ≥ 2) was associated with a 2.87-fold higher risk of AFCA complications (95% CI 1.174-7.033). The association between malnutrition and a higher risk of AFCA complications was consistently observed regardless of body mass index and sex. Malnutrition did not affect rhythm outcomes during the median follow-up of 40 months (clinical recurrence: 37.0% in normal nutrition vs. 36.5% in malnutrition).

Conclusion: Malnutrition, which is common in patients undergoing AFCA, was associated with a substantially higher risk for complications after AFCA.
A Multi-Gene Region Targeted Capture Approach to Detect Plant DNA in Environmental Samples: A Case Study From Coastal Environments
Authors: Foster Nicole R. , van Dijk Kor-jent , Biffin Ed , Young Jennifer M. , Thomson Vicki A. , Gillanders Bronwyn M. , Jones Alice R. , Waycott Michelle
Published: October 2021

Metabarcoding of plant DNA recovered from environmental samples, termed environmental DNA (eDNA), has been used to detect invasive species, track biodiversity changes, and reconstruct past ecosystems. The P6 loop of the trnL intron is the most widely utilised gene region for metabarcoding plants due to the short fragment length and subsequent ease of recovery from degraded DNA, which is characteristic of environmental samples. However, the taxonomic resolution for this gene region is limited, often precluding species level identification. Additionally, targeting gene regions using universal primers can bias results as some taxa will amplify more effectively than others. To increase the ability of DNA metabarcoding to better resolve flowering plant species (angiosperms) within environmental samples, and reduce bias in amplification, we developed a multi-gene targeted capture method that simultaneously targets 20 chloroplast gene regions in a single assay across all flowering plant species. Using this approach, we effectively recovered multiple chloroplast gene regions for three species within artificial DNA mixtures down to 0.001 ng/μL of DNA. We tested the detection level of this approach, successfully recovering target genes for 10 flowering plant species. Finally, we applied this approach to sediment samples containing unknown compositions of eDNA and confidently detected plant species that were later verified with observation data. Targeting multiple chloroplast gene regions in environmental samples, enabled species-level information to be recovered from complex DNA mixtures. Thus, the method developed here, confers an improved level of data on community composition, which can be used to better understand flowering plant assemblages in environmental samples.
The Clinical Significance and Immunization of MSMO1 in Cervical Squamous Cell Carcinoma Based on Bioinformatics Analysis
Authors: Zheng Guangfei , Wang Zhuan , Fan Yuchun , Wang Tian , Zhang Linli , Wang Mengling , Chen Su , Jiang Lihe
Published: October 2021

Objective: The genetic markers for the detection or treatment of cervical squamous cell carcinoma (CESC) are not yet complete. This study aimed to identify the role of MSMO1 (Alternative name: SC4MOL) in the occurrence and development of CESC.

Methods: We evaluated the significance of MSMO1 expression in CESC by using analysis of a public dataset from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Oncomine and GEPIA2 were used to validate MSMO1 as an independent prognostic factor in CESC. Multiple tools were used to analyze the factors and functions associated with MSMO1, such as methylation, miRNA, and co-expressed genes. Furthermore, TIMER and TISIDB were used to study the relationship between MSMO1 expression and immunization in CESC.

Results: MSMO1 was highly expressed in tumor specimens and could be used as an independent prognostic factor of CESC (p < 0.05). But Casiopeinas chemotherapeutics and p63 loss could reduce the expression of MSMO1. The level of methylation MSMO1 was significantly increased in tumor tissues but there was an insignificant effect on the prognosis. MSMO1 was also closely related to hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-130b-3p, and gene IDI1. Specifically, the expression level of MSMO1 had a significant negative correlation with the infiltration level of CD4+T cells, Macrophages, Neutrophils, and DCs in CESC. In addition, GSEA identified differential enrichment in systemic lupus erythematosus, vascular smooth muscle contraction, cytokine receptor interaction, focal adhesion, chemokine signaling pathway, and Leishmania infection pathway in KEGG.

