bluuebunny/crossref_metadata_2025 huggingface dataset:
Legal aspects of usage out-of-commerce works by libraries and other institutions
Authors: Trotska Valentyna
Published: July 2021

Keywords: copyright; out-of-commerce works; cultural heritage institutions; exceptionsand limitation; representative organizations of collective management

The article is devoted to the study of the norms of Directive2019/790 of the European Parliament and of the Council on copyright and relatedrights in the Digital Single Market, such as provisions on the permitted use of worksout-of-commercial circulation, that are permanently in the collections of libraries andothers cultural heritage institutions. The norms of this EU Directive, as well as theprovisions defined in the laws of some European countries, are analyzed in detail.The main provisions of the EU Directive are considered, which provide for a doublemechanism of permitted use of works of cultural heritage institutions: main and reserve.The essence of each mechanism is considered in detail.The article also considers the question of when the rights holders have the right torefuse, meaning not to allow cultural heritage institutions to use out-of-commerce works.A comparison is made between the norms of the legislation of Ukraine on copyrightand related rights concerning the free use of works by libraries and other culturalheritage institutions and the relevant norms of European legislation. It is establishedthat in the legislation of Ukraine the list of institutions that have the right tofreely reproduce works is limited only to libraries and archives. Unlike the provisionsof the EU Directive, norms of national legislation do not apply to museums, film andaudio funds. However, free reproduction is allowed only by reprographic method (photocopying)of copies, which restrains the possibility of freeing reproduction (digitization)of works using modern digital technologies.It is concluded that classical norms of the legislation on copyright and relatedrights with the development of relations in the digital environment are changing.Legislators are constantly searching for optimal ways to balance public and privateinterests. Whether the new rules will be successful depends on how states implementthe rules of the EU Directive in state law and how they will be applied in practice.
Methodology of technology transfer in the field of intellectual property: economic and legal nature of the origin and definition of certain terms
Authors: Butnik-Siverskyi Oleksandr , Dorozhko Hryhorii
Published: July 2021

Keywords: the concept of «technology transfer», technology fields, local and basictechnologies, the object of transfer, contractual relations, intellectual property.

The article considers the methodology of technologytransfer from the point of economic and legal content in the field of intellectualproperty. It is noted that there is no single definition of technology transfer, as scientistsin various fields interpret it due to the peculiarities of their field of activity. Atthe general level, the field of technology is considered as the birth of technologies,their types and maturity, which are the objects of transfer, taking into account the peculiaritiesof state regulation in the field of transfer. It is in the field of technologythat an invention (utility model) is born, as a result of intellectual, creative human activity;that is, they associate this process with the material carriers of technologies, orthe intangible phenomenon becomes a material state. The transfer of technology is associatedwith the transition to technical means, technological processes, and computernetworks. It is considered from the point of law as a type of communication betweenbusiness entities on the basis of contractual relations. It is determined thatfrom the point of methodology of technologies and their components transfer, theissue of technologies origin and the nature of their creation require in-depth study,and that is important to indicate the author(s) (owner(s)) of the result of intellectual,creative activity in the field of intellectual property. The main goal of the technology can be achieved only if there is a quantitative assessment of the perfection of theprocess and product quality. Technology uses two types of models: ideal objects ofbasic sciences, on the basis of which the most general laws and regularities of naturalsciences are formulated, and ideal objects of technology itself, on the basis of whichmorphological descriptions of separate stages and functional descriptions of the structureof technological lines are made. New local technologies are the result of inventions,utility models in the field of technologies, which have a specific author(s) (inventor(s)) and which are the object of transfer. Amendments to the terms of Article 1of the Law of Ukraine «On State Regulation of Technology Transfer Activities».
Creative Natives in the Digital Age: How Digital Technology Has Revolutionized Creative Work
Authors: Kabanda Patrick
Published: July 2021

Digital technologies have permeated modern life, and their impact on creative work has been revolutionary. This revolution, as widely noted, has disrupted the making, distribution, and consumption of creative output. On the downside, key concerns include Internet-induced piracy and inequality. Yet digital technologies also accelerate opportunities. So, how can these opportunities be reaped to promote creative work for development? Suggestions here include closing the digital gender gap, promoting appropriate intellectual property rights, and providing digital literacy. More needs to be done to understand the benefits and limitations of digital technologies on creative work for human development.
PEMODELAN JEMBATAN RANGKA DENGAN KOMBINASI TIPE RANGKA DITINJAU DARI LENDUTAN DAN BERAT JEMBATAN
Authors: Al Ansyorie Mohammad Musthofa , Kirom Mustofa Mohammad Alfin , Firdaus Sabila Madih Tahtal , Putri Nadia Mulia
Published: July 2021

Abstract The frame bridge structure has several types of frames, each of which has advantages in accordance with its application. Several studies have shown that the comparison between one frame type and another has the advantage of different strengths. In this study an analysis will be carried out by modeling the modified bridge structure truss type and combined with other types to obtain a structure that has the best strengths. The method used in this study is to model the bridge structure with the help of SAP2000 v20 software. The analysis process in this modeling refers to SNI 1725: 2016 concerning load on bridges, BMS (Bridge Management System) in 1992, and several related regulations. The results of modeling analysis show that the K-truss frame is the best frame by looking at the aspect ratio of the bridge, namely the ratio between deflection and weight of each type. The combination of the K-truss frame type and the warren frame type is the best combination of frame types based on the best deflection and weight values. The deflection value for this type of frame combination is -0.416 mm and the ratio value is 6.017. Keywords: modeling, truss bridge, k-truss, combine
Swimming Activity of Gilthead Seabream (Sparus aurata) in Swim-Tunnels: Accelerations, Oxygen Consumption and Body Motion
Authors: Arechavala-Lopez Pablo , Lankheet Martin J. , Díaz-Gil Carlos , Abbink Wout , Palstra Arjan P.
Published: July 2021

