bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic and Transcriptomic Analysis Identified Novel Putative Cassava lncRNAs Involved in Cold and Drought Stress
Authors: Suksamran Rungaroon , Saithong Treenut , Thammarongtham Chinae , Kalapanulak Saowalak
Published: April 2020

Long non-coding RNAs (lncRNAs) play important roles in the regulation of complex cellular processes, including transcriptional and post-transcriptional regulation of gene expression relevant for development and stress response, among others. Compared to other important crops, there is limited knowledge of cassava lncRNAs and their roles in abiotic stress adaptation. In this study, we performed a genome-wide study of ncRNAs in cassava, integrating genomics- and transcriptomics-based approaches. In total, 56,840 putative ncRNAs were identified, and approximately half the number were verified using expression data or previously known ncRNAs. Among these were 2229 potential novel lncRNA transcripts with unmatched sequences, 250 of which were differentially expressed in cold or drought conditions, relative to controls. We showed that lncRNAs might be involved in post-transcriptional regulation of stress-induced transcription factors (TFs) such as zinc-finger, WRKY, and nuclear factor Y gene families. These findings deepened our knowledge of cassava lncRNAs and shed light on their stress-responsive roles.
Genotyping by Sequencing Revealed QTL Hotspots for Trichome-Based Plant Defense in Gossypium hirsutum
Authors: Ahmed Haris , Nazir Mian Faisal , Pan Zhoe , Gong Wenfang , Iqbal Muhammad Shahid , He Shoupu , Du Xiongming
Published: April 2020

Cotton possesses certain physical features, including leaf and stem trichomes that help plants deter damage caused by insect pests, and to some extent, from abiotic factors as well. Among those features, trichomes (pubescence) hold a special place as a first line of defense and a managemental tool against sucking insect pests of cotton. Different insect pests of cotton (whiteflies, aphids, jassids, and boll weevil) severely damage the yield and quality of the crop. Likewise, whiteflies, aphids, jassids, and other insect pests are considered as potential carriers for cotton leaf curl viruses and other diseases. Genotyping by sequencing (GBS) study was conducted to understand and explore the genomic regions governing hairy (Pubescence) leaves and stem phenotypes. A total of 224 individuals developed from an intraspecific cross (densely haired cotton (Liaoyang duomao mian) × hairless cotton (Zong 128)) and characterized phenotypically for leaf and stem pubescence in different environments. Here we identify and report significant QTLs (quantitative trait loci) associated with leaf and stem pubescence, and the response of plant under pest (aphid) infestation. Further, we identified putative genes colocalized on chromosome A06 governing mechanism for trichome development and host–pest interaction. Our study provides a comprehensive insight into genetic architecture that can be employed to improve molecular marker-assisted breeding programs aimed at developing biotic (insect pests) resilient cotton cultivars.
A Comparative Analysis of CD32A and CD16A Polymorphisms in Relation to Autoimmune Responses in Pemphigus Diseases and Subepithelial Autoimmune Blistering Disorders
Authors: Gornowicz-Porowska Justyna , Kowalczyk Michał J. , Seraszek-Jaros Agnieszka , Bowszyc-Dmochowska Monika , Kaczmarek Elżbieta , Żaba Ryszard , Dmochowski Marian
Published: April 2020

Autoimmune blistering dermatoses (ABDs) are characterized by autoantibodies to keratinocyte surface antigens and molecules within the dermal–epidermal junction causing disruption of skin integrity. The affinity of Fc receptors (FcRs) causing an autoimmune response in ABDs may vary based on single-nucleotide polymorphisms (SNPs) in FcRs determining the course of disease. This study aimed to explore the effects of CD16A and CD32A SNPs on the autoimmune response in several ABDs. In total, 61 ABDs patients were investigated. ELISA tests, direct immunofluorescence (DIF), TaqMan SNP Genotyping Assays, and statistical analyses were performed. The CA genotype (composed of allele C and A) of rs396991 in CD16A had a higher affinity for tissue-bound IgG1 in pemphigus and for C3 in subepithelial ABDs, showing statistical significance. The greatest relative risk (odds ratio) was reported for AA (rs396991 of CD16A) and CC (rs1801274 of CD32A) homozygotes. There were no statistically significant differences between certain genotypes and specific circulating autoantibodies (anti-DSG1, anti-DSG3 IgG in pemphigus; anti-BP180, anti-BP230 IgG) in subepithelial ABDs. Our findings indicated that rs396991 in CD16A may be of greater importance in ABDs development. Moreover, FcR polymorphisms appeared to have a greater impact on tissue-bound antibodies detected using DIF than circulating serum antibodies in ABDs.
Complex Structure of Lasiopodomys mandarinus vinogradovi Sex Chromosomes, Sex Determination, and Intraspecific Autosomal Polymorphism
Authors: Romanenko Svetlana A. , Smorkatcheva Antonina V. , Kovalskaya Yulia M. , Prokopov Dmitry Yu. , Lemskaya Natalya A. , Gladkikh Olga L. , Polikarpov Ivan A. , Serdyukova Natalia A. , Trifonov Vladimir A. , Molodtseva Anna S. , O’Brien Patricia C. M. , Golenishchev Feodor N. , Ferguson-Smith Malcolm A. , Graphodatsky Alexander S.
Published: April 2020