Conclusion: Our findings provide evidence of the implications of MSMO1 in tumors, suggesting that MSMO1 is a promising prognostic biomarker in CESC.
Fc Binding by FcγRIIa Is Essential for Cellular Activation by the Anti-FcγRIIa mAbs 8.26 and 8.2
Authors: Wines Bruce D. , Trist Halina M. , Esparon Sandra , Impey Rachael E. , Mackay Graham A. , Andrews Robert K. , Soares da Costa Tatiana P. , Pietersz Geoffrey A. , Baker Ross I. , Hogarth P. Mark
Published: October 2021

FcγR activity underpins the role of antibodies in both protective immunity and auto-immunity and importantly, the therapeutic activity of many monoclonal antibody therapies. Some monoclonal anti-FcγR antibodies activate their receptors, but the properties required for cell activation are not well defined. Here we examined activation of the most widely expressed human FcγR; FcγRIIa, by two non-blocking, mAbs, 8.26 and 8.2. Crosslinking of FcγRIIa by the mAb F(ab’)2regions alone was insufficient for activation, indicating activation also required receptor engagement by the Fc region. Similarly, when mutant receptors were inactivated in the Fc binding site, so that intact mAb was only able to engage receptorsviaits two Fab regions, again activation did not occur. Mutation of FcγRIIa in the epitope recognized by the agonist mAbs, completely abrogated the activity of mAb 8.26, but mAb 8.2 activity was only partially inhibited indicating differences in receptor recognition by these mAbs. FcγRIIa inactivated in the Fc binding site was next co-expressed with the FcγRIIa mutated in the epitope recognized by the Fab so that each mAb 8.26 molecule can contribute only three interactions, each with separate receptors, oneviathe Fc and twoviathe Fab regions. When the Fab and Fc binding were thus segregated onto different receptor molecules receptor activation by intact mAb did not occur. Thus, receptor activation requires mAb 8.26 Fab and Fc interaction simultaneously with the same receptor molecules. Establishing the molecular nature of FcγR engagement required for cell activation may inform the optimal design of therapeutic mAbs.
Clinical Immunogenicity Evaluation of Eptinezumab, a Therapeutic Humanized Monoclonal Antibody Targeting Calcitonin Gene-Related Peptide (CGRP) for the Preventive Treatment of Migraine
Authors: Pederson Susan , Biondi David M. , Allan Brent , Cady Roger , Schaeffler Barbara , Baker Brian , Latham John
Published: October 2021

Background

Eptinezumab is a humanized monoclonal antibody that selectively binds calcitonin gene-related peptide and is indicated for the preventive treatment of migraine in adults. This analysis characterizes the immunogenic profile of eptinezumab using data from clinical trials of eptinezumab for migraine prevention.

Methods

Immunogenicity data were collected from five studies that included 2076 patients with episodic or chronic migraine treated with eptinezumab at dose levels ranging from 10 to 1000 mg, administered intravenously for up to 4 doses at 12-week intervals. Anti-drug antibody (ADA) results were available from 2074 of these patients. Four studies were randomized, double-blind, placebo-controlled trials with ADA monitoring for up to 56 weeks; one was a 2-year, open-label, phase 3 safety study with ADA monitoring for 104 weeks. Patients who had a confirmed ADA-positive result at the end-of-study visit were monitored for up to 6 additional months. Development of ADA and neutralizing antibodies (NAbs) were evaluated to explore three key areas of potential impact: pharmacokinetic exposure profile (eptinezumab trough plasma concentrations), efficacy (change in monthly migraine days), and safety (rates of treatment-emergent adverse events). These studies included methods designed to capture the dynamics of a potential humoral immune response to eptinezumab treatment, and descriptive analyses were applied to interpret the relationship of ADA signals to drug exposure, efficacy, and safety.

Results

Pooled across the five clinical trials, treatment-emergent ADAs and NAbs occurred in 15.8 and 6.2% of eptinezumab-treated patients, respectively. Highly consistent profiles were observed across all studies, with initial onset of detectable ADA observed at the week 8 measurement and maximal ADA frequency and titer observed at week 24, regardless of eptinezumab dose level or number of doses. After 24 weeks, the ADA and NAb titers steadily declined despite additional doses of eptinezumab.