Acoustic transmitters equipped with accelerometer sensors are considered a useful tool to study swimming activity, including energetics and movement patterns, of fish species in aquaculture and in nature. However, given the novelty of this technique, further laboratory-derived calibrations are needed to assess the characteristics and settings of accelerometer acoustic transmitters for different species and specific environmental conditions. In this study, we compared accelerometer acoustic transmitter outputs with swimming performance and body motion of gilthead seabream (Sparus aurata L.) in swim-tunnels at different flow speeds, which allowed us to characterize the swimming activity of this fish species of high aquaculture interest. Tag implantation in the abdominal cavity had no significant effects on swimming performance and body motion parameters. Accelerations, cost of transport and variations on head orientation (angle with respect to flow direction) were negatively related to flow speed in the tunnel, whereas oxygen consumption and frequencies of tail-beat and head movements increased with flow speed. These results show that accelerometer acoustic transmitters mainly recorded deviations from sustained swimming in the tunnel, due to spontaneous and explorative swimming at the lowest speeds or intermittent burst and coast actions to cope with water flow. In conclusion, accelerometer acoustic transmitters applied in this study provided a proxy for unsustained swimming activity, but did not contemplate the high-energy cost spent by gilthead seabream on sustained swimming, and therefore, it did not provide a proxy for general activity. Despite this limitation, accelerometer acoustic transmitters provide valuable insight in swim patterns and therefore may be a good strategy for advancing our understanding of fish swimming behavior in aquaculture, allowing for rapid detection of changes in species-specific behavioral patterns considered indicators of fish welfare status, and assisting in the refinement of best management practices.
Biomechanical Identification of High-Risk Patients Requiring Permanent Pacemaker After Transcatheter Aortic Valve Replacement
Authors: Zhang Guangming , Liu Rong , Pu Min , Zhou Xiaobo
Published: July 2021

Background

Cardiac conduction disturbance requiring new permanent pacemaker implantation (PPI) is an important complication of TAVR that has been associated with increased mortality. It is extremely challenging to optimize the valve size alone to prevent a complete atrioventricular block (AVB).

Methods

In this study, we randomly took 48 patients who underwent TAVR and had been followed for at least 2 years to assess the risk of AVB. CT images of 48 patients with TAVR were analyzed using three-dimensional (3D) anatomical models of the aortic valve apparatus. The stresses were formulated according to loading force and tissue properties. Support vector regression (SVR) was used to model the relationship between AVB risk and biomechanical stresses. To avoid AVB, overlapping regions on the prosthetic valve where AV bundle passes will be removed as cylindrical sector with the angle θ. Thus, the optimization of the valve shape will be predicted with the joint optimization of the θ and valve size R.

Results

The average AVB risk prediction accuracy was 83.33% in the range from 0.8–0.85 with 95% CI for all cases; specifically, 85.71% for Group A (no AVB), and 80.0% for Group B (undergoing AVB after the TAVR).

Conclusions

This model can estimate the optimal valve size and shape to avoid the risk of AVB after TAVR. This optimization may eliminate the excessive stresses to keep the normal function of both AV bundle and valve leaflets, leading to a favorable clinical outcome. The combination of biomechanical properties and machine learning method substantially improved prediction of surgical results.
Toward a Holistic Rating System: An Attempt to Expand the Boundaries of Building Sustainability Using SDGs
Authors: Vitale Pierluca , Alfano Vincenzo , Pastore Tommaso , Menna Costantino , Maffettone Pietro , Asprone Domenico
Published: July 2021

Several frameworks have been developed for mitigating the environmental impact of human activities. Among them, possibly the most forward-thinking are the Sustainable Development Goals set out in UN Agenda 2030, which are often cited by stakeholders at various levels. Nevertheless, when it comes to policy tools, defining goals relating to sustainability is not straightforward. In this contribution, we use a mathematical framework to compare the goals of Agenda 2030 with the assessments possible with three different building-rating systems, BREEAM, LEED and ITACA. Our results show that these tools address sustainability very differently to the intentions of the SDGs. However, a number of minor changes could easily make the assessments produced by these evaluation systems on this issue more complete.
Branchiomeric Muscle Development Requires Proper Retinoic Acid Signaling
Authors: Wang Qi , Xu Lin , Miura Jiro , Saha Mithun Kumar , Uemura Yume , Sandell Lisa L. , Trainor Paul A. , Yamashiro Takashi , Kurosaka Hiroshi
Published: July 2021

