bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms
Authors: Poeta Loredana , Drongitis Denise , Verrillo Lucia , Miano Maria Giuseppina
Published: June 2020

Unstable repeat disorders comprise a variable group of incurable human neurological and neuromuscular diseases caused by an increase in the copy number of tandem repeats located in various regions of their resident genes. It has become clear that dense DNA methylation in hyperexpanded non-coding repeats induces transcriptional silencing and, subsequently, insufficient protein synthesis. However, the ramifications of this paradigm reveal a far more profound role in disease pathogenesis. This review will summarize the significant progress made in a subset of non-coding repeat diseases demonstrating the role of dense landscapes of 5-methylcytosine (5mC) as a common disease modifier. However, the emerging findings suggest context-dependent models of 5mC-mediated silencing with distinct effects of excessive DNA methylation. An in-depth understanding of the molecular mechanisms underlying this peculiar group of human diseases constitutes a prerequisite that could help to discover novel pathogenic repeat loci, as well as to determine potential therapeutic targets. In this regard, we report on a brief description of advanced strategies in DNA methylation profiling for the identification of unstable Guanine-Cytosine (GC)-rich regions and on promising examples of molecular targeted therapies for Fragile X disease (FXS) and Friedrich ataxia (FRDA) that could pave the way for the application of this technique in other hypermethylated expansion disorders.
From Genes to -Omics: The Evolving Molecular Landscape of Malignant Peripheral Nerve Sheath Tumor
Authors: Lemberg Kathryn M. , Wang Jiawan , Pratilas Christine A.
Published: June 2020

Malignant peripheral nerve sheath tumors (MPNST) are rare, aggressive soft tissue sarcomas that occur with significantly increased incidence in people with the neuro-genetic syndrome neurofibromatosis type I (NF1). These complex karyotype sarcomas are often difficult to resect completely due to the involvement of neurovascular bundles, and are relatively chemotherapy- and radiation-insensitive. The lifetime risk of developing MPNST in the NF1 population has led to great efforts to characterize the genetic changes that drive the development of these tumors and identify mutations that may be used for diagnostic or therapeutic purposes. Advancements in genetic sequencing and genomic technologies have greatly enhanced researchers’ abilities to broadly and deeply investigate aberrations in human MPNST genomes. Here, we review genetic sequencing efforts in human MPNST samples over the past three decades. Particularly for NF1-associated MPNST, these overall sequencing efforts have converged on a set of four common genetic changes that occur in most MPNST, including mutations in neurofibromin 1 (NF1), CDKN2A, TP53, and members of the polycomb repressor complex 2 (PRC2). However, broader genomic studies have also identified recurrent but less prevalent genetic variants in human MPNST that also contribute to the molecular landscape of MPNST and may inform further research. Future studies to further define the molecular landscape of human MPNST should focus on collaborative efforts across multiple institutions in order to maximize information gathered from large numbers of well-annotated MPNST patient samples, both in the NF1 and the sporadic MPNST populations.
Mass Spectrometry Based-Proteomic Analysis of Anisakis spp.: A Preliminary Study towards a New Diagnostic Tool
Authors: Marzano Valeria , Pane Stefania , Foglietta Gianluca , Levi Mortera Stefano , Vernocchi Pamela , Onetti Muda Andrea , Putignani Lorenza
Published: June 2020

Anisakiasis is nowadays a well-known infection, mainly caused by the accidental ingestion of Anisakis larvae, following the consumption of raw or undercooked fishes and cephalopods. Due to the similarity of symptoms with those of common gastrointestinal disorders, this infection is often underestimated, and the need for new specific diagnostic tools is becoming crucial. Given the remarkable impact that MALDI–TOF MS biotyping had in the last decade in clinical routine practice for the recognition of bacterial and fungi strains, a similar scenario could be foreseen for the identification of parasites, such as nematodes. In this work, a MALDI–TOF MS profiling of Anisakis proteome was pursued with a view to constructing a first spectral library for the diagnosis of Anisakis infections. At the same time, a shotgun proteomics approach by LC–ESI–MS/MS was performed on the two main fractions obtained from protein extraction, to evaluate the protein species enriched by the protocol. A set of MALDI–TOF MS signals associated with proteins originating in the ribosomal fraction of the nematode extract was selected as a potential diagnostic tool for the identification of Anisakis spp.
Cultural Adaptation and Validation of the Korean Version of the iMTA Productivity Cost Questionnaire
Authors: Kim Hyungtae , Park Kyoung Sun , Yoo Jeong-Eun , Kim Siin , Han Sola , Suh Hae Sun
Published: June 2020