Interpretation

Collectively, these integrated analyses did not demonstrate any clinically meaningful impact from ADA occurring after treatment with eptinezumab. The ADA profiles were low titer and transient, with the incidence and magnitude of ADA or NAb responses declining after week 24. Development of ADAs and NAbs did not impact the efficacy and safety profiles of eptinezumab.
Verification of TRI3 Acetylation of Trichodermol to Trichodermin in the Plant Endophyte Trichoderma taxi
Authors: Chen Haijiang , Mao Lijuan , Zhao Nan , Xia Chenyang , Liu Jian , Kubicek Christian P. , Wu Wenneng , Xu Su , Zhang Chulong
Published: October 2021

Trichodermin, a trichothecene first isolated inTrichodermaspecies, is a sesquiterpenoid antibiotic that exhibits significant inhibitory activity to the growth of many pathogenic fungi such asCandida albicans,Rhizoctonia solani, andBotrytis cinereaby inhibiting the peptidyl transferase involved in eukaryotic protein synthesis. Trichodermin has also been shown to selectively induce cell apoptosis in several cancer cell lines and thus can act as a potential lead compound for developing anticancer therapeutics. The biosynthetic pathway of trichodermin inTrichodermahas been identified, and most of the involved genes have been functionally characterized. An exception isTRI3, which encodes a putative acetyltransferase. Here, we report the identification of a gene cluster that contains seven genes expectedly involved in trichodermin biosynthesis (TRI3,TRI4,TRI6,TRI10,TRI11,TRI12, andTRI14) in the trichodermin-producing endophytic fungusTrichoderma taxi. As inTrichoderma brevicompactum,TRI5is not included in the cluster. Functional analysis provides evidence that TRI3 acetylates trichodermol, the immediate precursor, to trichodermin. Disruption ofTRI3gene eliminated the inhibition toR. solanibyT. taxiculture filtrates and significantly reduced the production of trichodermin but not of trichodermol. Both the inhibitory activity and the trichodermin production were restored when nativeTRI3gene was reintroduced into the disruption mutant. Furthermore, a His-tag-purified TRI3 protein, expressed inEscherichia coli, was able to convert trichodermol to trichodermin in the presence of acetyl-CoA. The disruption ofTRI3also resulted in lowered expression of both the upstream biosynthesisTRIgenes and the regulator genes. Our data demonstrate thatT. taxi TRI3encodes an acetyltransferase that catalyzes the esterification of the C-4 oxygen atom on trichodermol and thus plays an essential role in trichodermin biosynthesis in this fungus.
DNA Dye Sytox Green in Detection of Bacteriolytic Activity: High Speed, Precision and Sensitivity Demonstrated With Endolysins
Authors: Harhala Marek , Gembara Katarzyna , Miernikiewicz Paulina , Owczarek Barbara , Kaźmierczak Zuzanna , Majewska Joanna , Nelson Daniel C. , Dąbrowska Krystyna
Published: October 2021

Introduction: Increasing number of deaths from multi-drug resistant bacterial infections has caused both the World Health Organization and the Centers for Disease Control and Prevention to repeatedly call for development of new, non-traditional antibacterial treatments. Antimicrobial enzymes, including those derived from bacteriophages, known as endolysins or enzybiotics, are considered promising solutions among the emerging therapies. These naturally occurring proteins specifically destroy bacterial cell walls (peptidoglycan) and as such, are capable of killing several logs of bacteria within minutes. Some endolysins cause lysis of a wide range of susceptible bacteria, including both Gram-positive and Gram-negative organisms, whereas other endolysins are species- or even strain-specific. To make wide use of endolysins as antibacterial agents, some basic research issues remain to be clarified or addressed. Currently available methods for testing endolysin kinetics are indirect, require large numbers of bacteria, long incubation times and are affected by technical problems or limited reproducibility. Also, available methods are focused more on enzymatic activity rather than killing efficiency which is more relevant from a medical perspective.