The first and second branchiomeric (branchial arch) muscles are craniofacial muscles that derive from branchial arch mesoderm. In mammals, this set of muscles is indispensable for jaw movement and facial expression. Defects during embryonic development that result in congenital partial absence of these muscles can have significant impact on patients’ quality of life. However, the detailed molecular and cellular mechanisms that regulate branchiomeric muscle development remains poorly understood. Herein we investigated the role of retinoic acid (RA) signaling in developing branchiomeric muscles using mice as a model. We administered all-trans RA (25 mg/kg body weight) to Institute of Cancer Research (ICR) pregnant mice by gastric intubation from E8.5 to E10.5. In their embryos at E13.5, we found that muscles derived from the first branchial arch (temporalis, masseter) and second branchial arch (frontalis, orbicularis oculi) were severely affected or undetectable, while other craniofacial muscles were hypoplastic. We detected elevated cell death in the branchial arch mesoderm cells in RA-treated embryos, suggesting that excessive RA signaling reduces the survival of precursor cells of branchiomeric muscles, resulting in the development of hypoplastic craniofacial muscles. In order to uncover the signaling pathway(s) underlying this etiology, we focused on Pitx2, Tbx1, and MyoD1, which are critical for cranial muscle development. Noticeably reduced expression of all these genes was detected in the first and second branchial arch of RA-treated embryos. Moreover, elevated RA signaling resulted in a reduction in Dlx5 and Dlx6 expression in cranial neural crest cells (CNCCs), which disturbed their interactions with branchiomeric mesoderm cells. Altogether, we discovered that embryonic craniofacial muscle defects caused by excessive RA signaling were associated with the downregulation of Pitx2, Tbx1, MyoD1, and Dlx5/6, and reduced survival of cranial myogenic precursor cells.
Neuropeptide Y and Metabolism Syndrome: An Update on Perspectives of Clinical Therapeutic Intervention Strategies
Authors: Huang Yinqiong , Lin Xiahong , Lin Shu
Published: July 2021

Through the past decade of research, the pathogenic mechanisms underlying metabolic syndrome have been suggested to involve not only the peripheral tissues, but also central metabolic regulation imbalances. The hypothalamus, and the arcuate nucleus in particular, is the control center for metabolic homeostasis and energy balance. Neuropeptide Y neurons are particularly abundantly expressed in the arcuate of the hypothalamus, where the blood-brain barrier is weak, such as to critically integrate peripheral metabolic signals with the brain center. Herein, focusing on metabolic syndrome, this manuscript aims to provide an overview of the regulatory effects of Neuropeptide Y on metabolic syndrome and discuss clinical intervention strategy perspectives for neurometabolic disease.
Edge Mostar Indices of Cacti Graph With Fixed Cycles
Authors: Yasmeen Farhana , Akhter Shehnaz , Ali Kashif , Rizvi Syed Tahir Raza
Published: July 2021

Topological invariants are the significant invariants that are used to study the physicochemical and thermodynamic characteristics of chemical compounds. Recently, a new bond additive invariant named the Mostar invariant has been introduced. For any connected graph ℋ, the edge Mostar invariant is described as Moe(ℋ)=∑gx∈E(ℋ)|mℋ(g)−mℋ(x)|, where mℋ(g)(or mℋ(x)) is the number of edges of ℋ lying closer to vertex g (or x) than to vertex x (or g). A graph having at most one common vertex between any two cycles is called a cactus graph. In this study, we compute the greatest edge Mostar invariant for cacti graphs with a fixed number of cycles and n vertices. Moreover, we calculate the sharp upper bound of the edge Mostar invariant for cacti graphs in ℭ(n,s), where s is the number of cycles.
Gold Nanomaterials and Bone/Cartilage Tissue Engineering: Biomedical Applications and Molecular Mechanisms
Authors: Shi Yifeng , Han Xuyao , Pan Shuang , Wu Yuhao , Jiang Yuhan , Lin Jinghao , Chen Yihuang , Jin Haiming
Published: July 2021

Recently, as our population increasingly ages with more pressure on bone and cartilage diseases, bone/cartilage tissue engineering (TE) have emerged as a potential alternative therapeutic technique accompanied by the rapid development of materials science and engineering. The key part to fulfill the goal of reconstructing impaired or damaged tissues lies in the rational design and synthesis of therapeutic agents in TE. Gold nanomaterials, especially gold nanoparticles (AuNPs), have shown the fascinating feasibility to treat a wide variety of diseases due to their excellent characteristics such as easy synthesis, controllable size, specific surface plasmon resonance and superior biocompatibility. Therefore, the comprehensive applications of gold nanomaterials in bone and cartilage TE have attracted enormous attention. This review will focus on the biomedical applications and molecular mechanism of gold nanomaterials in bone and cartilage TE. In addition, the types and cellular uptake process of gold nanomaterials are highlighted. Finally, the current challenges and future directions are indicated.
Prognostic Value of Coronary Artery Calcium Score in Hospitalized COVID-19 Patients
Authors: Luchian Maria-Luiza , Lochy Stijn , Motoc Andreea , Belsack Dries , Magne Julien , Roosens Bram , de Mey Johan , Tanaka Kaoru , Scheirlynck Esther , Boeckstaens Sven , Van den Bussche Karen , De Potter Tom , von Kemp Berlinde , Galloo Xavier , François Clara , Weytjens Caroline , Droogmans Steven , Cosyns Bernard
Published: July 2021

Background: The association of known cardiovascular risk factors with poor prognosis of coronavirus disease 2019 (COVID-19) has been recently emphasized. Coronary artery calcium (CAC) score is considered a risk modifier in the primary prevention of cardiovascular disease. We hypothesized that the absence of CAC might have an additional predictive value for an improved cardiovascular outcome of hospitalized COVID-19 patients.

Materials and methods: We prospectively included 310 consecutive hospitalized patients with COVID-19. Thirty patients with history of coronary artery disease were excluded. Chest computed tomography (CT) was performed in all patients. Demographics, medical history, clinical characteristics, laboratory findings, imaging data, in-hospital treatment, and outcomes were retrospectively analyzed. A composite endpoint of major adverse cardiovascular events (MACE) was defined.