The mandarin vole, Lasiopodomys mandarinus, is one of the most intriguing species among mammals with non-XX/XY sex chromosome system. It combines polymorphism in diploid chromosome numbers, variation in the morphology of autosomes, heteromorphism of X chromosomes, and several sex chromosome systems the origin of which remains unexplained. Here we elucidate the sex determination system in Lasiopodomys mandarinus vinogradovi using extensive karyotyping, crossbreeding experiments, molecular cytogenetic methods, and single chromosome DNA sequencing. Among 205 karyotyped voles, one male and three female combinations of sex chromosomes were revealed. The chromosome segregation pattern and karyomorph-related reproductive performances suggested an aberrant sex determination with almost half of the females carrying neo-X/neo-Y combination. The comparative chromosome painting strongly supported this proposition and revealed the mandarin vole sex chromosome systems originated due to at least two de novo autosomal translocations onto the ancestral X chromosome. The polymorphism in autosome 2 was not related to sex chromosome variability and was proved to result from pericentric inversions. Sequencing of microdissection derived of sex chromosomes allowed the determination of the coordinates for syntenic regions but did not reveal any Y-specific sequences. Several possible sex determination mechanisms as well as interpopulation karyological differences are discussed.
Novel Variants in GDF9 Gene Affect Promoter Activity and Litter Size in Mongolia Sheep
Authors: Tong Bin , Wang Jiapeng , Cheng Zixuan , Liu Jiasen , Wu Yiran , Li Yunhua , Bai Chunling , Zhao Suwen , Yu Haiquan , Li Guangpeng
Published: April 2020

Litter size is an economically important trait in sheep breeding. The objectives of this study were as follows: (1) to ascertain if any of the 19 known variants in the BMPRIB, BMP15, and GDF9 genes are present and associated with the litter size of Mongolia sheep; (2) to identify novel variants in GDF9 and perform association analysis; and (3) to validate the effects of these GDF9 promoter variants on the activity of the gene. The results of the 19 known variants showed that the FecBB affected the litter size of Mongolia sheep (p < 0.001). The association analysis results of novel variants showed that the g.46544883A>G (GenBank accession: NC_040256, the same below) in the 3’ untranslated region (3’ UTR), the c.1040T>C (Phe347Ser) in the exon 2, and the g.46547859C>T SNP in the promotor of GDF9 were significantly associated with litter size of Mongolia ewes (p < 0.01, p < 0.05, and p < 0.001, respectively). In addition, the GDF9 promoter activity analysis showed that the C allele at the −332 position (g.46547859C>T) could decrease luciferase activity compared with the T allele (p < 0.01). Our findings may facilitate effective marker-assisted selection to increase litter size in Mongolia sheep populations, as well as bring new insights into GDF9 expression.
Mother and Embryo Cross-Communication
Authors: Idelevich Anna , Vilella Felipe
Published: April 2020

Endometrial receptivity is a biosensor for embryo quality, as embryos with reduced developmental potential are rejected. However, embryo quality only accounts for an estimated one-third of implantation failures, with suboptimal endometrial receptivity accounting for the remaining two-thirds. As pregnancy progresses, a uterus continues to engage in close communication with an embryo/fetus, exchanging information in the form of endocrine, paracrine, and other cues. Given the long mammalian gestation period, this dialogue is intricate, diverse, and, currently, not fully understood. Recent progress and the availability of high-throughput techniques, including transcriptomics, proteomics, and metabolomics, has allowed the simultaneous examination of multiple molecular changes, enhancing our knowledge in this area. This review covers the known mechanisms of mother–embryo cross-communication gathered from animal and human studies.
Compound Phenotype Due to Recessive Variants in LARP7 and OTOG Genes Disclosed by an Integrated Approach of SNP-Array and Whole Exome Sequencing
Authors: Palumbo Pietro , Palumbo Orazio , Leone Maria Pia , di Muro Ester , Castellana Stefano , Bisceglia Luigi , Mazza Tommaso , Carella Massimo , Castori Marco
Published: April 2020

Neurodevelopmental disorders are a challenge in medical genetics due to genetic heterogeneity and complex genotype-phenotype correlations. For this reason, the resolution of single cases not belonging to well-defined syndromes often requires an integrated approach of multiple whole-genome technologies. Such an approach has also unexpectedly revealed a complex molecular basis in an increasing number of patients, for whom the original suspect of a pleiotropic syndrome has been resolved as the summation effect of multiple genes. We describe a 10-year-old boy, the third son of first-cousin parents, with global developmental delay, facial dysmorphism, and bilateral deafness. SNP-array analysis revealed regions of homozygosity (ROHs) in multiple chromosome regions. Whole-exome sequencing prioritized on gene-mapping into the ROHs showed homozygosity for the likely pathogenic c.1097_1098delAG p. (Arg366Thrfs*2) frameshift substitution in LARP7 and the likely pathogenic c.5743C>T p.(Arg1915*) nonsense variant in OTOG. Recessive variants in LARP7 cause Alazami syndrome, while variants in OTOG cause an extremely rare autosomal recessive form of neurosensorial deafness. Previously unreported features were acrocyanosis and palmoplantar hyperhidrosis. This case highlights the utility of encouraging technological updates in medical genetics laboratories involved in the study of neurodevelopmental disorders and integrating laboratory outputs with the competencies of next-generation clinicians.
Time Series RNA-seq in Pigeonpea Revealed the Core Genes in Metabolic Pathways under Aluminum Stress
Authors: Gao Zhaoxu , Dong Biying , Cao Hongyan , He Hang , Yang Qing , Meng Dong , Fu Yujie
Published: April 2020

