bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic Response Characterization of Floating Structures Based on Numerical Simulations
Authors: Pimenta Francisco , Ruzzo Carlo , Failla Giuseppe , Arena Felice , Alves Marco , Magalhães Filipe
Published: October 2020

Output-only methods are widely used to characterize the dynamic behavior of very diverse structures. However, their application to floating structures may be limited due to their strong nonlinear behavior. Therefore, since there is very little experience on the application of these experimental tools to these very peculiar structures, it is very important to develop studies, either based on numerical simulations or on real experimental data, to better understand their potential and limitations. In an initial phase, the use of numerical simulations permits a better control of all the involved variables. In this work, the Covariance-driven Stochastic Subspace Identification (SSI-COV) algorithm is applied to numerically simulated data of two different solutions to Floating Offshore Wind Turbines (FOWT) and for its capability of tracking the rigid body motion modal properties and susceptibility to different modeling restrictions and environmental conditions tested. The feasibility of applying the methods in an automated fashion in the processing of a large number of datasets is also evaluated. While the structure natural frequencies were consistently obtained from all the simulations, some difficulties were observed in the estimation of the mode shape components in the most changeling scenarios. The estimated modal damping coefficients were in good agreement with the expected results. From all the results, it can be concluded that output-only methods are capable of characterizing the dynamic behavior of a floating structure, even in the context of continuous dynamic monitoring using automated tracking of the modal properties, and should now be tested under uncontrolled environmental loads.
Linking Tree Health, Rhizosphere Physicochemical Properties, and Microbiome in Acute Oak Decline
Authors: Pinho Diogo , Barroso Cristina , Froufe Hugo , Brown Nathan , Vanguelova Elena , Egas Conceição , Denman Sandra
Published: October 2020

Forest decline diseases are complex processes driven by biotic and abiotic factors. Although information about host–microbiome–environment interactions in agricultural systems is emerging rapidly, similar studies on tree health are still in their infancy. We used acute oak decline (AOD) as a model system to understand whether the rhizosphere physicochemical properties and microbiome are linked to tree health by studying these two factors in healthy and diseased trees located in three sites in different AOD stages—low, mid and severe. We found significant changes in the rhizosphere properties and microbiome composition across the different AOD sites and between the tree health conditions. Rhizosphere pH correlated with microbiome composition, with the microbial assemblages changing in more acidic soils. At the severe AOD site, the oak trees exhibited the lowest rhizosphere pH and distinct microbiome, regardless of their health condition, whereas, at the low and mid-stage AOD sites, only diseased trees showed lower pH and the microbial composition differed significantly from healthy trees. On these two sites, less extreme soil conditions and a high presence of host-beneficial microbiota were observed in the healthy oak trees. For the first time, this study gathers evidence of associations among tree health conditions, rhizosphere properties and microbiome as well as links aboveground tree decline symptoms to the belowground environment. This provides a baseline of rhizosphere community profiling of UK oak trees and paves the way for these associations to be investigated in other tree species suffering decline disease events.
Genetic-Based Hypertension Subtype Identification Using Informative SNPs
Authors: Ma Yuanjing , Jiang Hongmei , Shah Sanjiv J , Arnett Donna , Irvin Marguerite R , Luo Yuan
Published: October 2020

In this work, we proposed a process to select informative genetic variants for identifying clinically meaningful subtypes of hypertensive patients. We studied 575 African American (AA) and 612 Caucasian hypertensive participants enrolled in the Hypertension Genetic Epidemiology Network (HyperGEN) study and analyzed each race-based group separately. All study participants underwent GWAS (Genome-Wide Association Studies) and echocardiography. We applied a variety of statistical methods and filtering criteria, including generalized linear models, F statistics, burden tests, deleterious variant filtering, and others to select the most informative hypertension-related genetic variants. We performed an unsupervised learning algorithm non-negative matrix factorization (NMF) to identify hypertension subtypes with similar genetic characteristics. Kruskal–Wallis tests were used to demonstrate the clinical meaningfulness of genetic-based hypertension subtypes. Two subgroups were identified for both African American and Caucasian HyperGEN participants. In both AAs and Caucasians, indices of cardiac mechanics differed significantly by hypertension subtypes. African Americans tend to have more genetic variants compared to Caucasians; therefore, using genetic information to distinguish the disease subtypes for this group of people is relatively challenging, but we were able to identify two subtypes whose cardiac mechanics have statistically different distributions using the proposed process. The research gives a promising direction in using statistical methods to select genetic information and identify subgroups of diseases, which may inform the development and trial of novel targeted therapies.
Sequence Transpositions Restore Genes on the Highly Degenerated W Chromosomes of Songbirds
Authors: Xu Luohao , Irestedt Martin , Zhou Qi
Published: October 2020