Results: Two hundred eighty patients (63.2 ± 16.7 years old, 57.5% male) were included in the analysis. 46.7% patients had a CAC score of 0. MACE rate was 21.8% (61 patients). The absence of CAC was inversely associated with MACE (OR 0.209, 95% CI 0.052–0.833, p = 0.027), with a negative predictive value of 84.5%.

Conclusion: The absence of CAC had a high negative predictive value for MACE in patients hospitalized with COVID-19, even in the presence of cardiac risk factors. A semi-qualitative assessment of CAC is a simple, reproducible, and non-invasive measure that may be useful to identify COVID-19 patients at a low risk for developing cardiovascular complications.
Responsible Relations: A Systematic Scoping Review of the Therapeutic Alliance in Text-Based Digital Psychotherapy
Authors: van Lotringen Charlotte M. , Jeken Lars , Westerhof Gerben J. , ten Klooster Peter M. , Kelders Saskia M. , Noordzij Matthijs L.
Published: July 2021

Introduction: Developing a good therapeutic alliance is considered essential for the responsible delivery of psychotherapy. Text-based digital psychotherapy has become increasingly common, yet much remains unclear about the alliance and its importance for delivering mental health care via a digital format. To employ text-based digital therapies responsibly, more insight is needed into the type and strength of the therapeutic alliance online.

Methods: A systematic scoping review was performed searching four databases: Scopus, PsycINFO, Web of Science, and Wiley Online Library. A total of 23 studies were selected and data was extracted and tabulated to explore the characteristics of studies on text-based psychotherapy, measurements of the therapeutic alliance and associations of the alliance with treatment outcome.

Results: The therapeutic alliance in text-based digital interventions was studied with a variety of client groups, though mostly for clients diagnosed with anxiety and/or depression issues. Treatment modalities were predominantly internet-based cognitive behavioral therapy (ICBT) and tailored platforms for distinct client groups (e.g., PTSD). Almost all treatments used asynchronous text-based communication, such as e-mails and integrated messaging functions, which were mainly used to give feedback on tasks. For measurements, a version of the Working Alliance Inventory (WAI) was used in most studies. Measurements with the WAI or WAI- short form indicated a good therapeutic alliance with a weighted mean score of 5.66 (on a scale of 1 to 7) and a weighted standard deviation of 0.84. Relations between the therapeutic alliance and treatment outcomes were mostly positive, with many studies reporting significant associations (n = 8 out of 10) or significant effects of the therapeutic alliance on treatment outcomes (n = 5 out of 6).

Discussion: Our scoping review suggests that a good therapeutic alliance can be established in digital psychotherapy through text-based communication, and shows support for a positive relationship between the alliance and treatment outcomes. These findings illustrate that text-based online psychotherapy can be a responsible treatment option as far as the establishment of the therapeutic alliance is concerned. However, current measures of the therapeutic alliance might miss important aspects of the alliance in digital treatment, such as the presence of empathy or compassion.
The Effects of Covid-19 on the Digital Literacy of the Elderly: Norms for Digital Inclusion
Authors: Martínez-Alcalá Claudia I. , Rosales-Lagarde Alejandra , Pérez-Pérez Yonal M. , Lopez-Noguerola Jose S. , Bautista-Díaz María L. , Agis-Juarez Raul A.
Published: July 2021

The current sanitary crisis due to COVID-19 has further evidenced the enormous digital exclusion of older adults. Furthermore, the crisis has urged older adults to adopt new technologies to facilitate their tasks, as well as to provide them with an effective means against loneliness and social isolation caused by the confinement. In light of this, Digital Literacy is necessary for all those excluded from the digital era, who are characterized mainly by little or no ability to effectively use technologies. Nevertheless, detailed studies showing the leap from mixed (Blended Learning, BL) to digital literacy in the elderly have not been published. The objective of the present research was to analyze the level of Digital Literacy with the Digital Literacy Evaluation (DILE) of two groups of elderly adults with different levels of literacy (Group 1: G1, and Group 2: G2) during three stages: BL (Aug–Dec 2019); Transition (Feb–Jun 2020); and Digital (Aug–Dec 2020). Comparisons were made before each educational level (pre-pre-pre) and after each educational level (post-post-post) and during consecutive periods before and after each semester (pre vs post) and throughout different educational levels (G1: Basic 1, B1; Basic 2, B2; and intermediate 1, I1; and G2: Intermediate 1 to 3, I1, I2, and I3). Subsequently, considering all the elderly who had passed at least one of the literacy levels, we worked with a total sample of 176 older adults. The comparisons showed that, before the pandemic, G1’s pre digital literacy levels increased between B1 and B2 and that the differences continued with that increasing trend between the B1 level and the I1 completely digital treatment, and the same was observed for post measurements. On the other hand, for the G2, the differences in the DILE were statistically significant between the pre-condition of I2 (before the pandemic) and the I3 (completely digital treatment); and between the pre-conditions of I1 and I3; the same results were obtained for post treatments. Also, pre vs post scores on the DILE were statistically significant and older adults increased progressively their digital literacy despite the COVID-19 pandemic and jumped to the digital age.
Significance of Tumor Mutation Burden Combined With Immune Infiltrates in the Progression and Prognosis of Advanced Gastric Cancer
Authors: Guo Xiong , Liang Xiaolong , Wang Yujun , Cheng Anqi , Zhang Han , Qin Chuan , Wang Ziwei
Published: July 2021