This study develops the Korean version of the Institute for Medical Technology Assessment Productivity Cost Questionnaire (iPCQ) through translation/cultural adaptation and evaluation of psychometric properties. We included 110 outpatients visiting a gynecology clinic. We conducted the translation and cross-cultural adaptation of the iPCQ, including forward and back-translation, pilot test with cognitive debriefing, and finalization. We analyzed the feasibility (using average time of filling in the iPCQ and the proportion of missing values), test–retest reliability (using the intra-class correlation coefficient [ICC]), and validity (concurrent validity with the Work Productivity and Activity Impairment [WPAI] and construct validity with the 36-Item Short Form Survey [SF-36], using Spearman’s ρ). The Korean version of iPCQ showed appropriate feasibility (average filling in time was 5.0 min without missing values), and had excellent values in the domains of absenteeism, presenteeism, and unpaid work for test–retest reliability (ICC: 0.92–0.99). For concurrent validity, the Korean version of iPCQ showed moderate–high correlation for absenteeism and presenteeism with the WPAI. All domains of productivity losses measured by the Korean version of iPCQ showed negative correlation with the quality of life estimated by the SF-36. Through this study, we developed a Korean instrument that can measure and value health-related productivity losses including unpaid work as well as absenteeism and presenteeism.
Testing the Multiple Pathways of Residential Greenness to Pregnancy Outcomes Model in a Sample of Pregnant Women in the Metropolitan Area of Donostia-San Sebastián
Authors: Anabitarte Asier , Subiza-Pérez Mikel , Ibarluzea Jesús , Azkona Kepa , García-Baquero Gonzalo , Miralles-Guasch Carme , Irazusta Jon , Whitworth Kristina W. , Vich Guillem , Lertxundi Aitana
Published: June 2020

Residential greenness may positively impact diverse human health indicators through the reduction of air pollution, the improvement of psychological health, and the promotion of physical activity. Previous studies indicate a weak but positive association with pregnancy outcomes. Our aim was to test the multiple pathways from residential greenness to pregnancy outcomes model, using residential NO2 concentrations, psychological health, and moderate-to-vigorous physical activity (MVPA) during the first trimester of pregnancy, in a sample of 440 pregnant women residing in Donostia, Spain. Three metrics of residential greenness were calculated around each participant’s home address: normalized difference vegetation index (NDVI) within 300 m, and green space (>5000 m2) availability within 300 and 500 m. Residential NO2 concentrations, psychological health, and MVPA were explored as mediators of the associations between these metrics and the following pregnancy outcomes: birth weight (BW), low birth weight (LBW), prematurity, small for gestational age (SGA), and large for gestational age (LGA). Educational attainment, parity, and body mass index (BMI) were treated as covariates. Counterfactual mediation analyses showed very low to null statistical support for an association between any of the greenspace metrics and pregnancy outcomes in the full sample. Green space availability (300 m) was associated with lower BW and showed a marginal protective effect against LGA.
The Office Work and Stretch Training (OST) Study: An Individualized and Standardized Approach to Improve the Quality of Life in Office Workers
Authors: Holzgreve Fabian , Maltry Laura , Hänel Jasmin , Schmidt Helmut , Bader Andreas , Frei Markus , Filmann Natalie , Groneberg David Alexander , Ohlendorf Daniela , van Mark Anke
Published: June 2020

In the context of workplace health promotion, physical activity programs have been shown to reduce musculoskeletal diseases and stress, and to improve the quality of life. The aim of this study was to examine the effects of using the “five-Business” stretch training device for office workers on their quality of life. A total of 313 office workers (173m/137f) participated voluntarily in this intervention–control study with an average age of 43.37 ± 11.24 (SD) years, 175.37 ± 9.35 cm in height and 75.76 ± 15.23 kg in weight, with an average BMI of 24.5 ± 3.81 kg/m2. The participants completed the stretch training twice a week for approximately 10 min for a duration of 12 weeks. The SF-36 questionnaire was used to evaluate the effectiveness of the intervention at baseline and after 12 weeks. Significantly improved outcomes in mental sum score (p = 0.008), physical functioning (p < 0.001), bodily pain (p = 0.01), vitality (p = 0.025), role limitations due to physical problems (p = 0.018) and mental health (p = 0.012) were shown after the stretching training. The results suggest that a 12-week stretching program for office desk workers is suitable to improve significantly their health-related quality of life.
Utilizing Green Design as Workplace Innovation to Relieve Service Employee Stress in the Luxury Hotel Sector
Authors: Han Heesup , Ariza-Montes Antonio , Giorgi Gabriele , Lee Soyeun
Published: June 2020

This study is an empirical endeavor to provide a clear comprehension regarding how hotel green design as a workplace innovation contributes to relieving employee stress and emotional fatigue and improves job satisfaction and involvement in the formation of organizational citizenship behavior. A quantitative process was employed to attain the research goal. Our empirical findings demonstrated that a green design as a workplace innovation boosts the stress resilience that leads to the decreased emotional exhaustion and increased job satisfaction. In addition, job satisfaction and job involvement were the crucial drivers of the organizational citizenship behavior among the luxury hotel service employees. Moreover, stress resilience, satisfaction and involvement were significant mediators. Job satisfaction and involvement had the strongest influence on organizational citizenship behavior than other variables. The findings of our research will help hotel proprietors to invent efficient strategies to minimize employee stress and maximize fulfillment at work, which will eventually enhance the organizational citizenship behavior.
Lung Function Testing and Prediction Equations in Adult Population from Maputo, Mozambique
Authors: Ivanova Olena , Khosa Celso , Bakuli Abhishek , Bhatt Nilesh , Massango Isabel , Jani Ilesh , Saathoff Elmar , Hoelscher Michael , Rachow Andrea
Published: June 2020