Pigeonpea is an important economic crop in the world and is mainly distributed in tropical and subtropical regions. In order to further expand the scope of planting, one of the problems that must be solved is the impact of soil acidity on plants in these areas. Based on our previous work, we constructed a time series RNA sequencing (RNA-seq) analysis under aluminum (Al) stress in pigeonpea. Through a comparison analysis, 11,425 genes were found to be differentially expressed among all the time points. After clustering these genes by their expression patterns, 12 clusters were generated. Many important functional pathways were identified by gene ontology (GO) analysis, such as biological regulation, localization, response to stimulus, metabolic process, detoxification, and so on. Further analysis showed that metabolic pathways played an important role in the response of Al stress. Thirteen out of the 23 selected genes related to flavonoids and phenols were downregulated in response to Al stress. In addition, we verified these key genes of flavonoid- and phenol-related metabolism pathways by qRT-PCR. Collectively, our findings not only revealed the regulation mechanism of pigeonpea under Al stress but also provided methodological support for further exploration of plant stress regulation mechanisms.
Surgical Treatment of Femoral Neck Fractures: A Brief Review
Authors: Lutnick Ellen , Kang Jeansol , Freccero David M.
Published: April 2020

Hip fracture is a cause for concern in the geriatric population. It is one of the leading causes of traumatic injury in this demographic and correlates to a higher risk of all-cause morbidity and mortality. The Garden classification of femoral neck fractures (FNF) dictates treatment via internal fixation or hip replacement, including hemiarthroplasty or total hip arthroplasty. This review summarizes existing literature that has explored the difference in outcomes between internal fixation, hemiarthroplasty, and total hip arthroplasty for nondisplaced and displaced FNF in the geriatric population, and more specifically highlights the risks and benefits of a cemented vs. uncemented approach to hemiarthroplasty.
Reliability and Validity of the Activity Diversity Questionnaire for Older Adults in Japan
Authors: Takahashi Junta , Kawai Hisashi , Suzuki Hiroyuki , Fujiwara Yoshinori , Watanabe Yutaka , Hirano Hirohiko , Kim Hunkyung , Ihara Kazushige , Ishii Kaori , Oka Koichiro , Obuchi Shuichi
Published: April 2020

Recent research has suggested that the breadth and evenness of activity and activity diversity contribute to health outcomes among older adults. However, few established assessment tools for activity diversity have been developed. This study developed an Activity Diversity Questionnaire (ADQ) for older adults through expert consultation and a preliminary survey among 18 community-dwelling older adults. The diversity score was calculated according to Shannon’s entropy. In study 1, the intraclass correlation coefficients (ICC) of the diversity scores were determined for community-dwelling older adults (n = 30). In study 2, concurrent validity was tested with participants receiving comprehensive health checkups at the Itabashi ward in Japan in 2018 (n = 766). The correlation coefficients of the diversity scores were then calculated in reference to the Tokyo Metropolitan Institute of Gerontology Index of Competence and Japan Science and Technology Agency Index of Competence. The final version of the ADQ consisted of 20 total items with excellent test-retest reliability (ICC = 0.84) and moderate correlations with both the Tokyo Metropolitan Institute of Gerontology Index of Competence and Japan Science and Technology Agency Index of Competence (r = 0.48 and 0.60, respectively). The ADQ was developed through scientific procedures and revealed sufficient reliability and validity. As such, it is a scientifically validated tool for assessing activity diversity among older adults.
Maintaining Preparedness to Severe Though Infrequent Threats—Can It Be Done?
Authors: Siman-Tov Maya , Davidson Benny , Adini Bruria
Published: April 2020

Background: A mass casualty incident (MCI) caused by toxicological/chemical materials constitutes a potential though uncommon risk that may cause great devastation. Presentation of casualties exposed to such materials in hospitals, if not immediately identified, may cause secondary contamination resulting in dysfunction of the emergency department. The study examined the impact of a longitudinal evaluation process on the ongoing emergency preparedness of hospitals for toxicological MCIs, over a decade. Methods: Emergency preparedness for toxicological incidents of all Israeli hospitals were periodically evaluated, over ten years. The evaluation was based on a structured tool developed to encourage ongoing preparedness of Standard Operating Procedures (SOPs), equipment and infrastructure, knowledge of personnel, and training and exercises. The benchmarks were distributed to all hospitals, to be used as a foundation to build and improve emergency preparedness. Scores were compared within and between hospitals. Results: Overall mean scores of emergency preparedness increased over the five measurements from 88 to 95. A significant increase between T1 (first evaluation) and T5 (last evaluation) occurred in SOPs (p = 0.006), training and exercises (p = 0.003), and in the overall score (p = 0.004). No significant changes were found concerning equipment and infrastructure and knowledge; their scores were consistently very high throughout the decade. An interaction effect was found between the cycles of evaluation and the hospitals’ geographical location (F (1,20) = 3.0, p = 0.056), proximity to other medical facilities (F (1,20) = 10.0 p = 0.005), and type of area (Urban vs. Periphery) (F (1,20) = 13.1, p = 0.002). At T5, all hospitals achieved similar high scores of emergency preparedness. Conclusions: Use of accessible benchmarks, which clearly delineate what needs to be continually implemented, facilitates an ongoing sustenance of effective levels of emergency preparedness. As this was demonstrated for a risk that does not frequently occur, it may be assumed that it is possible and practical to achieve and maintain emergency preparedness for other potential risks.
Colorectal Polyp Prevalence According to Alcohol Consumption, Smoking and Obesity
Authors: Lee Kyujin , Kim Yong Hwan
Published: April 2020