Gastric cancer (GC) is a serious malignant tumor with high mortality and poor prognosis. The prognosis and survival are much worse for advanced gastric cancer (AGC). Recently, immunotherapy has been widely promoted for AGC patients, and studies have shown that tumor mutation burden (TMB) is closely related to immunotherapy response. Here, RNA-seq data, matched clinical information, and MAF files were downloaded from the cancer genome atlas (TCGA)-STAD project in the TCGA database. The collation and visual analysis of mutation data were implemented by the “maftools” package in R. We calculated the TMB values for AGC patients and divided the patients into high- and low-TMB groups according to the median value of TMB. Then, the correlation between high or low TMB and clinicopathological parameters was calculated. Next, we examined the differences in gene expression patterns between the two groups by using the “limma” R package and identified the immune-related genes among the DEGs. Through univariate Cox regression analysis, 15 genes related to prognosis were obtained. Furthermore, the two hub genes (APOD and SLC22A17) were used to construct a risk model to evaluate the prognosis of AGC patients. ROC and survival curves and GEO data were used as a validation set to verify the reliability of this risk model. In addition, the correlation between TMB and tumor-infiltrating immune cells was examined. In conclusion, our results suggest that AGC patients with high TMB have a better prognosis. By testing the patient’s TMB, we could better guide immunotherapy and understand patient response to immunotherapy.
Integrated Analysis of Multiple Microarray Studies to Identify Novel Gene Signatures in Ulcerative Colitis
Authors: Chen Zi-An , Sun Yu-Feng , Wang Quan-Xu , Ma Hui-Hui , Ma Zhi-Zhao , Yang Chuan-Jie
Published: July 2021

Background: Ulcerative colitis (UC) is a chronic, complicated, inflammatory disease with an increasing incidence and prevalence worldwide. However, the intrinsic molecular mechanisms underlying the pathogenesis of UC have not yet been fully elucidated.

Methods: All UC datasets published in the GEO database were analyzed and summarized. Subsequently, the robust rank aggregation (RRA) method was used to identify differentially expressed genes (DEGs) between UC patients and controls. Gene functional annotation and PPI network analysis were performed to illustrate the potential functions of the DEGs. Some important functional modules from the protein-protein interaction (PPI) network were identified by molecular complex detection (MCODE), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG), and analyses were performed. The results of CytoHubba, a plug for integrated algorithm for biomolecular interaction networks combined with RRA analysis, were used to identify the hub genes. Finally, a mouse model of UC was established by dextran sulfate sodium salt (DSS) solution to verify the expression of hub genes.

Results: A total of 6 datasets met the inclusion criteria (GSE38713, GSE59071, GSE73661, GSE75214, GSE87466, GSE92415). The RRA integrated analysis revealed 208 significant DEGs (132 upregulated genes and 76 downregulated genes). After constructing the PPI network by MCODE plug, modules with the top three scores were listed. The CytoHubba app and RRA identified six hub genes: LCN2, CXCL1, MMP3, IDO1, MMP1, and S100A8. We found through enrichment analysis that these functional modules and hub genes were mainly related to cytokine secretion, immune response, and cancer progression. With the mouse model, we found that the expression of all six hub genes in the UC group was higher than that in the control group (P < 0.05).

Conclusion: The hub genes analyzed by the RRA method are highly reliable. These findings improve the understanding of the molecular mechanisms in UC pathogenesis.
Muscle Tissue Damage and Recovery After EV71 Infection Correspond to Dynamic Macrophage Phenotypes
Authors: Lu Mei-Yi , Lin Ya-Lin , Kuo Yali , Chuang Chi-Fen , Wang Jen-Ren , Liao Fang
Published: July 2021

Enterovirus 71 (EV71) is a positive single-stranded RNA virus from the enterovirus genus of the Picornaviridae family. Most young children infected with EV71 develop mild symptoms of hand, foot and mouth disease, but some develop severe symptoms with neurological involvement. Limb paralysis from EV71 infection is presumed to arise mainly from dysfunction of motor neurons in the spinal cord. However, EV71 also targets and damages skeletal muscle, which may also contribute to the debilitating symptoms. In this study, we have delineated the impacts of EV71 infection on skeletal muscle using a mouse model. Mouse pups infected with EV71 developed limb paralysis, starting at day 3 post-infection and peaking at day 5-7 post-infection. At later times, mice recovered gradually but not completely. Notably, severe disease was associated with high levels of myositis accompanied by muscle calcification and persistent motor end plate abnormalities. Interestingly, macrophages exhibited a dynamic change in phenotype, with inflammatory macrophages (CD45+CD11b+Ly6Chi) appearing in the early stage of infection and anti-inflammatory/restorative macrophages (CD45+CD11b+Ly6Clow/-) appearing in the late stage. The presence of inflammatory macrophages was associated with severe inflammation, while the restorative macrophages were associated with recovery. Altogether, we have demonstrated that EV71 infection causes myositis, muscle calcification and structural defects in motor end plates. Subsequent muscle regeneration is associated with a dynamic change in macrophage phenotype.
Promising Therapeutic Targets for Treatment of Rheumatoid Arthritis
Authors: Huang Jie , Fu Xuekun , Chen Xinxin , Li Zheng , Huang Yuhong , Liang Chao
Published: July 2021