The female-specific W chromosomes of most Neognathae birds are highly degenerated and gene-poor. Previous studies have demonstrated that the gene repertoires of the Neognathae bird W chromosomes, despite being in small numbers, are conserved across bird species, likely due to purifying selection maintaining the regulatory and dosage-sensitive genes. Here we report the discovery of DNA-based sequence duplications from the Z to the W chromosome in birds-of-paradise (Paradisaeidae, Passeriformes), through sequence transposition. The original transposition involved nine genes, but only two of them (ANXA1 and ALDH1A1) survived on the W chromosomes. Both ANXA1 and ALDH1A1 are predicted to be dosage-sensitive, and the expression of ANXA1 is restricted to ovaries in all the investigated birds. These analyses suggest the newly transposed gene onto the W chromosomes can be favored for their role in restoring dosage imbalance or through female-specific selection. After examining seven additional songbird genomes, we further identified five other transposed genes on the W chromosomes of Darwin’s finches and one in the great tit, expanding the observation of the Z-to-W transpositions to a larger range of bird species, but not all transposed genes exhibit dosage-sensitivity or ovary-biased expression We demonstrate a new mechanism by which the highly degenerated W chromosomes of songbirds can acquire genes from the homologous Z chromosomes, but further functional investigations are needed to validate the evolutionary forces underlying the transpositions.
The Y Chromosome: A Complex Locus for Genetic Analyses of Complex Human Traits
Authors: Parker Katherine , Erzurumluoglu A. Mesut , Rodriguez Santiago
Published: October 2020

The Human Y chromosome (ChrY) has been demonstrated to be a powerful tool for phylogenetics, population genetics, genetic genealogy and forensics. However, the importance of ChrY genetic variation in relation to human complex traits is less clear. In this review, we summarise existing evidence about the inherent complexities of ChrY variation and their use in association studies of human complex traits. We present and discuss the specific particularities of ChrY genetic variation, including Y chromosomal haplogroups, that need to be considered in the design and interpretation of genetic epidemiological studies involving ChrY.
Secondary Genome-Wide Association Study Using Novel Analytical Strategies Disentangle Genetic Components of Cleft Lip and/or Cleft Palate in 1q32.2
Authors: Yang Yunju , Suzuki Akiko , Iwata Junichi , Jun Goo
Published: October 2020

Orofacial cleft (OFC) is one of the most prevalent birth defects, leading to substantial and long-term burdens in a newborn’s quality of life. Although studies revealed several genetic variants associated with the birth defect, novel approaches may provide additional clues about its etiology. Using the Center for Craniofacial and Dental Genetics project data (n = 10,542), we performed linear mixed-model analyses to study the genetic compositions of OFC and investigated the dependence among identified loci using conditional analyses. To identify genes associated with OFC, we conducted a transcriptome-wide association study (TWAS) based on predicted expression levels. In addition to confirming the previous findings at four loci, 1q32.2, 8q24, 2p24.2 and 17p13.1, we untwined two independent loci at 1q32.2, TRAF3IP3 and IRF6. The sentinel SNP in TRAF3IP3 (rs2235370, p-value = 5.15 × 10−9) was independent of the sentinel SNP at IRF6 (rs2235373, r2 < 0.3). We found that the IRF6 effect became nonsignificant once the 8q24 effect was conditioned, while the TRAF3IP3 effect remained significant. Furthermore, we identified nine genes associated with OFC in TWAS, implicating a glutathione synthesis and drug detoxification pathway. We identified some meaningful additions to the OFC etiology using novel statistical methods in the existing data.
Hybrid of Restricted and Penalized Maximum Likelihood Method for Efficient Genome-Wide Association Study
Authors: Ren Wenlong , Liang Zhikai , He Shu , Xiao Jing
Published: October 2020

In genome-wide association studies, linear mixed models (LMMs) have been widely used to explore the molecular mechanism of complex traits. However, typical association approaches suffer from several important drawbacks: estimation of variance components in LMMs with large scale individuals is computationally slow; single-locus model is unsatisfactory to handle complex confounding and causes loss of statistical power. To address these issues, we propose an efficient two-stage method based on hybrid of restricted and penalized maximum likelihood, named HRePML. Firstly, we performed restricted maximum likelihood (REML) on single-locus LMM to remove unrelated markers, where spectral decomposition on covariance matrix was used to fast estimate variance components. Secondly, we carried out penalized maximum likelihood (PML) on multi-locus LMM for markers with reasonably large effects. To validate the effectiveness of HRePML, we conducted a series of simulation studies and real data analyses. As a result, our method always had the highest average statistical power compared with multi-locus mixed-model (MLMM), fixed and random model circulating probability unification (FarmCPU), and genome-wide efficient mixed model association (GEMMA). More importantly, HRePML can provide higher accuracy estimation of marker effects. HRePML also identifies 41 previous reported genes associated with development traits in Arabidopsis, which is more than was detected by the other methods.
Novel Pathogenic Sequence Variants in NR2E3 and Clinical Findings in Three Patients
Authors: Al-khuzaei Saoud , Broadgate Suzanne , Halford Stephanie , Jolly Jasleen K. , Shanks Morag , Clouston Penny , Downes Susan M.
Published: October 2020