This study aimed to analyze colorectal polyp prevalence associated with health behavior. Data from 1180 Korean men (young adult (YA), aged 40–49; middle age (MA) aged 50–59; old aged (OA), aged 60–79 years) were collected. Health behavior included alcohol consumption, smoking status, and obesity. Obesity was determined using body mass index (BMI) and waist circumference (WC). Odds ratio (OR) was calculated by logistic regression. The prevalence of polyps increased for current smokers by 2.642 times in the YA group, 3.468 times in the MA group, and 3.104 times in the OA group compared to the never-smokers. The OR for WC increased in subjects with obesity by 1.514 in the MA and 1.451 in the OA group compared to normal. The prevalence of three or more polyps increased with WC obesity by 2.3 times in YA, 2.2 times in MA, and 1.9 times in OA compared to normal WC. Therefore, smoking cessation and obesity management may reduce the risk of colorectal polyps.
The Relationship Exploration between Public Migration Attention and Population Migration from a Perspective of Search Query
Authors: Li Chun , He Jianhua , Duan Xingwu
Published: April 2020

Rapid population migration has been viewed as a critical factor impacting urban network construction and regional sustainable development. The supervision and analysis of population migration are necessary for guiding the optimal allocation of urban resources and for attaining the high efficiency development of region. Currently, the explorations of population migration are often restricted by the limitation of data. In the information era, search engines widely collect public attention, implying potential individual actions, and freely provide open, timelier, and large-scope search query data for helping explore regional phenomena and problems. In this paper, we endeavor to explore the possibility of adopting such data to depict population migration. Based on the search query from Baidu search engine, three migration attention indexes (MAIs) are constructed to capture public migration attention in cyber space. Taking three major urban agglomerations in China as case study, we conduct the correlation analysis among the cyber MAIs and population migration in geographical space. Results have shown that external-MAI and local-MAI can positively reflect the population migration inner regions and across regions from a holistic lens and that intercity-MAI can be a helpful supplement for the delineation of specific population flow. Along with the accumulation of cyber search query data, its potential in exploring population migration can be further reinforced.
Jump Driven Risk Model Performance in Cryptocurrency Market
Authors: Nekhili Ramzi , Sultan Jahangir
Published: April 2020

This paper aims at identifying a validated risk model for the cryptocurrency market. We propose a stochastic volatility model with co-jumps in return and volatility (SVCJ) to highlight the role of jumps in returns and volatility in affecting Value-at-Risk (VaR) and Expected Shortfall (ES) in cryptocurrency market. Validation results based on backtesting show that SVCJ model is superior in terms of statistical accuracy of VaR and ES estimates, compared to alternative models such as TGARCH (Threshold GARCH) volatility and RiskMetrics models. The results imply that for the cryptocurrency market, the best performing model is a stochastic process that accounts for both jumps in returns and volatility.
Flotillins: At the Intersection of Protein S-Palmitoylation and Lipid-Mediated Signaling
Authors: Kwiatkowska Katarzyna , Matveichuk Orest V. , Fronk Jan , Ciesielska Anna
Published: April 2020

Flotillin-1 and flotillin-2 are ubiquitously expressed, membrane-associated proteins involved in multifarious cellular events from cell signaling, endocytosis, and protein trafficking to gene expression. They also contribute to oncogenic signaling. Flotillins bind the cytosolic leaflet of the plasma membrane and endomembranes and, upon hetero-oligomerization, serve as scaffolds facilitating the assembly of multiprotein complexes at the membrane–cytosol interface. Additional functions unique to flotillin-1 have been discovered recently. The membrane-binding of flotillins is regulated by S-palmitoylation and N-myristoylation, hydrophobic interactions involving specific regions of the polypeptide chain and, to some extent, also by their oligomerization. All these factors endow flotillins with an ability to associate with the sphingolipid/cholesterol-rich plasma membrane domains called rafts. In this review, we focus on the critical input of lipids to the regulation of the flotillin association with rafts and thereby to their functioning. In particular, we discuss how the recent developments in the field of protein S-palmitoylation have contributed to the understanding of flotillin1/2-mediated processes, including endocytosis, and of those dependent exclusively on flotillin-1. We also emphasize that flotillins affect directly or indirectly the cellular levels of lipids involved in diverse signaling cascades, including sphingosine-1-phosphate and PI(4,5)P2. The mutual relations between flotillins and distinct lipids are key to the regulation of their involvement in numerous cellular processes.
Nutrition and Cardiovascular Health
Authors: Tappia Paramjit S. , Blewett Heather
Published: April 2020

There is unequivocal experimental, epidemiological and clinical evidence demonstrating a correlation between diet and increased risk of cardiovascular disease (CVD) [...]
Musashi-1: An Example of How Polyalanine Tracts Contribute to Self-Association in the Intrinsically Disordered Regions of RNA-Binding Proteins
Authors: Chen Tsai-Chen , Huang Jie-rong
Published: April 2020