Background: Local spirometric prediction equations are of great importance for interpreting lung function results and deciding on the management strategies for respiratory patients, yet available data from African countries are scarce. The aim of this study was to collect lung function data using spirometry in healthy adults living in Maputo, Mozambique and to derive first spirometric prediction equations for this population. Methods: We applied a cross-sectional study design. Participants, who met the inclusion criteria, underwent a short interview, anthropometric measurements, and lung function testing. Different modelling approaches were followed for generating new, Mozambican, prediction equations and for comparison with the Global Lung Initiative (GLI) and South African equations. The pulmonary function performance of participants was assessed against the different reference standards. Results: A total of 212 males and females were recruited, from whom 155 usable spirometry results were obtained. The mean age of participants was 35.20 years (SD 10.99) and 93 of 155 (59.35%) were females. The predicted values for forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and the FEV1/FVC ratio based on the Mozambican equations were lower than the South African—and the GLI-based predictions. Conclusions: This study provides first data on pulmonary function in healthy Mozambican adults and describes how they compare to GLI and South African reference values for spirometry.
Analysis of the Relationship between Stress Intensity and Coping Strategy and the Quality of Life of Nursing Students in Poland, Spain and Slovakia
Authors: Kupcewicz Ewa , Grochans Elżbieta , Kadučáková Helena , Mikla Marzena , Jóźwik Marcin
Published: June 2020

Background: This study aimed to determine the relationship between stress intensity and coping strategies and the quality of life and health among nursing students in Poland, Spain and Slovakia. Methods: The study was performed on a group of 1002 nursing students from three European countries. A diagnostic survey was used as a research method and the data collection was based on the Perceived Stress Scale PSS-10, Mini-COPE Coping Inventory-and the WHOQoL-Bref questionnaire. Results: The average age of all the respondents was 21.6 years (±3.4). Most of the surveyed students rated their stress intensity over the last month as moderate or high. Comparison of the results of the stress levels in relation to the country of residence did not reveal statistically significant differences. In the group of Polish students, the most positive relationship between active coping strategies and the quality of life in the psychological (r = 0.43; p < 0.001) and physical health domain (r = 0.42; p < 0.001) were most strongly marked. Among Slovak students, significant correlations of low intensity were found between active coping strategies and the quality of life in the physical health (r = 0.15; p < 0.01), psychological (r = 0.21; p < 0.001), social relationships (r = 0.12; p < 0.05) and environment (r = 0.19; p < 0.001) domain. In overcoming stressful situations, Spanish students used the Sense of Humour strategy, which is considered less effective, although very useful in some cases. In this group, the strongest positive correlation was found for the psychological domain (r = 0.40; p < 0.001). Conclusions: There is a need to implement prevention and stress coping programmes at every stage of studies to ensure effective protection against the negative effects of stress and to improve the quality of life of nursing students.
Ocean Acidification and Human Health
Authors: Falkenberg Laura J. , Bellerby Richard G.J. , Connell Sean D. , Fleming Lora E. , Maycock Bruce , Russell Bayden D. , Sullivan Francis J. , Dupont Sam
Published: June 2020

The ocean provides resources key to human health and well-being, including food, oxygen, livelihoods, blue spaces, and medicines. The global threat to these resources posed by accelerating ocean acidification is becoming increasingly evident as the world’s oceans absorb carbon dioxide emissions. While ocean acidification was initially perceived as a threat only to the marine realm, here we argue that it is also an emerging human health issue. Specifically, we explore how ocean acidification affects the quantity and quality of resources key to human health and well-being in the context of: (1) malnutrition and poisoning, (2) respiratory issues, (3) mental health impacts, and (4) development of medical resources. We explore mitigation and adaptation management strategies that can be implemented to strengthen the capacity of acidifying oceans to continue providing human health benefits. Importantly, we emphasize that the cost of such actions will be dependent upon the socioeconomic context; specifically, costs will likely be greater for socioeconomically disadvantaged populations, exacerbating the current inequitable distribution of environmental and human health challenges. Given the scale of ocean acidification impacts on human health and well-being, recognizing and researching these complexities may allow the adaptation of management such that not only are the harms to human health reduced but the benefits enhanced.
The Splicing Factor SF2 Is Critical for Hyperproliferation and Survival in a TORC1-Dependent Model of Early Tumorigenesis in Drosophila
Authors: Parniewska Malgorzata Maria , Stocker Hugo
Published: June 2020

The Target of Rapamycin complex 1 (TORC1) is an evolutionarily conserved kinase complex coordinating cellular growth with nutritional conditions and growth factor signaling, and its activity is elevated in many cancer types. The use of TORC1 inhibitors as anticancer drugs is, however, limited by unwanted side-effects and development of resistance. We therefore attempted to identify limiting modulators or downstream effectors of TORC1 that could serve as therapeutic targets. Drosophila epithelial tissues that lack the tumor suppressor Pten hyperproliferate upon nutrient restriction in a TORC1-dependent manner. We probed candidates of the TORC1 signaling network for factors limiting the overgrowth of Pten mutant tissues. The serine/arginine-rich splicing factor 2 (SF2) was identified as the most limiting factor: SF2 knockdown drives Pten mutant cells into apoptosis, while not affecting control tissue. SF2 acts downstream of or in parallel to TORC1 but is not required for the activation of the TORC1 target S6K. Transcriptomics analysis revealed transcripts with alternatively used exons regulated by SF2 in the tumor context, including p53. SF2 may therefore represent a highly specific therapeutic target for tumors with hyperactive TORC1 signaling.
Structural Basis of Oligomerization of N-Terminal Domain of Spider Aciniform Silk Protein
Authors: Chakraborty Rusha , Fan Jing-song , Lai Chong Cheong , Raghuvamsi Palur Venkata , Chee Pin Xuan , Anand Ganesh Srinivasan , Yang Daiwen
Published: June 2020