A retrospective review of the clinical records of patients seen at the Oxford Eye Hospital identified as having NR2E3 mutations was performed. The data included symptoms, best-corrected visual acuity, multimodal retinal imaging, visual fields and electrophysiology testing. Three participants were identified with biallelic NR2E3 pathogenic sequence variants detected using a targeted NGS gene panel, two of which were novel. Participant I was a Nepalese male aged 68 years, and participants II and III were white Caucasian females aged 69 and 10 years old, respectively. All three had childhood onset nyctalopia, a progressive decrease in central vision, and visual field loss. Patients I and III had photopsia, patient II had photosensitivity and patient III also had photophobia. Visual acuities in patients I and II were preserved even into the seventh decade, with the worst visual acuity measured at 6/36. Visual field constriction was severe in participant I, less so in II, and fields were full to bright targets targets in participant III. Electrophysiology testing in all three demonstrated loss of rod function. The three patients share some of the typical distinctive features of NR2E3 retinopathies, as well as a novel clinical observation of foveal ellipsoid thickening.
The Role of Salmonella Genomic Island 4 in Metal Tolerance of Salmonella enterica Serovar I 4,[5],12:i:- Pork Outbreak Isolate USDA15WA-1
Authors: Bearson Bradley L. , Trachsel Julian M. , Shippy Daniel C. , Sivasankaran Sathesh K. , Kerr Brian J. , Loving Crystal L. , Brunelle Brian W. , Curry Shelby M. , Gabler Nicholas K. , Bearson Shawn M. D.
Published: October 2020

Multidrug-resistant (MDR; resistance to >3 antimicrobial classes) Salmonella enterica serovar I 4,[5],12:i:- strains were linked to a 2015 foodborne outbreak from pork. Strain USDA15WA-1, associated with the outbreak, harbors an MDR module and the metal tolerance element Salmonella Genomic Island 4 (SGI-4). Characterization of SGI-4 revealed that conjugational transfer of SGI-4 resulted in the mobile genetic element (MGE) replicating as a plasmid or integrating into the chromosome. Tolerance to copper, arsenic, and antimony compounds was increased in Salmonella strains containing SGI-4 compared to strains lacking the MGE. Following Salmonella exposure to copper, RNA-seq transcriptional analysis demonstrated significant differential expression of diverse genes and pathways, including induction of at least 38 metal tolerance genes (copper, arsenic, silver, and mercury). Evaluation of swine administered elevated concentrations of zinc oxide (2000 mg/kg) and copper sulfate (200 mg/kg) as an antimicrobial feed additive (Zn+Cu) in their diet for four weeks prior to and three weeks post-inoculation with serovar I 4,[5],12:i:- indicated that Salmonella shedding levels declined at a slower rate in pigs receiving in-feed Zn+Cu compared to control pigs (no Zn+Cu). The presence of metal tolerance genes in MDR Salmonella serovar I 4,[5],12:i:- may provide benefits for environmental survival or swine colonization in metal-containing settings.
Carbon Source Influence on Extracellular pH Changes along Bacterial Cell-Growth
Authors: Sánchez-Clemente Rubén , Guijo M. Isabel , Nogales Juan , Blasco Rafael
Published: October 2020

The effect of initial pH on bacterial cell-growth and its change over time was studied under aerobic heterotrophic conditions by using three bacterial strains: Escherichia coli ATCC 25922, Pseudomonas putida KT2440, and Pseudomonas pseudoalcaligenes CECT 5344. In Luria-Bertani (LB) media, pH evolved by converging to a certain value that is specific for each bacterium. By contrast, in the buffered Minimal Medium (MM), pH was generally more stable along the growth curve. In MM with glucose as carbon source, a slight acidification of the medium was observed for all strains. In the case of E. coli, a sudden drop in pH was observed during exponential cell growth that was later recovered at initial pH 7 or 8, but was irreversible below pH 6, thus arresting further cell-growth. When using other carbon sources in MM at a fixed initial pH, pH changes depended mainly on the carbon source itself. While glucose, glycerol, or octanoate slightly decreased extracellular pH, more oxidized carbon sources, such as citrate, 2-furoate, 2-oxoglutarate, and fumarate, ended up with the alkalinization of the medium. These observations are in accordance with pH change predictions using genome-scale metabolic models for the three strains, thus revealing the metabolic reasons behind pH change. Therefore, we conclude that the composition of the medium, specifically the carbon source, determines pH change during bacterial growth to a great extent and unravel the main molecular mechanism behind this phenotype. These findings pave the way for predicting pH changes in a given bacterial culture and may anticipate the interspecies interactions and fitness of bacteria in their environment.
Tectono-Sedimentary Evolution of the Madrid Basin (Spain) during the Late Miocene: Data from Paleokarst Profiles in Diagenetically-Complex Continental Carbonates
Authors: Cañaveras Juan Carlos , Calvo Jose Pedro , Ordóñez Salvador , Muñoz-Cervera María Concepción , Sánchez-Moral Sergio
Published: October 2020