RNA-binding proteins (RBPs) have intrinsically disordered regions (IDRs) whose biophysical properties have yet to be explored to the same extent as those of the folded RNA interacting domains. These IDRs are essential to the formation of biomolecular condensates, such as stress and RNA granules, but dysregulated assembly can be pathological. Because of their structural heterogeneity, IDRs are best studied by NMR spectroscopy. In this study, we used NMR spectroscopy to investigate the structural propensity and self-association of the IDR of the RBP Musashi-1. We identified two transient α-helical regions (residues ~208–218 and ~270–284 in the IDR, the latter with a polyalanine tract). Strong NMR line broadening in these regions and circular dichroism and micrography data suggest that the two α-helical elements and the hydrophobic residues in between may contribute to the formation of oligomers found in stress granules and implicated in Alzheimer’s disease. Bioinformatics analysis suggests that polyalanine stretches in the IDRs of RBPs may have evolved to promote RBP assembly.
The Emerging Role of Curcumin in the Modulation of TLR-4 Signaling Pathway: Focus on Neuroprotective and Anti-Rheumatic Properties
Authors: Panaro Maria Antonietta , Corrado Addolorata , Benameur Tarek , Paolo Cantatore Francesco , Cici Daniela , Porro Chiara
Published: April 2020

Natural products have been used in medicine for thousands of years. Given their potential health benefits, they have gained significant popularity in recent times. The administration of phytochemicals existed shown to regulate differential gene expression and modulate various cellular pathways implicated in cell protection. Curcumin is a natural dietary polyphenol extracted from Curcuma Longa Linn with different biological and pharmacological effects. One of the important targets of curcumin is Toll-like receptor-4 (TLR-4), the receptor which plays a key role in the modulation of the immune responses and the stimulation of inflammatory chemokines and cytokines production. Different studies have demonstrated that curcumin attenuates inflammatory response via TLR-4 acting directly on receptor, or by its downstream pathway. Curcumin bioavailability is low, so the use of exosomes, as nano drug delivery, could improve the efficacy of curcumin in inflammatory diseases. The focus of this review is to explore the therapeutic effect of curcumin interacting with TLR-4 receptor and how this modulation could improve the prognosis of neuroinflammatory and rheumatic diseases.
Biophysical Techniques for Target Validation and Drug Discovery in Transcription-Targeted Therapy
Authors: Moustaqil Mehdi , Gambin Yann , Sierecki Emma
Published: April 2020

In the post-genome era, pathologies become associated with specific gene expression profiles and defined molecular lesions can be identified. The traditional therapeutic strategy is to block the identified aberrant biochemical activity. However, an attractive alternative could aim at antagonizing key transcriptional events underlying the pathogenesis, thereby blocking the consequences of a disorder, irrespective of the original biochemical nature. This approach, called transcription therapy, is now rendered possible by major advances in biophysical technologies. In the last two decades, techniques have evolved to become key components of drug discovery platforms, within pharmaceutical companies as well as academic laboratories. This review outlines the current biophysical strategies for transcription manipulation and provides examples of successful applications. It also provides insights into the future development of biophysical methods in drug discovery and personalized medicine.
Muscular Development in Urechis unicinctus (Echiura, Annelida)
Authors: Han Yong-Hee , Ryu Kyoung-Bin , Medina Jiménez Brenda I. , Kim Jung , Lee Hae-Youn , Cho Sung-Jin
Published: April 2020

Echiura is one of the most intriguing major subgroups of phylum Annelida because, unlike most other annelids, echiuran adults lack metameric body segmentation. Urechis unicinctus lives in U-shape burrows of soft sediments. Little is known about the molecular mechanisms underlying the development of U. unicinctus. Herein, we overviewed the developmental process from zygote to juvenile U. unicinctus using immunohistochemistry and F-actin staining for the nervous and muscular systems, respectively. Through F-actin staining, we found that muscle fibers began to form in the trochophore phase and that muscles for feeding were produced first. Subsequently, in the segmentation larval stage, the transversal muscle was formed in the shape of a ring in an anterior-to-posterior direction with segment formation, as well as a ventromedian muscle for the formation of a ventral nerve cord. After that, many muscle fibers were produced along the entire body and formed the worm-shaped larva. Finally, we investigated the spatiotemporal expression of Uun_st-mhc, Uun_troponin I, Uun_calponin, and Uun_twist genes found in U. unicinctus. During embryonic development, the striated and smooth muscle genes were co-expressed in the same region. However, the adult body wall muscles showed differential gene expression of each muscle layer. The results of this study will provide the basis for the understanding of muscle differentiation in Echiura.
Epigenetic Regulation of Auxin-Induced Somatic Embryogenesis in Plants
Authors: Wójcikowska Barbara , Wójcik Anna M. , Gaj Małgorzata D.
Published: April 2020