Rheumatoid arthritis (RA) is a systemic poly-articular chronic autoimmune joint disease that mainly damages the hands and feet, which affects 0.5% to 1.0% of the population worldwide. With the sustained development of disease-modifying antirheumatic drugs (DMARDs), significant success has been achieved for preventing and relieving disease activity in RA patients. Unfortunately, some patients still show limited response to DMARDs, which puts forward new requirements for special targets and novel therapies. Understanding the pathogenetic roles of the various molecules in RA could facilitate discovery of potential therapeutic targets and approaches. In this review, both existing and emerging targets, including the proteins, small molecular metabolites, and epigenetic regulators related to RA, are discussed, with a focus on the mechanisms that result in inflammation and the development of new drugs for blocking the various modulators in RA.
Comparative Characterization and Risk Stratification of Asymptomatic and Presymptomatic Patients With COVID-19
Authors: Shi Lei , Ding Rong , Zhang Tingting , Wu Wei , Wang Ziyu , Jia Xiuzhi , Li Kening , Liang Yuan , Li Jie , Zhu Mengyan , Huang Bin , Wu Lingxiang , Wu Min , Chen Jing , Wang Chaochen , Huang Bin , Liu Caidong , Shen Hongbing , Wang Qianghu , Xia Xinyi , Li Pengping , Lyu Sali , Xiao Ying
Published: July 2021

The identification of asymptomatic, non-severe presymptomatic, and severe presymptomatic coronavirus disease 2019 (COVID-19) in patients may help optimize risk-stratified clinical management and improve prognosis. This single-center case series from Wuhan Huoshenshan Hospital, China, included 2,980 patients with COVID-19 who were hospitalized between February 4, 2020 and April 10, 2020. Patients were diagnosed as asymptomatic (n = 39), presymptomatic (n = 34), and symptomatic (n = 2,907) upon admission. This study provided an overview of asymptomatic, presymptomatic, and symptomatic COVID-19 patients, including detection, demographics, clinical characteristics, and outcomes. Upon admission, there was no significant difference in clinical symptoms and CT image between asymptomatic and presymptomatic patients for diagnosis reference. The mean area under the receiver operating characteristic curve (AUC) of the differential diagnosis model to discriminate presymptomatic patients from asymptomatic patients was 0.89 (95% CI, 0.81-0.98). Importantly, the severe and non-severe presymptomatic patients can be further stratified (AUC = 0.82). In conclusion, the two-step risk-stratification model based on 10 laboratory indicators can distinguish among asymptomatic, severe presymptomatic, and non-severe presymptomatic COVID-19 patients on admission. Moreover, single-cell data analyses revealed that the CD8+T cell exhaustion correlated to the progression of COVID-19.
First Molecular Characterization of Siphoviridae-Like Bacteriophages Infecting Staphylococcus hyicus in a Case of Exudative Epidermitis
Authors: Tetens Julia , Sprotte Sabrina , Thimm Georg , Wagner Natalia , Brinks Erik , Neve Horst , Hölzel Christina Susanne , Franz Charles M. A. P.
Published: July 2021

Exudative epidermitis (EE), also known as greasy pig disease, is one of the most frequent skin diseases affecting piglets. Zoonotic infections in human occur. EE is primarily caused by virulent strains of Staphylococcus (S.) hyicus. Generally, antibiotic treatment of this pathogen is prone to decreasing success, due to the incremental development of multiple resistances of bacteria against antibiotics. Once approved, bacteriophages might offer interesting alternatives for environmental sanitation or individualized treatment, subject to the absence of virulence and antimicrobial resistance genes. However, genetic characterization of bacteriophages for S. hyicus has, so far, been missing. Therefore, we investigated a piglet raising farm with a stock problem due to EE. We isolated eleven phages from the environment and wash water of piglets diagnosed with the causative agent of EE, i.e., S. hyicus. The phages were morphologically characterized by electron microscopy, where they appeared Siphoviridae-like. The genomes of two phages were sequenced on a MiSeq instrument (Illumina), resulting in the identification of a new virulent phage, PITT-1 (PMBT8), and a temperate phage, PITT-5 (PMBT9). Sequencing of three host bacteria (S. hyicus) from one single farm revealed the presence of two different strains with genes coding for two different exfoliative toxin genes, i.e., exhA (2 strains) and exhC (1 strain). The exhC-positive S. hyicus strain was only weakly lysed by most lytic phages. The occurrence of different virulent S. hyicus strains in the same outbreak limits the prospects for successful phage treatment and argues for the simultaneous use of multiple and different phages attacking the same host.
Rapid Antibiotic Susceptibility Testing of Tier-1 Agents Bacillus anthracis, Yersinia pestis, and Francisella tularensis Directly From Whole Blood Samples
Authors: Rotem Shahar , Shifman Ohad , Aftalion Moshe , Gur David , Aminov Tamar , Aloni-Grinstein Ronit
Published: July 2021

Rapid antibiotic susceptibility tests, performed directly on whole blood samples, will offer great clinical advantages. This issue is of considerable importance when it comes to bioterror pathogens where prompt antibiotic treatment should be offered to infected patients as well as prophylaxis to suspected exposed individuals. Herein, we describe a novel and rapid method, named MAPt, that is based on the direct application of a blood sample onto solid agar that has been embedded with different concentrations of the tested antibiotic. Following a short incubation, bacterial growth is monitored by qPCR. The method was applied on blood cultures and whole blood samples inoculated with the Tier-1 pathogens Bacillus anthracis, Yersinia pestis, and Francisella tularensis. The use of agar medium, which better supports the growth of bacteria at low concentrations, together with the use of qPCR, which provides sensitivity and specificity, allowed minimal inhibitory concentration (MIC) determination to a wide range of bacterial concentrations, ranging from ∼5 × 102 cfu/ml up to 108 cfu/ml. The omission of the enrichment procedure in blood culture and the isolation step, both required in standard antibiotic susceptibility tests (ASTs), allowed a dramatic reduction in time to answer, from a few days to a few hours. The total time required for MIC determination was ∼6 h for fast-growing bacteria, such as B. anthracis, and 12–16 h for slow-growing bacteria, represented by Y. pestis and F. tularensis. Accordingly, MAPt may offer health authorities means for public preparedness in the case of a bioterror attack as well as prompt clinical treatment options in common blood stream infections.
An Overview of 24 Years of Molecular Phylogenetic Studies in Phallales (Basidiomycota) With Notes on Systematics, Geographic Distribution, Lifestyle, and Edibility
Authors: Melanda Gislaine C. S. , Silva-Filho Alexandre G. S. , Lenz Alexandre Rafael , Menolli Nelson , Lima Alexandro de Andrade de , Ferreira Renato Juciano , Assis Nathalia Mendonça de , Cabral Tiara S. , Martín María P. , Baseia Iuri Goulart
Published: July 2021