An intra-Vallesian (Upper Miocene) paleokarst developed at the top of the Intermediate Miocene Unit in the continental intracratonic Madrid Basin is recognized. This paleokarst is an early shallow, tabular-shaped karst that shows a marked control by the depositional facies pattern and lithologies. By integrating morphological, petrological, and geochemical data, three hydrogeological zones were established throughout the paleokarstic profiles: (i) a paleo-vadose zone, characterized by vertically elongated caves and vadose cementation; (ii) a 3–7 m thick paleo-epiphreatic zone (paleo-water table fringe), with development of stratiform breccia bodies, the superimposition of both vadose and phreatic features, and the lowest Fe and Mn contents in host-rock carbonates; and (iii) a paleo-phreatic zone characterized by an increase in δ13C values and the predominance of phreatic cementation. The paleogeographic reconstruction for the intra-Vallesian paleokarst using profiles revealed relative topographic highs to the north and topographic lows to the south, drawing the paleokarst landscape. Immediately overlaying the paleokarst surface are fluvio-lacustrine facies belonging to the Miocene Upper Unit (Late Vallesian to Late Turolian). Their lowermost deposits consist of fluvial terrigenous facies deposited by approximately N–S fluvial streams, and pass upward into fluvio-lacustrine fresh-water limestones. This paleokarstic surface represents a major change in the evolution of sedimentary patterns of basin, from endorheic to exorheic conditions, as the result of a change from compressive to extensional conditions in the tectonic regime.
A Sisterhood of Hope: How China’s Transgender Sex Workers Cope with Intimate Partner Violence
Authors: Tsang Eileen Yuk-ha
Published: October 2020

Transgender sex workers (TSWs/TSW) face considerable challenges that affect their mental health and make their situations more vulnerable and precarious. TSWs often experience violence from clients, police, and others, but it is estimated that 50% of these acts of violence are at the hands of their intimate partners. The marginalization of TSWs is fueled by abuse through isolation and shaming which prevents them from seeking help through formal channels like police or counselling services. There is limited research on intimate partner violence (IPV) involving transgender sex workers (biologically male at birth who transition to women) and their partners who are typically heterosexual/bisexual men. In China, stigmatization, homophobia, heterosexism, and transphobia structurally disadvantage TSWs and this power structure tacitly supports violence and abuse against them. To survive, TSWs rely on informal networks with their ‘sisters’ for advice and emotional support which is more effective at combatting IPV than criminal justice or social policy efforts. Ethnographic data from in-depth interviews with 25 TSWs provide insight about IPV and how informal social support is a protective factor that helps them cope with routine acts of violence. The findings identify the importance of the ‘sisterhood’ and how it protects and helps TSWs manage their physical and mental health.
Evaluating Animal-Based Foods and Plant-Based Alternatives Using Multi-Criteria and SWOT Analyses
Authors: Blanco-Gutiérrez Irene , Varela-Ortega Consuelo , Manners Rhys
Published: October 2020

Global diets have transitioned in recent decades with animal and processed products increasing. Promoting a reversal in these trends towards plant-based diets could reduce the environmental impacts of food systems and reduce the prevalence of non-communicable diseases and malnutrition. In Spain, a reference point for the Mediterranean diet (predominantly plant-source based), plant-based alternatives to traditional animal-based products are receiving increased attention. However, limited focus has been given to the opinions of stakeholder groups on the potential of these novel products. We evaluate the opinions of stakeholders within the Spanish agri-food sector, using multicriteria and SWOT analyses, on traditional and novel food products. Stakeholders involved in the supply chain of food products (producers, processors, and distributors) were critical of novel plant-based foods, highlighting problems with their taste, processing technology, and high prices. These results contrast with the perspectives of policymakers, researchers, environmental NGOs, and consumers who see novel products more positively - healthier, more sustainable, and highly profitable. These results illustrate the more traditional mindset seen in Spanish production systems, contrasting with the rapidly shifting tastes and demands of consumers and the potential legislative orientation of policymakers. This study calls for improved understanding and collaboration between stakeholders to better manage complex choices that affect the future of food systems during their needed transformation.
Association of Oral Status and Early Primary Hypertension Biomarkers among Children and Adolescents
Authors: Paszynska Elzbieta , Dmitrzak-Weglarz Monika , Ostalska-Nowicka Danuta , Nowicki Michal , Gawriolek Maria , Zachwieja Jacek
Published: October 2020

The aim of this case–control study was the evaluation of the association between biomarkers of early primary arterial hypertension (HA) and oral diseases among children and adolescents. Material and methods. Subjects suspected of primary HA (n = 180) underwent a complex evaluation of their vascular status: blood pressure, heart rate, vascular stiffness, sympathetic activity in a 24 h ambulatory examination, followed by measurement of serum uric acid (UA), cystatin C, and creatinine. This procedure allowed the identification of children with primary (n = 58) and secondary HA (n = 74), as well as of children with normal arterial blood pressure, who served as a control group (n = 48). All subjects with secondary HA were excluded from further investigation. Oral examination included the measurement of caries intensity (using the decayed, missing, filled index for permanent teeth DMFT /primary teeth dmft), bacterial plaque (by the plaque control record index, PCR%), and gingivitis (by the bleeding on probing index, BOP%). For statistical analysis, a linear regression model and Spearman rank correlation were used. Results. UA, cystatin C, and creatinine were not altered in the HA group. However, the number of decayed permanent teeth (DT) and the DMFT, PCR%, and BOP% indexes were significantly higher in the primary HA group compared to the control group (p = 0.0006; p = 0.02; p = 0.0009; p = 0.003). Our results are not sufficient to prove the important role of caries and gingival inflammation in the modulation of HA symptoms, although they prove the association of oral diseases with primary HA symptoms. This may indicate future strategies for preventive measures for hypertensive children and adolescents.
Maternal and Early-Life Nutrition and Health
Authors: Huang Li-Tung
Published: October 2020