Spider silk is self-assembled from water-soluble silk proteins through changes in the environment, including pH, salt concentrations, and shear force. The N-terminal domains of major and minor ampullate silk proteins have been found to play an important role in the assembly process through salt- and pH-dependent dimerization. Here, we identified the sequences of the N-terminal domains of aciniform silk protein (AcSpN) and major ampullate silk protein (MaSpN) from Nephila antipodiana (NA). Different from MaSpN, our biophysical characterization indicated that AcSpN assembles to form large oligomers, instead of a dimer, upon condition changes from neutral to acidic pH and/or from a high to low salt concentration. Our structural studies, by nuclear magnetic resonance spectroscopy and homology modelling, revealed that AcSpN and MaSpN monomers adopt similar overall structures, but have very different charge distributions contributing to the differential self-association features. The intermolecular interaction interfaces for AcSp oligomers were identified using hydrogen–deuterium exchange mass spectrometry and mutagenesis. On the basis of the monomeric structure and identified interfaces, the oligomeric structures of AcSpN were modelled. The structural information obtained will facilitate an understanding of silk fiber formation mechanisms for aciniform silk protein.
Impact of SRY-Box Transcription Factor 11 Gene Polymorphisms on Oral Cancer Risk and Clinicopathologic Characteristics
Authors: Yeh Chia-Ming , Lin Chiao-Wen , Lu Hsueh-Ju , Chuang Chun-Yi , Chou Chia-Hsuan , Yang Shun-Fa , Chen Mu-Kuan
Published: June 2020

Oral cancer is among the most common cancers worldwide and has become a major global health problem because of its relatively high morbidity and mortality rates. The sex-determining region on the Y-chromosome-related high-mobility-group box (SOX) transcription factor 11 (SOX11) plays a key role in human development and differentiation and is frequently increased in various human cancers. However, the clinical significance of SOX11 polymorphisms in oral cancer and their association with oral cancer risk are unclear. In this study, we included 1196 patients with oral cancer and 1200 controls. Real-time polymerase chain reaction was applied to analyze three SOX11 single-nucleotide polymorphisms (rs77996007, rs66465560, and rs68114586). Our results shown that SOX11 polymorphisms carriers with betel quid chewing were found to have an 8.38- to 9.23-fold risk to have oral cancer compared to SOX11 wild-type carriers without betel quid chewing. Furthermore, oral cancer patients who carried SOX11 rs77996007 “TC + CC” variants were significantly associated with large tumor size (AOR, 1.324; 95% CI, 1.047–1.674; p = 0.019). Moreover, a database analysis using the Cancer Genome Atlas suggested that SOX11 mRNA expression was high during the tumor development process. In conclusion, our results suggest that SOX11 rs77996007 is involved in oral cancer progression and clinical characteristics.
Life in the Current: Anatomy and Morphology of Utricularia neottioides
Authors: Płachno Bartosz J. , Adamec Lubomír , Świątek Piotr , Kapusta Małgorzata , Miranda Vitor F. O.
Published: June 2020

Rheophytism is extremely rare in the Utricularia genus (there are four strictly rheophytic species out of a total of about 260). Utricularia neottioides is an aquatic rheophytic species exclusively growing attached to bedrocks in the South American streams. Utricularia neottioides was considered to be trap-free by some authors, suggesting that it had given up carnivory due to its specific habitat. Our aim was to compare the anatomy of rheophytic U. neottioides with an aquatic Utricularia species with a typical linear monomorphic shoot from the section Utricularia, U. reflexa, which grows in standing or very slowly streaming African waters. Additionally, we compared the immunodetection of cell wall components of both species. Light microscopy, histochemistry, scanning, and transmission electron microscopy were used to address our aims. In U. neottioides, two organ systems can be distinguished: organs (stolons, inflorescence stalk) which possess sclerenchyma and are thus resistant to water currents, and organs without sclerenchyma (leaf-like shoots), which are submissive to the water streaming/movement. Due to life in the turbulent habitat, U. neottioides evolved specific characters including an anchor system with stolons, which have asymmetric structures, sclerenchyma and they form adhesive trichomes on the ventral side. This anchor stolon system performs additional multiple functions including photosynthesis, nutrient storage, vegetative reproduction. In contrast with typical aquatic Utricularia species from the section Utricularia growing in standing waters, U. neottioides stems have a well-developed sclerenchyma system lacking large gas spaces. Plants produce numerous traps, so they should still be treated as a fully carnivorous plant.
Changes in DNA Methylation and Gene Expression of Insulin and Obesity-Related Gene PIK3R1 after Roux-en-Y Gastric Bypass
Authors: Pinhel Marcela A S , Noronha Natália Y , Nicoletti Carolina F , Pereira Vanessa AB , de Oliveira Bruno AP , Cortes-Oliveira Cristiana , Salgado Wilson , Barbosa Fernando , Marchini Júlio S , Souza Doroteia RS , Nonino Carla B
Published: June 2020