Results: We show a novel application of a DNA dye, SYTOX Green. It can be applied in comprehensive, real-time and rapid measurement of killing efficiency, lytic activity, and susceptibility of a bacterial population to lytic enzymes. Use of DNA dyes shows improved reaction times, higher sensitivity in low concentrations of bacteria, and independence of bacterial growth. Our data show high precision in lytic activity and enzyme efficiency measurements. This solution opens the way to the development of new, high throughput, precise measurements and tests in variety of conditions, thus unlocking new possibilities in development of novel antimicrobials and analysis of bacterial samples.
Construction of a ceRNA Network and Analysis of Tumor Immune Infiltration in Pancreatic Adenocarcinoma
Authors: Xiao Jingjing , Lv Chao , Xiao Chuan , Ma Jinyu , Liao Jun , Liu Tao , Du Jun , Zuo Shi , Li Haiyang , Gu Huajian
Published: October 2021

Pancreatic adenocarcinoma (PAAD) is characterized by high malignancy, frequent metastasis, and recurrence with an unfavorable prognosis. This study is aimed at constructing a prognostic model for tumor-infiltrating immune cells and a competing endogenous RNA (ceRNA) network in PAAD and analyzing susceptibilities of chemotherapy and immunotherapy of PAAD. Gene expression profiles and clinical information of PAAD were downloaded from The Cancer Genome Atlas (TCGA) database and divided into the tumor group and the normal group. A total of five PAAD survival-related key genes in the ceRNA network and three survival-related immune infiltrating cells were uncovered, and two survival risk models and nomograms were constructed. The efficiency and performance of the two models were verified using multi-index area under the curve analysis at different time points, decision curve analysis, and calibration curves. Co-expression analysis showed that LRRC1, MIR600HG, and RNF166 in the ceRNA network and tumor-infiltrating immune cells including CD8 T cells and M1 macrophages were likely related to the PAAD prognosis, and the expression of key ceRNA-related genes was experimently validated in tissues and cell lines by RT-qPCR. Patients with low risk scores for key genes in the ceRNA network displayed a positive response to anti-programmed death-1 (PD-1) treatment and greater sensitivity to chemotherapeutic drugs such as docetaxel, lapatinib, and paclitaxel. More importantly, our results suggested that the IC50 values of gemcitabine in PAAD were not significantly different between the high and low risk groups. The expression levels of immune checkpoints were significantly different in the high-risk and low-risk groups. The prognostic model, nomogram, and drug analysis may provide an essential reference for PAAD patient management in the clinic.
How do Chaperones Bind (Partly) Unfolded Client Proteins?
Authors: Sučec Iva , Bersch Beate , Schanda Paul
Published: October 2021

Molecular chaperones are central to cellular protein homeostasis. Dynamic disorder is a key feature of the complexes of molecular chaperones and their client proteins, and it facilitates the client release towards a folded state or the handover to downstream components. The dynamic nature also implies that a given chaperone can interact with many different client proteins, based on physico-chemical sequence properties rather than on structural complementarity of their (folded) 3D structure. Yet, the balance between this promiscuity and some degree of client specificity is poorly understood. Here, we review recent atomic-level descriptions of chaperones with client proteins, including chaperones in complex with intrinsically disordered proteins, with membrane-protein precursors, or partially folded client proteins. We focus hereby on chaperone-client interactions that are independent of ATP. The picture emerging from these studies highlights the importance of dynamics in these complexes, whereby several interaction types, not only hydrophobic ones, contribute to the complex formation. We discuss these features of chaperone-client complexes and possible factors that may contribute to this balance of promiscuity and specificity.
Improved Motion Classification With an Integrated Multimodal Exoskeleton Interface
Authors: Langlois Kevin , Geeroms Joost , Van De Velde Gabriel , Rodriguez-Guerrero Carlos , Verstraten Tom , Vanderborght Bram , Lefeber Dirk
Published: October 2021