Nutritional challenges prior to and during gestation, lactation, and early life are known to influence the lifelong health of the infant. In this editorial, I briefly discuss the 13 articles published in this Special Issue, “Maternal and Early-Life Nutrition and Health”. This Special Issue discusses topics including maternal nutrition behaviors, maternal overnutrition/obesity, maternal iron deficiency, breastfeeding, and others. This issue paves the way to better understand perinatal nutrition and how it can impact maternal and offspring health.
Increasing HPV Vaccination Uptake among Adolescents: A Systematic Review
Authors: Acampora Anna , Grossi Adriano , Barbara Andrea , Colamesta Vittoria , Causio Francesco Andrea , Calabrò Giovanna Elisa , Boccia Stefania , de Waure Chiara
Published: October 2020

Human Papillomavirus (HPV) vaccination is a well-known fundamental strategy in the prevention of cervical cancer, as it is always caused by HPV infection. In fact, primary prevention of the infection corresponds to primary prevention of HPV-related cancers and other diseases. Since an effective prevention at the population level is the final goal, it is mandatory for healthcare systems to achieve a high HPV vaccination coverage among the adolescents to reduce the circulation of the virus and the burden of HPV-related diseases. This research identified, through a systematic literature review, 38 papers on strategies adopted to increase HPV vaccination coverage among adolescents. The evaluated strategies targeted adolescents/parents and/or healthcare providers and could be grouped in three main types: (1) reminder-based, (2) education, information, and communication activities, and (3) multicomponent strategies. Several types of strategy, such as those relied only on reminders and integrating different interventions, showed a positive impact on vaccination coverage. Nonetheless, the heterogeneity of the interventions suggests the importance to adapt such strategies to the specific national/local contexts to maximize vaccination coverage.
HRV-Based Training for Improving VO2max in Endurance Athletes. A Systematic Review with Meta-Analysis
Authors: Granero-Gallegos Antonio , González-Quílez Alberto , Plews Daniel , Carrasco-Poyatos María
Published: October 2020

This review aimed to synthesize evidence regarding interventions based on heart rate variability (HRV)-guided training for VO2max improvements in endurance athletes and address the issues that impact this performance enhancement. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL Complete, the Web of Science Core Collection, Global Health, Current Contents Connect, and the SciELO citation index were searched. Inclusion criteria were: randomized controlled trials; studies with trained athletes enrolled in any regular endurance training; studies that recruited men, women, and both sexes combined; studies on endurance training controlled by HRV; studies that measured performance with VO2max. A random-effects meta-analysis calculating the effect size (ES) was used. Moderator analyses (according to the athlete’s level and gender) and metaregression (according to the number of participants in each group) were undertaken to examine differences in ES. HRV-guided training and control training enhanced the athletes’ VO2max (p < 0.0001), but the ES for the HRV-guided training group was significantly higher (p < 0.0001; ESHRVG-CG = 0.187). The amateur level and female subgroup reported better and significant results (p < 0.0001) for VO2max. HRV-guided training had a small (ES = 0.402) but positive effect on endurance athlete performance (VO2max), conditioned by the athlete’s level and sex.
Healthy Living and Co-Production: Evaluation of Processes and Outcomes of a Health Promotion Initiative Co-Produced with Adolescents
Authors: De Rosis Sabina , Pennucci Francesca , Noto Guido , Nuti Sabina
Published: October 2020

Co-production is an approach to designing, delivering, and evaluating public services through strict collaboration among professionals and the people using services with an equal and reciprocal relationship. Health promotion initiatives that include education services rarely use the co-production approach. Nevertheless, the value of co-production is widely recognized, although it is considered a normative good, and scarce and mixed evidence is available in literature. The purpose of this paper is to provide evidence supporting the hypothesis that a co-production approach, applied to an intervention for preventing obesity, can be effective and efficient. To this end, an evaluation of the processes, outputs meant as intermediate results, and behavioral and economic outcomes of a public health-promotion initiative co-produced and co-delivered with adolescents (beFood) was conducted. Mixed methods were used, including field-observations, two self-reported questionnaires, and an opportunity–cost analysis that compared beFood to traditional approaches of public health promotion. The co-production model was successfully implemented and appears to be effective—more than 5000 adolescents were reached by only 49 co-producer adolescents, who reported behavioral changes (e.g., eating better and practicing more physical activity). The cost analysis showed that the co-production approach was also efficient, producing relevant savings and potentially making available more than 3000 h of professionals’ time. This research can support a re-thinking of public institutions’ organization, public initiatives’ design, and public servants’ role.
Transcriptional Regulation of Inflammasomes
Authors: Cornut Maxence , Bourdonnay Emilie , Henry Thomas
Published: October 2020