The order Phallales (Basidiomycota) is represented by gasteroid fungi with expanded and sequestrate basidiomata, known as stinkhorns and false truffles. In phalloids, the first DNA sequence was published in 1997, and after that, some studies aimed to resolve phylogenetic conflicts and propose new species based on DNA markers; however, the number of families and genera in the order still generates controversies among researchers. Thus, this work aims to provide an overview of Phallales diversity represented by selected DNA markers available in public databases. We retrieved Phallales sequences from DNA databases (GenBank and UNITE) of seven markers: ITS (internal transcribed spacer), nuc-LSU (nuclear large subunit rDNA), nuc-SSU (nuclear small subunit rDNA), mt-SSU (mitochondrial small subunit rDNA), ATP6 (ATPase subunit 6), RPB2 (nuclear protein-coding second largest subunit of RNA polymerase), and TEF1-α (translation elongation factor subunit 1α). To compose our final dataset, all ITS sequences retrieved were subjected to BLASTn searches to identify additional ITS sequences not classified as Phallales. Phylogenetic analyses based on Bayesian and maximum likelihood approaches using single and combined markers were conducted. All ITS sequences were clustered with a cutoff of 98% in order to maximize the number of species hypotheses. The geographic origin of sequences was retrieved, as well as additional information on species lifestyle and edibility. We obtained a total of 1,149 sequences, representing 664 individuals. Sequences of 41 individuals were unidentified at genus level and were assigned to five distinct families. We recognize seven families and 22 genera in Phallales, although the delimitation of some genera must be further revisited in order to recognize only monophyletic groups. Many inconsistencies in species identification are discussed, and the positioning of genera in each family is shown. The clustering revealed 118 species hypotheses, meaning that approximately 20% of all described species in Phallales have DNA sequences available. Information related to geographic distribution represents 462 individuals distributed in 46 countries on all continents, except Antarctica. Most genera are saprotrophic with only one putative ectomycorrhizal genus, and 2.1% of the legitimate specific names recognized in Phallales are confirmed edible species. Great progress in the molecular analyses of phalloids has already been made over these years, but it is still necessary to solve some taxonomic inconsistencies, mainly at genus level, and generate new data to expand knowledge of the group.
Identification of Arp2/3 Complex Subunits as Prognostic Biomarkers for Hepatocellular Carcinoma
Authors: Huang Shenglan , Li Dan , Zhuang LingLing , Sun Liying , Wu Jianbing
Published: July 2021

The actin-related protein 2/3 complex (Arp2/3) is a major actin nucleator that has been widely reported and plays an important role in promoting the migration and invasion of various cancers. However, the expression patterns and prognostic values of Arp2/3 subunits in hepatocellular carcinoma (HCC) remain unclear. In this study, The Cancer Genome Atlas (TCGA) and UCSC Xena databases were used to obtain mRNA expression and the corresponding clinical information, respectively. The differential expression and Arp2/3 subunits in HCC were analyzed using the “limma” package of R 4.0.4 software. The prognostic value of each subunit was evaluated using Kaplan–Meier survival analysis and Cox proportional hazards regression analyses. The results revealed that mRNA expression of Arp2/3 members (ACTR2, ACTR3, ARPC1A, APRC1B, ARPC2, ARPC3, ARPC4, ARPC5, and ARPC5L) was upregulated in HCC. Higher expression of Arp2/3 members was significantly correlated with worse overall survival (OS) and shorter progression-free survival (PFS) in HCC patients. Cox proportional hazards regression analyses demonstrated that ACTR3, ARPC2, and ARPC5 were independent prognostic biomarkers of survival in patients with HCC. The relation between tumor immunocyte infiltration and the prognostic subunits was determined using the TIMER 2.0 platform and the GEPIA database. Gene set enrichment analysis (GSEA) was performed to explore the potential mechanisms of prognostic subunits in the carcinogenesis of HCC. The results revealed that ACTR3, ARPC2, and ARPC5 were significantly positively correlated with the infiltration of immune cells in HCC. The GSEA results indicated that ACTR3, ARPC2, and ARPC5 are involved in multiple cancer-related pathways that promote the development of HCC. In brief, various analyses indicated that Arp2/3 complex subunits were significantly upregulated and predicted worse survival in HCC, and they found that ACTR3, ARPC2, and ARPC5 could be used as independent predictors of survival and might be applied as promising molecular targets for diagnosis and therapy of HCC in the future.
Extreme Delta Brush in Anti-NMDAR Encephalitis Correlates With Poor Functional Outcome and Death
Authors: Nathoo Nabeela , Anderson Dustin , Jirsch Jeffrey
Published: July 2021

Objective: To characterize EEG findings in anti-NMDAR encephalitis patients looking for the proportion of EEGs that were abnormal, presence of extreme delta brush (EDB), and to relate EEG findings to clinical outcomes (Glasgow Outcome Scale (GOS) at 6 months, need for ICU admission, and death).