Somatic embryogenesis (SE) that is induced in plant explants in response to auxin treatment is closely associated with an extensive genetic reprogramming of the cell transcriptome. The significant modulation of the gene transcription profiles during SE induction results from the epigenetic factors that fine-tune the gene expression towards embryogenic development. Among these factors, microRNA molecules (miRNAs) contribute to the post-transcriptional regulation of gene expression. In the past few years, several miRNAs that regulate the SE-involved transcription factors (TFs) have been identified, and most of them were involved in the auxin-related processes, including auxin metabolism and signaling. In addition to miRNAs, chemical modifications of DNA and chromatin, in particular the methylation of DNA and histones and histone acetylation, have been shown to shape the SE transcriptomes. In response to auxin, these epigenetic modifications regulate the chromatin structure, and hence essentially contribute to the control of gene expression during SE induction. In this paper, we describe the current state of knowledge with regard to the SE epigenome. The complex interactions within and between the epigenetic factors, the key SE TFs that have been revealed, and the relationships between the SE epigenome and auxin-related processes such as auxin perception, metabolism, and signaling are highlighted.
Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes
Authors: Caspar Sylvan M. , Schneider Timo , Meienberg Janine , Matyas Gabor
Published: April 2020

Although several pharmacogenetic (PGx) predispositions affecting drug efficacy and safety are well established, drug selection and dosing as well as clinical trials are often performed in a non-pharmacogenetically-stratified manner, ultimately burdening healthcare systems. Pre-emptive PGx testing offers a solution which is often performed using microarrays or targeted gene panels, testing for common/known PGx variants. However, as an added value, whole-genome sequencing (WGS) could detect not only disease-causing but also pharmacogenetically-relevant variants in a single assay. Here, we present our WGS-based pipeline that extends the genetic testing of Mendelian diseases with PGx profiling, enabling the detection of rare/novel PGx variants as well. From our in-house WGS (PCR-free 60× PE150) data of 547 individuals we extracted PGx variants with drug-dosing recommendations of the Dutch Pharmacogenetics Working Group (DPWG). Furthermore, we explored the landscape of DPWG pharmacogenes in gnomAD and our in-house cohort as well as compared bioinformatic tools for WGS-based structural variant detection in CYP2D6. We show that although common/known PGx variants comprise the vast majority of detected DPWG pharmacogene alleles, for better precision medicine, PGx testing should move towards WGS-based approaches. Indeed, WGS-based PGx profiling is not only feasible and future-oriented but also the most comprehensive all-in-one approach without generating significant additional costs.
miR-216a Acts as a Negative Regulator of Breast Cancer by Modulating Stemness Properties and Tumor Microenvironment
Authors: Roscigno Giuseppina , Cirella Assunta , Affinito Alessandra , Quintavalle Cristina , Scognamiglio Iolanda , Palma Francesco , Ingenito Francesco , Nuzzo Silvia , De Micco Francesca , Cuccuru Antonio , Thomas Renato , Condorelli Gerolama
Published: April 2020

Breast cancer is the most frequent malignancy in females in terms of both incidence and mortality. Underlying the high mortality rate is the presence of cancer stem cells, which divide indefinitely and are resistant to conventional chemotherapies, so causing tumor relapse. In the present study, we identify miR-216a-5p as a downregulated microRNA in breast cancer stem cells vs. the differentiated counterpart. We demonstrate that overexpression of miR-216a-5p impairs stemness markers, mammosphere formation, ALDH activity, and the level of Toll-like receptor 4 (TLR4), which plays a significant role in breast cancer progression and metastasis by leading to the release of pro-inflammatory molecules, such as interleukin 6 (IL-6). Indeed, miR-216a regulates the crosstalk between cancer cells and the cells of the microenvironment, in particular cancer-associated fibroblasts (CAFs), through regulation of the TLR4/IL6 pathway. Thus, miR-216a has an important role in the regulation of stem phenotype, decreasing stem-like properties and affecting the cross-talk between cancer cells and the tumor microenvironment.
The Implications for Cells of the Lipid Switches Driven by Protein–Membrane Interactions and the Development of Membrane Lipid Therapy
Authors: Torres Manuel , Rosselló Catalina Ana , Fernández-García Paula , Lladó Victoria , Kakhlon Or , Escribá Pablo Vicente
Published: April 2020

The cell membrane contains a variety of receptors that interact with signaling molecules. However, agonist–receptor interactions not always activate a signaling cascade. Amphitropic membrane proteins are required for signal propagation upon ligand-induced receptor activation. These proteins localize to the plasma membrane or internal compartments; however, they are only activated by ligand-receptor complexes when both come into physical contact in membranes. These interactions enable signal propagation. Thus, signals may not propagate into the cell if peripheral proteins do not co-localize with receptors even in the presence of messengers. As the translocation of an amphitropic protein greatly depends on the membrane’s lipid composition, regulation of the lipid bilayer emerges as a novel therapeutic strategy. Some of the signals controlled by proteins non-permanently bound to membranes produce dramatic changes in the cell’s physiology. Indeed, changes in membrane lipids induce translocation of dozens of peripheral signaling proteins from or to the plasma membrane, which controls how cells behave. We called these changes “lipid switches”, as they alter the cell’s status (e.g., proliferation, differentiation, death, etc.) in response to the modulation of membrane lipids. Indeed, this discovery enables therapeutic interventions that modify the bilayer’s lipids, an approach known as membrane-lipid therapy (MLT) or melitherapy.
Polylactide/Hydroxyapatite Nonwovens Incorporated into Chitosan/Graphene Materials Hydrogels to Form Novel Hierarchical Scaffolds
Authors: Kosowska Karolina , Domalik-Pyzik Patrycja , Krok-Borkowicz Małgorzata , Chłopek Jan
Published: April 2020