Inflammasomes are multimolecular complexes with potent inflammatory activity. As such, their activity is tightly regulated at the transcriptional and post-transcriptional levels. In this review, we present the transcriptional regulation of inflammasome genes from sensors (e.g., NLRP3) to substrates (e.g., IL-1β). Lineage-determining transcription factors shape inflammasome responses in different cell types with profound consequences on the responsiveness to inflammasome-activating stimuli. Pro-inflammatory signals (sterile or microbial) have a key transcriptional impact on inflammasome genes, which is largely mediated by NF-κB and that translates into higher antimicrobial immune responses. Furthermore, diverse intrinsic (e.g., circadian clock, metabolites) or extrinsic (e.g., xenobiotics) signals are integrated by signal-dependent transcription factors and chromatin structure changes to modulate transcriptionally inflammasome responses. Finally, anti-inflammatory signals (e.g., IL-10) counterbalance inflammasome genes induction to limit deleterious inflammation. Transcriptional regulations thus appear as the first line of inflammasome regulation to raise the defense level in front of stress and infections but also to limit excessive or chronic inflammation.
Inhibition of Porcine Epidemic Diarrhea Virus Replication and Viral 3C-Like Protease by Quercetin
Authors: Li Zhonghua , Cao Hua , Cheng Yufang , Zhang Xiaoqian , Zeng Wei , Sun Yumei , Chen Shuhua , He Qigai , Han Heyou
Published: October 2020

For the last decade, porcine epidemic diarrhea virus (PEDV) variant strains have caused severe damage to the global pig industry. Until now, no effective antivirals have been developed for the therapeutic treatment of PEDV infection. In the present study, we found that quercetin significantly suppressed PEDV infection at noncytotoxic concentrations. A molecular docking study indicated that quercetin might bind the active site and binding pocket of PEDV 3C-like protease (3CLpro). Surface plasmon resonance (SPR) analysis revealed that quercetin exhibited a binding affinity to PEDV 3CLpro. Based on the results of the fluorescence resonance energy transfer (FRET) assay, quercetin was proven to exert an inhibitory effect on PEDV 3CLpro. Since coronavirus 3CLpro is an important drug target and participates in the viral replication process, quercetin should be developed as a novel drug in the control of PEDV infection.
Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation
Authors: Spasskaya Daria S. , Nadolinskaia Nonna I. , Tutyaeva Vera V. , Lysov Yuriy P. , Karpov Vadim L. , Karpov Dmitry S.
Published: October 2020

Environmental and intracellular factors often damage DNA, but multiple DNA repair pathways maintain genome integrity. In yeast, the 26S proteasome and its transcriptional regulator and substrate Rpn4 are involved in DNA damage resistance. Paradoxically, while proteasome dysfunction may induce hyper-resistance to DNA-damaging agents, Rpn4 malfunction sensitizes yeasts to these agents. Previously, we proposed that proteasome inhibition causes Rpn4 stabilization followed by the upregulation of Rpn4-dependent DNA repair genes and pathways. Here, we aimed to elucidate the key Rpn4 targets responsible for DNA damage hyper-resistance in proteasome mutants. We impaired the Rpn4-mediated regulation of candidate genes using the CRISPR/Cas9 system and tested the sensitivity of mutant strains to 4-NQO, MMS and zeocin. We found that the separate or simultaneous deregulation of 19S or 20S proteasome subcomplexes induced MAG1, DDI1, RAD23 and RAD52 in an Rpn4-dependent manner. Deregulation of RAD23, DDI1 and RAD52 sensitized yeast to DNA damage. Genetic, epigenetic or dihydrocoumarin-mediated RAD52 repression restored the sensitivity of the proteasome mutants to DNA damage. Our results suggest that the Rpn4-mediated overexpression of DNA repair genes, especially RAD52, defines the DNA damage hyper-resistant phenotype of proteasome mutants. The developed yeast model is useful for characterizing drugs that reverse the DNA damage hyper-resistance phenotypes of cancers.
Intramolecular Lactones of Sialic Acids
Authors: Rota Paola , La Rocca Paolo , Allevi Pietro , Pappone Carlo , Anastasia Luigi
Published: October 2020

The so-called “sialo-chemical-biology” has become an attractive research area, as an increasing number of natural products containing a sialic acid moiety have been shown to play important roles in biological, pathological, and immunological processes. The intramolecular lactones of sialic acids are a subclass from this crucial family that could have central functions in the discrimination of physiological and pathological conditions. In this review, we report an in-depth analysis of the synthetic achievements in the preparation of the intramolecular lactones of sialic acids (1,4-, 1,7- and γ-lactones), in their free and/or protected form. In particular, recent advances in the synthesis of the 1,7-lactones have allowed the preparation of key sialic acid derivatives. These compounds could be used as authentic reference standards for their correct determination in biological samples, thus overcoming some of the limitations of the previous analytical procedures.
The Tumor Microenvironment of Primitive and Metastatic Breast Cancer: Implications for Novel Therapeutic Strategies
Authors: Zarrilli Giovanni , Businello Gianluca , Dieci Maria Vittoria , Paccagnella Silvia , Carraro Valentina , Cappellesso Rocco , Miglietta Federica , Griguolo Gaia , Guarneri Valentina , Lo Mele Marcello , Fassan Matteo
Published: October 2020