Weight regulation and the magnitude of weight loss after a Roux-en-Y gastric bypass (RYGB) can be genetically determined. DNA methylation patterns and the expression of some genes can be altered after weight loss interventions, including RYGB. The present study aimed to evaluate how the gene expression and DNA methylation of PIK3R1, an obesity and insulin-related gene, change after RYGB. Blood samples were obtained from 13 women (35.9 ± 9.2 years) with severe obesity before and six months after surgical procedure. Whole blood transcriptome and epigenomic patterns were assessed by microarray-based, genome-wide technologies. A total of 1966 differentially expressed genes were identified in the pre- and postoperative periods of RYGB. From these, we observed that genes involved in obesity and insulin pathways were upregulated after surgery. Then, the PIK3R1 gene was selected for further RT-qPCR analysis and cytosine-guanine nucleotide (CpG) sites methylation evaluation. We observed that the PI3KR1 gene was upregulated, and six DNA methylation CpG sites were differently methylated after bariatric surgery. In conclusion, we found that RYGB upregulates genes involved in obesity and insulin pathways.
Meta-Analysis of Gene Expressions in Testicular Germ Cell Tumor Histologies
Authors: von Eyben Finn Edler , Parraga-Alava Jorge
Published: June 2020

There is no consensus as to how a precursor lesion, germ cell neoplasia in situ (GCNIS), develops into the histologic types of testicular germ cell tumor type II (TGCT). The present meta-analysis examined RNA expressions of 24 candidate genes in three datasets. They included 203 samples of normal testis (NT) and histologic types of TGCT. The Fisher’s test for combined p values was used for meta-analysis of the RNA expressions in the three datasets. The histologic types differed in RNA expression of PRAME, KIT, SOX17, NANOG, KLF4, POU5F1, RB1, DNMT3B, and LIN28A (p < 0.01). The histologic types had concordant differences in RNA expression of the genes in the three datasets. Eight genes had overlap with a high RNA expression in at least two histologic types. In contrast, only seminoma (SE) had a high RNA expression of KLF4 and only embryonal carcinoma (EC) had a high RNA expression of DNMT3B. In conclusion, the meta-analysis showed that the development of the histologic types of TGCT was driven by changes in RNA expression of candidate genes. According to the RNA expressions of the ten genes, TGCT develops from NT over GCNIS, SE, EC, to the differentiated types of TGCT.
Mediterranean Diet: Lipids, Inflammation, and Malaria Infection
Authors: Silva Adriana R. , Moraes Bianca P. T. , Gonçalves-de-Albuquerque Cassiano F.
Published: June 2020

The Mediterranean diet (MedDiet) consists of consumption of vegetables and healthy oils and have beneficial effects on metabolic and inflammatory diseases. Our goal here is to discuss the role of fatty acid content in MedDiet, mostly omega-3, omega-6, and omega-9 on malaria. Malaria affects millions of people around the globe. The parasite Plasmodium causes the disease. The metabolic and inflammatory alterations in the severe forms have damaging consequences to the host. The lipid content in the MedDiet holds anti-inflammatory and pro-resolutive features in the host and have detrimental effects on the Plasmodium. The lipids from the diet impact the balance of pro- and anti-inflammation, thus, lipids intake from the diet is critical to parasite elimination and host tissue damage caused by an immune response. Herein, we go into the cellular and molecular mechanisms and targets of the MedDiet fatty acids in the host and the parasite, reviewing potential benefits of the MedDiet, on inflammation, malaria infection progression, and clinical outcome.
Trans-Cinnamaldehyde Alleviates Amyloid-Beta Pathogenesis via the SIRT1-PGC1α-PPARγ Pathway in 5XFAD Transgenic Mice
Authors: Do Jimin , Kim Namkwon , Jeon Seung Ho , Gee Min Sung , Ju Yeon-Joo , Kim Jong-Ho , Oh Myung Sook , Lee Jong Kil
Published: June 2020

Abnormal amyloid-β (Aβ) accumulation is the most significant feature of Alzheimer’s disease (AD). Among the several secretases involved in the generation of Aβ, β-secretase (BACE1) is the first rate-limiting enzyme in Aβ production that can be utilized to prevent the development of Aβ-related pathologies. Cinnamon extract, used in traditional medicine, was shown to inhibit the aggregation of tau protein and Aβ aggregation. However, the effect of trans-cinnamaldehyde (TCA), the main component of cinnamon, on Aβ deposition is unknown. Five-month-old 5XFAD mice were treated with TCA for eight weeks. Seven-month-old 5XFAD mice were evaluated for cognitive and spatial memory function. Brain samples collected at the conclusion of the treatment were assessed by immunofluorescence and biochemical analyses. Additional in vivo experiments were conducted to elucidate the mechanisms underlying the effect of TCA in the role of Aβ deposition. TCA treatment led to improvements in cognitive impairment and reduced Aβ deposition in the brains of 5XFAD mice. Interestingly, the levels of BACE1 were decreased, whereas the mRNA and protein levels of three well-known regulators of BACE1, silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC1α), and PPARγ, were increased in TCA-treated 5XFAD mice. TCA led to an improvement in AD pathology by reducing BACE1 levels through the activation of the SIRT1-PGC1α-PPARγ pathway, suggesting that TCA might be a useful therapeutic approach in AD.
Intratumoral Administration of a Novel Cytotoxic Formulation with Strong Tissue Dispersive Properties Regresses Tumor Growth and Elicits Systemic Adaptive Immunity in In Vivo Models
Authors: Bender Lewis H. , Abbate Franco , Walters Ian B.
Published: June 2020