Human motion intention detection is an essential part of the control of upper-body exoskeletons. While surface electromyography (sEMG)-based systems may be able to provide anticipatory control, they typically require exact placement of the electrodes on the muscle bodies which limits the practical use and donning of the technology. In this study, we propose a novel physical interface for exoskeletons with integrated sEMG- and pressure sensors. The sensors are 3D-printed with flexible, conductive materials and allow multi-modal information to be obtained during operation. A K-Nearest Neighbours classifier is implemented in an off-line manner to detect reaching movements and lifting tasks that represent daily activities of industrial workers. The performance of the classifier is validated through repeated experiments and compared to a unimodal EMG-based classifier. The results indicate that excellent prediction performance can be obtained, even with a minimal amount of sEMG electrodes and without specific placement of the electrode.
Long Noncoding Competing Endogenous RNA Networks in Pancreatic Cancer
Authors: Xiong Guangbing , Pan Shutao , Jin Jikuan , Wang Xiaoxiang , He Ruizhi , Peng Feng , Li Xu , Wang Min , Zheng Jianwei , Zhu Feng , Qin Renyi
Published: October 2021

Pancreatic cancer (PC) is a highly malignant disease characterized by insidious onset, rapid progress, and poor therapeutic effects. The molecular mechanisms associated with PC initiation and progression are largely insufficient, hampering the exploitation of novel diagnostic biomarkers and development of efficient therapeutic strategies. Emerging evidence recently reveals that noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs) and microRNAs (miRNAs), extensively participate in PC pathogenesis. Specifically, lncRNAs can function as competing endogenous RNAs (ceRNAs), competitively sequestering miRNAs, therefore modulating the expression levels of their downstream target genes. Such complex lncRNA/miRNA/mRNA networks, namely, ceRNA networks, play crucial roles in the biological processes of PC by regulating cell growth and survival, epithelial–mesenchymal transition and metastasis, cancer stem cell maintenance, metabolism, autophagy, chemoresistance, and angiogenesis. In this review, the emerging knowledge on the lncRNA-associated ceRNA networks involved in PC initiation and progression will be summarized, and the potentials of the competitive crosstalk as diagnostic, prognostic, and therapeutic targets will be comprehensively discussed.
Psychosocial and Neurobiological Vulnerabilities of the Hospitalized Preterm Infant and Relevant Non-pharmacological Pain Mitigation Strategies
Authors: Shiff Ilana , Bucsea Oana , Pillai Riddell Rebecca
Published: October 2021

Background:Preterm pain is common in the Neonatal Intensive Care Unit (NICU), with multiple invasive procedures occurring daily.

Objective:To review the psychosocial and neurobiological vulnerabilities of preterm infants and to provide an updated overview of non-pharmacological strategies for acute procedural pain in hospitalized preterm infants.

Methods:We utilized a narrative review methodology, which also included a synthesis of key pieces of published systematic reviews that are relevant to the current work.

Results and Conclusions:Preterm infants are uniquely susceptible to the impact of painful procedures and prolonged separation from caregivers that are often inherent in a NICU stay. Non-pharmacological interventions can be efficacious for mitigating procedural pain for preterm infants. Interventions should continue to be evaluated with high quality randomized controlled trials, and should endeavor to take into account the neurobiological and psychosocial aspects of preterm vulnerability for pain prevention and management strategies.
Concentration-Dependent Decitabine Effects on Primary NK Cells Viability, Phenotype, and Function in the Absence of Obvious NK Cells Proliferation–Original Article
Authors: Li Xiang , Zhang Min , Cai Sisi , Wu Yaohui , You Yong , Wang Xianghong , Wang Li
Published: October 2021

Acute myeloid leukemia (AML) cells can evade innate immune killing by modulating natural killer (NK) cells receptors and their cognate ligands in tumor cells, thus it may be possible to restore proper expression of immune receptors or ligands with immune sensitive drugs. Decitabine, as a hypomethylation agent, was approved for the treatment of AML and myelodysplastic syndrome. While clinical responses were contributed by epigenetic effects and the induction of cancer cell apoptosis, decitabine also has immune-mediated anti-tumor effects. After exposure to various concentration of decitabine for 24 h, the primary NK cells (AML-NK cells) cytotoxicity and receptor expression (NKG2D and NKp46) displayed parabola-shaped response, while U-shaped response was seen in cytokine release (IFN-γ and IL-10), and these effects were regulated by ERK and STAT3 phosphorylation level. Furthermore, AML-NK cells function displayed different response when the competitive MEK and STAT3 inhibitors applied respectively. Thus, we could conclude that the different dose of decitabine makes various effects on AML-NK cells function and receptors expression.