In this study, hierarchical, cylindrical scaffolds based on polylactide (PLA) microfibers incorporated into chitosan (CS) hydrogel were prepared for potential use in bone tissue engineering. PLA nonwovens modified with hydroxyapatite particles (HAp) were obtained using the electrospinning method. Then, three-dimensional scaffolds were created by rolling up the nonwovens and immersing them in CS-based solutions with graphene oxide (GO) or reduced graphene oxide (rGO) dispersed in the polymer matrix. Hydrogels were cross-linked using a novel freezing-thawing-gelling method. A broad spectrum of research methods was applied in order to thoroughly characterize both the nanofillers and the composite systems: scanning electron microscopy, X-ray photoelectron spectroscopy, X-ray diffractometry, attenuated total reflection Fourier transform infrared spectroscopy, rheological and mechanical testing, as well as the assessment of chemical stability, bioactivity and cytocompatibility.
Preface from the Guest Editor of Special Issue “Quantum-Chemical Modeling and Design of Chelate and Macrocyclic Metal Complexes”
Authors: Mikhailov Oleg V.
Published: April 2020

As is known, in the last fifty years of coordination of inorganic and organo-elemental chemistry, chemical compounds formed by chelating or macrocyclic organic and organo-elemental ligands (in particular, crown ethers, cryptands, calixarenes, cucurbituryls, porphyrins, and their various derivatives) and ions of various p-, d- and f-elements, have become of special interest [...]
Subcellular Localization of Copper—Cellular Bioimaging with Focus on Neurological Disorders
Authors: Witt Barbara , Schaumlöffel Dirk , Schwerdtle Tanja
Published: April 2020

As an essential trace element, copper plays a pivotal role in physiological body functions. In fact, dysregulated copper homeostasis has been clearly linked to neurological disorders including Wilson and Alzheimer’s disease. Such neurodegenerative diseases are associated with progressive loss of neurons and thus impaired brain functions. However, the underlying mechanisms are not fully understood. Characterization of the element species and their subcellular localization is of great importance to uncover cellular mechanisms. Recent research activities focus on the question of how copper contributes to the pathological findings. Cellular bioimaging of copper is an essential key to accomplish this objective. Besides information on the spatial distribution and chemical properties of copper, other essential trace elements can be localized in parallel. Highly sensitive and high spatial resolution techniques such as LA-ICP-MS, TEM-EDS, S-XRF and NanoSIMS are required for elemental mapping on subcellular level. This review summarizes state-of-the-art techniques in the field of bioimaging. Their strengths and limitations will be discussed with particular focus on potential applications for the elucidation of copper-related diseases. Based on such investigations, further information on cellular processes and mechanisms can be derived under physiological and pathological conditions. Bioimaging studies might enable the clarification of the role of copper in the context of neurodegenerative diseases and provide an important basis to develop therapeutic strategies for reduction or even prevention of copper-related disorders and their pathological consequences.
Novel Aspects of Toxicity Mechanisms of Dioxins and Related Compounds
Authors: Pohjanvirta Raimo , Viluksela Matti
Published: April 2020

Dioxins and related compounds are common environmental contaminants. Although their levels have gone down, they are still of concern, in particular regarding developmental toxicity. The adverse effects of these compounds are mediated by the aryl hydrocarbon receptor (AHR), whose canonical signaling pathway has been unveiled in fair detail. The alternative (non-genomic) pathways are much more obscure. AHR has also proven to be a master regulator of numerous physiological phenomena, which has led to the search of selective AHR modulators with low toxicity. Papers of this Special Issue address the developmental toxicity of dioxins and related compounds as well as selective modulators of AHR and both its canonical and alternative signaling pathways. In addition, new optical and stereoscopic methods for the detection of dioxins are presented. As a whole, this Special Issue provides an up-to-date view on a wide variety of aspects related to dioxin toxicity mechanisms from both original research articles and reviews.
Different Expression Pattern of TIM-3 and Galectin-9 Molecules by Peripheral and Peritoneal Lymphocytes in Women with and without Endometriosis
Authors: Meggyes Matyas , Szereday Laszlo , Bohonyi Noemi , Koppan Miklos , Szegedi Sarolta , Marics-Kutas Anna , Marton Mirjam , Totsimon Anett , Polgar Beata
Published: April 2020

Endometriosis is a gynecological condition that is associated with chronic pelvic inflammation, pain, and infertility. Although substantial evidence supports that immunological alterations contribute to its pathogenesis and we previously posed a pivotal role of Galectin-9 (Gal-9) in this disorder, the involvement of the TIM-3/Gal-9 pathway in the development of endometriosis-associated immunological abnormalities is not yet known. In the present study, multicolor flow cytometry was used to compare the immunophenotype and cell surface expression of TIM-3 and Gal-9 molecules on peripheral blood (PB) and peritoneal fluid (PF) lymphocytes of women with and without endometriosis. We found an altered distribution of different lymphocyte subpopulations, a markedly decreased TIM-3 labeling on all T and NK subsets and a significantly increased Gal-9 positivity on peripheral CD4+ T and Treg cells of the affected cohort. Furthermore, a significantly increased TIM-3 expression on CD4+T-cells and elevated Gal-9 labeling on all T and NK subsets was also revealed in the PF of the examined patients. In conclusion, our results suggest a persistent activation and disturbed TIM-3/Gal-9-dependent regulatory function in endometriosis, which may be involved in the impaired immune surveillance mechanisms, promotes the survival of ectopic lesions, and aids the evolution of reproductive failures in endometriosis.
The ULK1/2 and AMPK Inhibitor SBI-0206965 Blocks AICAR and Insulin-Stimulated Glucose Transport
Authors: Knudsen Jonas R. , Madsen Agnete B. , Persson Kaspar W. , Henríquez-Olguín Carlos , Li Zhencheng , Jensen Thomas E.
Published: April 2020