Methods: This retrospective cohort single center study included patients with anti-NMDAR encephalitis who had ≥1 EEGs obtained from 2014 to 2021. EEGs were retrospectively analyzed by 2 reviewers. Clinical outcomes of interest were extracted through hospital and clinic chart review.

Results: Twenty-one patients with anti-NMDAR encephalitis were included. Sixty-four EEGs were analyzed. Four EEGs (6.3%) were within normal limits. Focal or generalized slowing (without EDB) was seen on 44 EEGs (68.8%). EDB was seen on 16 EEGs (25.0%) in 9 of 21 patients (42.9%). The presence of EDB was significantly associated with need for ICU admission (p = 0.02), poorer outcome at 6 months as per the GOS (p = 0.002), and with death (p=0.02). EDB was present on ≥1 EEG of every patient who died.

Conclusions: The presence of EDB on EEG in anti-NMDAR encephalitis patients is associated with increased need for ICU admission, worse functional outcomes at 6 months, and risk of death.
Long Noncoding RNA DICER1-AS1 Functions in Methylation Regulation on the Multi-Drugresistance of Osteosarcoma Cells via miR-34a-5p and GADD45A
Authors: Wang Feng , Kong Lingsuo , Pu Youguang , Chao Fengmei , Zang Chunbao , Qin Wei , Zhao Fangfang , Cai Shanbao
Published: July 2021

Osteosarcoma (OS) is a common malignant bone tumor that commonly occurs in children and adolescents. Long noncoding RNAs (lncRNAs) are recognized as a novel class of regulators of gene expression associated with tumorigenesis. However, the effect and mechanism of lncRNAs in OS tumorigenesis and drug resistance have not been characterized. The purpose of the study is to screen potential biomarker and therapeutic target against OS. We compared the lncRNA expression profiles between OS cell lines with different drug resistance levels using RNA-seq analysis and found that lncRNA DICER1-AS1 was significantly differentially expressed in multi-drugresistant OS cells SJSA-1 versus multi-drugsensitive OS cells G-292. Bisulfite Sequencing PCR (BSP) assay was performed to analyze the differential methylation status of the promoter region of DICER1-AS1 in four OS cells. Subsequently, in vitro gain- and loss-of-function experiments demonstrated the roles of DICER1-AS1 and miR-34a-5p in the multi-drugresistance of OS cells. The main findings is that DICER1-AS1 directly binds to miR-34a-5p, and their expression has a negative correlation with each other. The hypermethylation of the promoter region of DICER1-AS1 silenced its expression in the drugresistant cells SJSA-1 and MNNG/HOS. Moreover, we found that growth arrest and DNA damage-inducible alpha (GADD45A) participates in the DICER1-AS1/miR-34a-5p-regulated drug resistance of OS cells, probably via the cell cycle/pRb-E2F pathway. Our results revealed DICER1-AS1/miR-34a-5p-regulated drug resistance of OS cells, a new lncRNA-regulated network in OS tumorigenesis, suggested that DICER1-AS1 can be considered as a potential biomarker and therapeutic target against OS cells.
Continuous Glucose Monitoring as a Valuable Tool in the Early Detection of Diabetes Related to Cystic Fibrosis
Authors: Gojsina Bojana , Minic Predrag , Todorovic Sladjana , Soldatovic Ivan , Sovtic Aleksandar
Published: July 2021

Aims: We evaluated the impact of cystic fibrosis-related diabetes (CFRD) on lung disease and nutritional status.

Study Design: The retrospective cohort study evaluated the subjects' medical records from 2004 to 2019. All participants older than 10 years diagnosed by a 30-minutely sampled OGTT formed OGTT-CFRD subgroup. The participants diagnosed with continuous glucose monitoring (CGM) (at least two peaks above 11.1 mmol/l and more than 10% of recorded time above 7.8 mmol/l) formed a CFRD-CGM subgroup. The participants without CFRD formed a non-CFRD group. The longitudinal follow-up was made 2 years before and 3 years after insulin therapy initiation.

Results: Of 144 participants included, aged 10–55 years (44% males), 28 (19.4%) had CFRD. The HbA1c was significantly lower in the CGM-CFRD in comparison to the OGTT-CFRD subgroup (5.9 ± 0.62 and 7.3 ± 1.7% respectfully; p = 0.04). Subjects with CFRD were malnourished in comparison to non-CFRD, with significant improvements with insulin replacement therapy in regard to BMI Z-score (−1.4 ± 1.3 vs. −0.5 ± 1.2%, p = 0.04) and pulmonary exacerbation score (p = 0.02). In OGTT-CFRD subgroup there is an increase in FEV1 (62.7 ± 26.3 to 65.1 ± 21.7%, p = 0.7) and decrease in FVC (from 76.4 ± 24.2 to 71.2 ± 20%, p = 0.003) from diagnosis to second year of follow-up. In CGM-CFRD subgroup there was a decrease in FEV1 (from 58.2 ± 28.2 to 52.8 ± 25.9%, p = 0.2) and FVC-values (from 72.4 ± 26.5 to 67.4 ± 29.1%, p = 0.08).Chronic Pseudomonas aeruginosa infection was more prevalent in the CFRD group (p = 0.003).

Conclusion: Continuous glucose monitoring is a useful tool for insight of glucose impairment and diagnosis of CFRD. Early recognition of CFRD and therapeutic intervention has favorable effects on clinical course of the disease.