Breast cancer evolves thanks to a dense and close interaction with the surrounding tumor microenvironment (TME). Fibroblasts, leukocytes, blood and lymphatic endothelial cells and extracellular matrix are the constituents of this entity, and they synergistically play a pivotal role in all of the stages of breast cancer development, from its onset to its metastatic spread. Moreover, it has been widely demonstrated that variations to the TME can correspond to prognosis variations. Breast cancer not only modulates the transformation of the environment within the mammary gland, but the same process is observed in metastases as well. In this minireview, we describe the features of TME within the primitive breast cancer, throughout its evolution and spread into the main metastatic sites.
Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition
Authors: Montalvo Ryan N. , Doerr Vivian , Kwon Oh Sung , Talbert Erin E. , Yoo Jeung-Ki , Hwang Moon-Hyon , Nguyen Branden L. , Christou Demetra D. , Kavazis Andreas N. , Smuder Ashley J.
Published: October 2020

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague–Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5–ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences.
A Novel Mutation of the NARROW LEAF 1 Gene Adversely Affects Plant Architecture in Rice (Oryza sativa L.)
Authors: Subudhi Prasanta K. , Garcia Richard S. , Coronejo Sapphire , De Leon Teresa B.
Published: October 2020

Plant architecture is critical for enhancing the adaptability and productivity of crop plants. Mutants with an altered plant architecture allow researchers to elucidate the genetic network and the underlying mechanisms. In this study, we characterized a novel nal1 rice mutant with short height, small panicle, and narrow and thick deep green leaves that was identified from a cross between a rice cultivar and a weedy rice accession. Bulked segregant analysis coupled with genome re-sequencing and cosegregation analysis revealed that the overall mutant phenotype was caused by a 1395-bp deletion spanning over the last two exons including the transcriptional end site of the nal1 gene. This deletion resulted in chimeric transcripts involving nal1 and the adjacent gene, which were validated by a reference-guided assembly of transcripts followed by PCR amplification. A comparative transcriptome analysis of the mutant and the wild-type rice revealed 263 differentially expressed genes involved in cell division, cell expansion, photosynthesis, reproduction, and gibberellin (GA) and brassinosteroids (BR) signaling pathways, suggesting the important regulatory role of nal1. Our study indicated that nal1 controls plant architecture through the regulation of genes involved in the photosynthetic apparatus, cell cycle, and GA and BR signaling pathways.
Soft Template Electropolymerization of Polypyrrole for Improved pH-Induced Drug Delivery
Authors: Liubchak Iryna , Lawrence Matthew T. , Holness F. Benjamin , Price Aaron D.
Published: October 2020

Chronic wounds are characterized by a localized pH change from acidic (healthy) to alkaline (unhealthy), which can be harnessed to act as a switch for drug release from a polymer medium covering the wound for improved healing. To realize this, a new polymer dressing material is needed to help heal chronic wounds. Polypyrrole (PPy) is a biocompatible electroactive polymer that has been proven as a successful drug delivery mechanism, but currently lacks the capacity for scalable clinical applications due to its poor processability. In this study, PPy films with and without microstructures were produced using electrochemical oxidation and subsequently doped with fluorescein, a model drug molecule. To increase the drug loading capacity, microstructures were created through soft template polymerization of pyrrole around hydrogen gas bubbles. Fluorescein release was measured using UV spectroscopy over a pH range of 2 to 11, showing increased release at higher pH values. Microstructured films showed an increased doping capacity compared to flat PPy films, attributed to the increase in drug incorporation sites. The pH-activated release mechanism was shown to be successful and can be applied as a pH-sensitive biosensor and drug delivery system in vitro.
Research of Pathogenesis and Novel Therapeutics in Arthritis 2.0
Authors: Tang Chih-Hsin
Published: October 2020

Arthritis has a high prevalence globally and includes over 100 types, the most common of which are rheumatoid arthritis, osteoarthritis, psoriatic arthritis, and inflammatory arthritis. All types of arthritis share common features of disease, including monocyte infiltration, inflammation, synovial swelling, pannus formation, stiffness in the joints and articular cartilage destruction. The exact etiology of arthritis remains unclear, and no cure exists as of yet. Anti-inflammatory drugs (NSAIDs and corticosteroids) are commonly used in the treatment of arthritis. However, these drugs are associated with significant side effects, such as gastric bleeding and an increased risk for heart attack and other cardiovascular problems. It is therefore crucial that we continue to research the pathogenesis of arthritis and seek to discover novel modes of therapy. This editorial summarizes and discusses the themes of the 27 articles published in our Special Issue “Research of Pathogenesis and Novel Therapeutics in Arthritis 2.0”, a continuation of our 2019 Special Issue “Research of Pathogenesis and Novel Therapeutics in Arthritis”. These Special Issues detail important novel research discoveries that contribute to our current understanding of arthritis.
Spliceosome-Associated microRNAs Signify Breast Cancer Cells and Portray Potential Novel Nuclear Targets
Authors: Mahlab-Aviv Shelly , Zohar Keren , Cohen Yael , Peretz Ayelet R. , Eliyahu Tsiona , Linial Michal , Sperling Ruth
Published: October 2020