The small molecule kinase inhibitor SBI-0206965 was originally described as a specific inhibitor of ULK1/2. More recently, it was reported to effectively inhibit AMPK and several studies now report its use as an AMPK inhibitor. Currently, we investigated the specificity of SBI-0206965 in incubated mouse skeletal muscle, measuring the effect on analog 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)-stimulated AMPK-dependent glucose transport and insulin-stimulated AMPK-independent glucose uptake. Pre-treatment with 10 µM SBI-0206965 for 50 min potently suppressed AICAR-stimulated glucose transport in both the extensor digitorum longus (EDL) and soleus muscle. This was despite only a modest lowering of AICAR-stimulated AMPK activation measured as ACC2 Ser212, while ULK1/2 Ser555 phosphorylation was prevented. Insulin-stimulated glucose transport was also potently inhibited by SBI-0206965 in soleus. No major changes were observed on insulin-stimulated cell signaling. No general effect of SBI-0206965 on intracellular membrane morphology was observed by transmission electron microscopy. As insulin is known to neither activate AMPK nor require AMPK to stimulate glucose transport, and insulin inhibits ULK1/2 activity, these data strongly suggest that SBI-0206965 has a non-specific off-target inhibitory effect on muscle glucose transport. Thus, SBI-0206965 is not a specific inhibitor of the AMPK/ULK-signaling axis in skeletal muscle, and data generated with this inhibitor must be interpreted with caution.
Cytotoxicity of NiO and Ni(OH)2 Nanoparticles Is Mediated by Oxidative Stress-Induced Cell Death and Suppression of Cell Proliferation
Authors: Cambre Melissa H. , Holl Natalie J. , Wang Bolin , Harper Lucas , Lee Han-Jung , Chusuei Charles C. , Hou Fang Y.S. , Williams Ethan T. , Argo Jerry D. , Pandey Raja R. , Huang Yue-Wern
Published: April 2020

The use of nanomaterial-based products continues to grow with advancing technology. Understanding the potential toxicity of nanoparticles (NPs) is important to ensure that products containing them do not impose harmful effects to human or environmental health. In this study, we evaluated the comparative cytotoxicity between nickel oxide (NiO) and nickel hydroxide (Ni(OH)2) in human bronchoalveolar carcinoma (A549) and human hepatocellular carcinoma (HepG2) cell lines. Cellular viability studies revealed cell line-specific cytotoxicity in which nickel NPs were toxic to A549 cells but relatively nontoxic to HepG2 cells. Time-, concentration-, and particle-specific cytotoxicity was observed in A549 cells. NP-induced oxidative stress triggered dissipation of mitochondrial membrane potential and induction of caspase-3 enzyme activity. The subsequent apoptotic events led to reduction in cell number. In addition to cell death, suppression of cell proliferation played an essential role in regulating cell number. Collectively, the observed cell viability is a function of cell death and suppression of proliferation. Physical and chemical properties of NPs such as total surface area and metal dissolution are in agreement with the observed differential cytotoxicity. Understanding the properties of NPs is essential in informing the design of safer materials.
Modulators of MicroRNA Function in the Immune System
Authors: Jia Yunhui , Wei Yuanyuan
Published: April 2020

MicroRNAs (miRNAs) play a key role in fine-tuning host immune homeostasis and responses through the negative regulation of mRNA stability and translation. The pathways regulated by miRNAs are well characterized, but the precise mechanisms that control the miRNA-mediated regulation of gene expression during immune cell-development and immune responses to invading pathogens are incompletely understood. Context-specific interactions of miRNAs with other RNA species or proteins may modulate the function of a given miRNA. Dysregulation of miRNA function is associated with various human diseases, such as cardiovascular diseases and cancers. Here, we review the potential modulators of miRNA function in the immune system, including the transcription regulators of miRNA genes, miRNA-processing enzymes, factors affecting miRNA targeting, and intercellular communication.
Towards a New Understanding of Decision-Making by Hematopoietic Stem Cells
Authors: Brown Geoffrey
Published: April 2020

Cells within the hematopoietic stem cell compartment selectively express receptors for cytokines that have a lineage(s) specific role; they include erythropoietin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, granulocyte/macrophage colony-stimulating factor and the ligand for the fms-like tyrosine kinase 3. These hematopoietic cytokines can instruct the lineage fate of hematopoietic stem and progenitor cells in addition to ensuring the survival and proliferation of cells that belong to a particular cell lineage(s). Expression of the receptors for macrophage colony-stimulating factor and granulocyte colony-stimulating factor is positively autoregulated and the presence of the cytokine is therefore likely to enforce a lineage bias within hematopoietic stem cells that express these receptors. In addition to the above roles, macrophage colony-stimulating factor and granulocyte/macrophage colony-stimulating factor are powerful chemoattractants. The multiple roles of some hematopoietic cytokines leads us towards modelling hematopoietic stem cell decision-making whereby these cells can ‘choose’ just one lineage fate and migrate to a niche that both reinforces the fate and guarantees the survival and expansion of cells as they develop.