The recent development of immune-based therapies has improved the outcome for cancer patients; however, adjuvant therapies remain an important line of treatment for several cancer types. To maximize efficacy, checkpoint inhibitors are often combined with cytotoxic agents. While this approach often leads to increased tumor regression, higher off target toxicity often results in certain patients. This report describes a novel formulation comprising a unique amphiphilic molecule, 8-((2-hydroxybenzoyl)amino)octanoate (SHAO), that non-covalently interacts with payloads to increase drug dispersion and diffusion when dosed intratumorally (IT) into solid tumors. SHAO is co-formulated with cisplatin and vinblastine (referred to as INT230-6). IT dosing of the novel formulation achieved greater tumor growth inhibition and improved survival in in vivo tumor models compared to the same drugs without enhancer given intravenously or IT. INT230-6 treatment increased immune infiltrating cells in injected tumors with 10% to 20% of the animals having complete responses and developing systemic immunity to the cancer. INT230-6 was also shown to be synergistic with programmed cell death protein 1 (PD-1) antibodies at improving survival and increasing complete responses. INT230-6 induced significant tumor necrosis potentially releasing antigens to induce the systemic immune-based anti-cancer attack. This research demonstrates a novel, local treatment approach for cancer that minimizes systemic toxicity while stimulating adaptive immunity.
Development of Specific Thinopyrum Cytogenetic Markers for Wheat-Wheatgrass Hybrids Using Sequencing and qPCR Data
Authors: Nikitina Ekaterina , Kuznetsova Victoria , Kroupin Pavel , Karlov Gennady I. , Divashuk Mikhail G.
Published: June 2020

The cytogenetic study of wide hybrids of wheat has both practical and fundamental values. Partial wheat-wheatgrass hybrids (WWGHs) are interesting as a breeding bridge to confer valuable genes to wheat genome, as well as a model object that contains related genomes of Triticeae. The development of cytogenetic markers is a process that requires long and laborious fluorescence in situ hybridization (FISH) testing of various probes before a suitable probe is found. In this study, we aimed to find an approach that allows to facilitate this process. Based on the data sequencing of Thinopyrum ponticum, we selected six tandem repeat (TR) clusters using RepeatExplorer2 pipeline and designed primers for each of them. We estimated the found TRs’ abundance in the genomes of Triticum aestivum, Thinopyrum ponticum, Thinopyrum intermedium and four different WWGH accessions using real-time qPCR, and localized them on the chromosomes of the studied WWGHs using fluorescence in situ hybridization. As a result, we obtained three tandem repeat cytogenetic markers that specifically labeled wheatgrass chromosomes in the presence of bread wheat chromosomes. Moreover, we designed and tested primers for these repeats, and demonstrated that they can be used as qPCR markers for quick and cheap monitoring of the presence of certain chromosomes of wheatgrass in breeding programs.
Mapping of Major Fusarium Head Blight Resistance from Canadian Wheat cv. AAC Tenacious
Authors: Dhariwal Raman , Henriquez Maria A. , Hiebert Colin , McCartney Curt A. , Randhawa Harpinder S.
Published: June 2020

Fusarium head blight (FHB) is one of the most devastating wheat disease due to its direct detrimental effects on grain-yield, quality and marketability. Resistant cultivars offer the most effective approach to manage FHB; however, the lack of different resistance resources is still a major bottleneck for wheat breeding programs. To identify and dissect FHB resistance, a doubled haploid wheat population produced from the Canadian spring wheat cvs AAC Innova and AAC Tenacious was phenotyped for FHB response variables incidence and severity, visual rating index (VRI), deoxynivalenol (DON) content, and agronomic traits days to anthesis (DTA) and plant height (PHT), followed by single nucleotide polymorphism (SNP) and simple sequence repeat (SSR) marker genotyping. A high-density map was constructed consisting of 10,328 markers, mapped on all 21 chromosomes with a map density of 0.35 cM/marker. Together, two major quantitative trait loci for FHB resistance were identified on chromosome 2D from AAC Tenacious; one of these loci on 2DS also colocated with loci for DTA and PHT. Another major locus for PHT, which cosegregates with locus for low DON, was also identified along with many minor and epistatic loci. QTL identified from AAC Tenacious may be useful to pyramid FHB resistance.
Identification of Brain-Specific Treatment Effects in NPC1 Disease by Focusing on Cellular and Molecular Changes of Sphingosine-1-Phosphate Metabolism
Authors: Gläser Anne , Hammerl Franziska , Gräler Markus H. , Coldewey Sina M. , Völkner Christin , Frech Moritz J. , Yang Fan , Luo Jiankai , Tönnies Eric , von Bohlen und Halbach Oliver , Brandt Nicola , Heimes Diana , Neßlauer Anna-Maria , Korenke Georg Christoph , Owczarek-Lipska Marta , Neidhardt John , Rolfs Arndt , Wree Andreas , Witt Martin , Bräuer Anja Ursula
Published: June 2020