MicroRNAs (miRNAs) act as negative regulators of gene expression in the cytoplasm. Previous studies have identified the presence of miRNAs in the nucleus. Here we study human breast cancer-derived cell-lines (MCF-7 and MDA-MB-231) and a non-tumorigenic cell-line (MCF-10A) and compare their miRNA sequences at the spliceosome fraction (SF). We report that the levels of miRNAs found in the spliceosome, their identity, and pre-miRNA segmental composition are cell-line specific. One such miRNA is miR-7704 whose genomic position overlaps HAGLR, a cancer-related lncRNA. We detected an inverse expression of miR-7704 and HAGLR in the tested cell lines. Specifically, inhibition of miR-7704 caused an increase in HAGLR expression. Furthermore, elevated levels of miR-7704 slightly altered the cell-cycle in MDA-MB-231. Altogether, we show that SF-miR-7704 acts as a tumor-suppressor gene with HAGLR being its nuclear target. The relative levels of miRNAs found in the spliceosome fractions (e.g., miR-100, miR-30a, and let-7 family) in non-tumorigenic relative to cancer-derived cell-lines was monitored. We found that the expression trend of the abundant miRNAs in SF was different from that reported in the literature and from the observation of large cohorts of breast cancer patients, suggesting that many SF-miRNAs act on targets that are different from the cytoplasmic ones. Altogether, we report on the potential of SF-miRNAs as an unexplored route for cancerous cell state.
Mutual and Opposing Responses of Carabid Beetles and Predatory Wasps to Local and Landscape Factors in Vineyards
Authors: Uzman Deniz , Entling Martin H. , Leyer Ilona , Reineke Annette
Published: October 2020

Preserving agro-biodiversity is one of the main means at the moment to counteract the global biodiversity crisis. Vineyard inter-rows offer vegetation covers which could function as foraging grounds for arthropods. Furthermore, organic management and enhanced landscape complexity often support biodiversity. Here, species richness and abundance of two groups of arthropod predators in vineyards were studied. Fifteen pairs of organically and conventionally managed vineyards were chosen along a gradient of landscape complexity in Rhine-Hesse, Germany. Carabid beetles were sampled using pitfall traps and cavity-nesting wasps with trap nests, respectively. Proportions of different land-use types surrounding the vineyards were calculated and inter-row vegetation cover was characterized. Species richness and abundances of both predator groups were not significantly affected by the management system. Likewise, increased cover of semi-natural habitats in the surrounding landscape did not promote their diversity or abundance. Instead, the increasing cover of annual crops diminished both groups. Cavity-nesting wasps profited from dense inter-row vegetation cover, while carabids were disadvantaged. The results indicate that distinct taxa within the same trophic group can respond oppositely to vineyard management. Thus, inter-row vegetation management with densely and sparsely vegetated elements might be best to support predator diversity. Overall, our results suggest that organic viticulture alone is insufficient to assist the studied insect groups, and that other local and landscape management options are needed for their protection.
The Extended Utility of CHA2DS2VASc and HAS-BLED Scores in the Selection for Transcutaneous Left Atrial Appendage Closure
Authors: Streb Witold , Mitręga Katarzyna , Morawski Stanisław , Kowalska Wiktoria , Kalarus Zbigniew
Published: October 2020

Background and purpose: Left atrial appendage closure (LAAC) is an option for stroke prevention in atrial fibrillation patients. Randomized studies have demonstrated the effectiveness and safety of LAAC but included patients with an average risk of stroke and bleeding complications. The current study aimed to assess the extended utility of CHA2DS2VASc (congestive heart failure; hypertension; age ≥75 years [doubled]; type 2 diabetes; previous stroke, transient ischemic attack, or thromboembolism [doubled]; vascular disease; age 65 to 75 years; and sex category) and HAS-BLED (hypertension; abnormal renal/liver function; stroke; bleeding history or predisposition; labile INR, elderly, drugs/alcohol concomitantly) scores for qualification and prognosis after LAAC. Methods: The study population comprised 270 patients aged 72.8 ± 8.78 years. The occluders used were the Amplatzer Amulet (N = 205), Amplatzer Cardiac Plug (N = 53), and Watchman device (N = 12). The prognosis after LAAC was analyzed for different cohorts of patients distinguished based on different CHA2DS2VASc and HAS-BLED scores. The mean duration of follow-up was 21.6 ± 10.3 months. Results: The observed rates of ischemic stroke and bleeding were much lower than that expected (2.2% vs. 5.6%, and 0.76% vs. 6.05%, respectively). The mortality rate did not differ concerning the CHA2DS2CVASc score. It was significantly lower (8.3%) for HAS-BLED < 3, and it raised to 17.9% for HAS-BLED = 3 and to 25.9% for HAS-BLED > 3. Significant differences (p = 0.003) occurred for Kaplan–Meier curves for extreme HAS-BLED subgroups. A composite endpoint was most often found in high/very high risk of bleeding patients. Conclusions: HAS-BLED, but not CHA2DS2CVASc score, may be a useful tool to predict the prognosis of patients after LAAC. Qualification for LAAC based on the risk of stroke should not differ from qualification for anticoagulation. Despite the worse prognosis of patients with the highest bleeding risk, this group is likely to experience the greatest benefit from reducing the bleeding risk from LAAC.