Niemann–Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an autosomal-recessive trait. Mutations in the Npc1 gene result in malfunction of the NPC1 protein, leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur. Here, we analyzed the sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) axis in different brain regions of Npc1−/− mice and evaluated specific effects of treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD) together with the iminosugar miglustat. Using high-performance thin-layer chromatography (HPTLC), mass spectrometry, quantitative real-time PCR (qRT-PCR) and western blot analyses, we studied lipid metabolism in an NPC1 mouse model and human skin fibroblasts. Lipid analyses showed disrupted S1P metabolism in Npc1−/− mice in all brain regions, together with distinct changes in S1pr3/S1PR3 and S1pr5/S1PR5 expression. Brains of Npc1−/− mice showed only weak treatment effects. However, side effects of the treatment were observed in Npc1+/+ mice. The S1P/S1PR axis seems to be involved in NPC1 pathology, showing only weak treatment effects in mouse brain. S1pr expression appears to be affected in human fibroblasts, induced pluripotent stem cells (iPSCs)-derived neural progenitor and neuronal differentiated cells. Nevertheless, treatment-induced side effects make examination of further treatment strategies indispensable.
Genetic and Neuroimaging Approaches to Understanding Post-Traumatic Stress Disorder
Authors: Nisar Sabah , Bhat Ajaz A. , Hashem Sheema , Syed Najeeb , Yadav Santosh K. , Uddin Shahab , Fakhro Khalid , Bagga Puneet , Thompson Paul , Reddy Ravinder , Frenneaux Michael P. , Haris Mohammad
Published: June 2020

Post-traumatic stress disorder (PTSD) is a highly disabling condition, increasingly recognized as both a disorder of mental health and social burden, but also as an anxiety disorder characterized by fear, stress, and negative alterations in mood. PTSD is associated with structural, metabolic, and molecular changes in several brain regions and the neural circuitry. Brain areas implicated in the traumatic stress response include the amygdala, hippocampus, and prefrontal cortex, which play an essential role in memory function. Abnormalities in these brain areas are hypothesized to underlie symptoms of PTSD and other stress-related psychiatric disorders. Conventional methods of studying PTSD have proven to be insufficient for diagnosis, measurement of treatment efficacy, and monitoring disease progression, and currently, there is no diagnostic biomarker available for PTSD. A deep understanding of cutting-edge neuroimaging genetic approaches is necessary for the development of novel therapeutics and biomarkers to better diagnose and treat the disorder. A current goal is to understand the gene pathways that are associated with PTSD, and how those genes act on the fear/stress circuitry to mediate risk vs. resilience for PTSD. This review article explains the rationale and practical utility of neuroimaging genetics in PTSD and how the resulting information can aid the diagnosis and clinical management of patients with PTSD.
Chromatin Architectural Factors as Safeguards against Excessive Supercoiling during DNA Replication
Authors: Ahmed Syed Moiz , Dröge Peter
Published: June 2020

Key DNA transactions, such as genome replication and transcription, rely on the speedy translocation of specialized protein complexes along a double-stranded, right-handed helical template. Physical tethering of these molecular machines during translocation, in conjunction with their internal architectural features, generates DNA topological strain in the form of template supercoiling. It is known that the build-up of transient excessive supercoiling poses severe threats to genome function and stability and that highly specialized enzymes—the topoisomerases (TOP)—have evolved to mitigate these threats. Furthermore, due to their intracellular abundance and fast supercoil relaxation rates, it is generally assumed that these enzymes are sufficient in coping with genome-wide bursts of excessive supercoiling. However, the recent discoveries of chromatin architectural factors that play important accessory functions have cast reasonable doubts on this concept. Here, we reviewed the background of these new findings and described emerging models of how these accessory factors contribute to supercoil homeostasis. We focused on DNA replication and the generation of positive (+) supercoiling in front of replisomes, where two accessory factors—GapR and HMGA2—from pro- and eukaryotic cells, respectively, appear to play important roles as sinks for excessive (+) supercoiling by employing a combination of supercoil constrainment and activation of topoisomerases. Looking forward, we expect that additional factors will be identified in the future as part of an expanding cellular repertoire to cope with bursts of topological strain. Furthermore, identifying antagonists that target these accessory factors and work synergistically with clinically relevant topoisomerase inhibitors could become an interesting novel strategy, leading to improved treatment outcomes.
Hub Proteins Involved in RAW 264.7 Macrophages Exposed to Direct Current Electric Field
Authors: Li Huijuan , Liu Shibin , Du Yongqian , Tan Jie , Luo Jiezhang , Sun Yulong
Published: June 2020

At present, studies on macrophage proteins mainly focus on biological stimuli, with less attention paid to the responses of macrophage proteins to physical stimuli, such as electric fields. Here, we exploited the electric field-sensitive hub proteins of macrophages. RAW 264.7 macrophages were treated with a direct current electric field (dcEF) (200 mV/mm) for four hours, followed by RNA-Seq analysis. Differentially expressed genes (DEGs) were obtained, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) and protein–protein interaction (PPI) analysis. Eight qPCR-verified DEGs were selected. Subsequently, three-dimensional protein models of DEGs were modeled by Modeller and Rosetta, followed by molecular dynamics simulation for 200 ns with GROMACS. Finally, dcEFs (10, 50, and 500 mV/mm) were used to simulate the molecular dynamics of DEG proteins for 200 ns, followed by trajectory analysis. The dcEF has no obvious effect on RAW 264.7 morphology. A total of 689 DEGs were obtained, and enrichment analysis showed that the steroid biosynthesis pathway was most affected by the dcEF. Moreover, the three-dimensional protein structures of hub proteins were constructed, and trajectory analysis suggested that the dcEF caused an increase in the atomic motion of the protein in a dcEF-intensity-dependent manner. Overall, we provide new clues and a basis for investigating the hub proteins of macrophages in response to electric field stimulation.
Linking Theories, Past Practices, and Archaeological Remains of Movement through Ontological Reasoning
Authors: Nuninger Laure , Verhagen Philip , Libourel Thérèse , Opitz Rachel , Rodier Xavier , Laplaige Clément , Fruchart Catherine , Leturcq Samuel , Levoguer Nathanael
Published: June 2020

The amount of information available to archaeologists has grown dramatically during the last ten years. The rapid acquisition of observational data and creation of digital data has played a significant role in this “information explosion”. In this paper, we propose new methods for knowledge creation in studies of movement, designed for the present data-rich research context. Using three case studies, we analyze how researchers have identified, conceptualized, and linked the material traces describing various movement processes in a given region. Then, we explain how we construct ontologies that enable us to explicitly relate material elements, identified in the observed landscape, to the knowledge or theory that explains their role and relationships within the movement process. Combining formal pathway systems and informal movement systems through these three case studies, we argue that these systems are not hierarchically integrated, but rather intertwined. We introduce a new heuristic tool, the “track graph”, to record observed material features in a neutral form which can be employed to reconstruct the trajectories of journeys which follow different movement logics. Finally, we illustrate how the breakdown of implicit conceptual references into explicit, logical chains of reasoning, describing basic entities and their relationships, allows the use of these constituent elements to reconstruct, analyze, and compare movement practices from the bottom up.
Influence of Sociodemographic, Premorbid, and Injury-Related Factors on Post-Concussion Symptoms after Traumatic Brain Injury
Authors: Zeldovich Marina , Wu Yi-Jhen , Gorbunova Anastasia , Mikolic Ana , Polinder Suzanne , Plass Anne , Covic Amra , Asendorf Thomas , Andelic Nada , Voormolen Daphne , von Steinbüchel Nicole ,   on behalf of the CENTER-TBI 7 Participants and Investigators
Published: June 2020

Background: Post-concussion symptoms (PCS) are often reported as consequences of mild and moderate traumatic brain injury (TBI), but these symptoms are not well documented in severe TBI. There is a lack of agreement as to which factors and covariates affect the occurrence, frequency, and intensity of PCS among TBI severity groups. The present study therefore aims to examine the association between sociodemographic, premorbid, and injury-related factors and PCS. Methods: A total of 1391 individuals (65% male) from the CENTER-TBI study were included in the analyses. The occurrence, frequency (number of PCS), and intensity (severity) of PCS were assessed using the Rivermead Post-concussion Symptoms Questionnaire (RPQ) at six months after TBI. To examine the association between selected factors (age, sex, living situation, employment status, educational background, injury and TBI severity, and premorbid problems) and PCS, a zero-inflated negative binomial model (ZINB) for occurrence and frequency of PCS and a standard negative binomial regression (NB) for intensity were applied. Results: Of the total sample, 72% of individuals after TBI reported suffering from some form of PCS, with fatigue being the most frequent among all TBI severity groups, followed by forgetfulness, and poor concentration. Different factors contributed to the probability of occurrence, frequency, and intensity of PCS. While the occurrence of PCS seemed to be independent of the age and sex of the individuals, both the frequency and intensity of PCS are associated with them. Both injury and TBI severity influence the occurrence and frequency of PCS, but are associated less with its intensity (except “acute” symptoms such as nausea, vomiting, and headaches). Analyses focusing on the mTBI subgroup only yielded results comparable to those of the total sample. Discussion: In line with previous studies, the results support a multifactorial etiology of PCS and show the importance of differentiating between their occurrence, frequency, and intensity to better provide appropriate treatment for individual subgroups with different symptoms (e.g., multiple PCS or more intense PCS). Although PCS often occur in mild to moderate TBI, individuals after severe TBI also suffer from PCS or post-concussion-like symptoms that require appropriate treatment. The chosen statistical approaches (i.e., ZINB and NB models) permit an ameliorated differentiation between outcomes (occurrence, frequency, and intensity of PCS) and should be used more widely in TBI research.