bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrokinetic Power Conversion Using Vortex-Induced Oscillation with Cubic Restoring Force
Authors: Li Mengyu , Bernitsas Christopher , Jing Guo , Hai Sun
Published: June 2020

A cubic-spring restoring function with high-deformation stiffening is introduced to passively improve the harnessed marine hydrokinetic power by using flow-induced oscillations/vibrations (FIO/V) of a cylinder. In these FIO/V experiments, a smooth, rigid, single-cylinder on elastic end-supports is tested at Reynolds numbers ranging from 24,000 < Re < 120,000. The parameters of the tested current energy converter (CEC) are cubic stiffness and linear damping. Using the second generation of digital virtual spring-damping (Vck) controller developed by the Marine Renewable Energy Laboratory (MRELab), the cubic modeling of the oscillator stiffness is tested. Experimental results show the influence of the parameter variation on the amplitude, frequency, energy conversion, energy efficiency, and power of the converter. All experiments are conducted in the low turbulence-free surface water (LTFSW) channel of the MRELab of the University of Michigan. The main conclusions are: (1) The nonlinearity in the cubic oscillator is an effective way to extend the vortex-induced vibration (VIV) upper branch, which results in higher harnessing power and efficiency compared to the linear stiffness cylinder converter. (2) Compared to the linear converter, the overall power increase is substantial. The nonlinear power optimum, occurring at the end of the VIV upper branch, is 63% higher than its linear counterpart. (3) The cubic stiffness converter with low harnessing damping achieves consistently good performance in all the VIV regions because of the hardening restoring force, especially at higher flow velocity.
Hydrothermal Desorption of Cs with Oxalic Acid from Hydrobiotite and Wastewater Treatment by Chemical Precipitation
Authors: Kim Sung-Man , Yoon In-Ho , Kim Ilgook , Kim June-Hyun , Park So-Jin
Published: June 2020

A hydrobiotite (HBT) clay contains more cesium (Cs)-specific adsorption sites than illitic clay, and the capacity of frayed edge sites can increase as the weathering of micaceous minerals proceeds. Thus, Cs can be selectively adsorbed to HBT clay. In this study, we investigated the removal efficiency of non-radioactive (133Cs) and radioactive (137Cs) Cs from HBT, using oxalic acid. We found the minimum optimal concentration of 0.15 M oxalic acid removed more than 90% of Cs. Subsequently, cations and Cs ions were removed using Ca(OH)2 and sodium tetraphenylborate (NaTPB) to treat the washing wastewater generated at the optimum concentration of the desorbent (0.15 M oxalic acid). In order to remove cations and heavy metal ions in the waste solution, Ca(OH)2 was treated at a mass ratio of 0.025 g/mL and pH 9–10 to derive optimal conditions. As a final step, to remove Cs, NaTPB was treated with a mass ratio of 2 mg/mL and reduced to below 0.1 mg/L Cs to find the optimal dose. The novelty of this study is that the amount of radioactive waste can be drastically reduced by removing the non-radioactive cations and heavy metals separately in the first step and removing the remaining radioactive Cs in the second step.
Forest Protection Unifies, Silviculture Divides: A Sociological Analysis of Local Stakeholders’ Voices after Coppicing in the Marganai Forest (Sardinia, Italy)
Authors: Branca Giampiero , Piredda Irene , Scotti Roberto , Chessa Laura , Murgia Ilenia , Ganga Antonio , Campus Sergio Francesco , Lovreglio Raffaella , Guastini Enrico , Schwarz Massimiliano , Giadrossich Filippo
Published: June 2020

Today, a forest is also understood as a real social actor with multiple-scale influences, capable of significantly conditioning the social, economic, and cultural system of a whole territory. The aim of this paper is to reconstruct and interpret the population’s perception of the silvicultural activities related to traditional use of forest resources of the southwestern Sardinian Marganai State Forest. The “Marganai case” has brought to the attention of the mass media the role of this forest and its silviculture. The research was carried out via semi-structured interviews with the main stakeholders in the area. The qualitative approach in the collection and analysis of the information gathered has allowed us to reconstruct the historical-cultural and social cohesion function that the forest plays in rural communities. The results highlight that the main risks concern the erosion of the cultural forest heritage due to the abandonment of the rural dimension (mainly by the new generations, but not only), with the consequent spread of deep distortions in the perception, interpretation, and necessity of forestry activities and policy.
Effect of Black Tea Infusion on Physicochemical Properties, Antioxidant Capacity and Microstructure of Acidified Dairy Gel during Cold Storage
Authors: Chen Han , Zheng Haotian , Anne Brennan Margaret , Chen Wenpin , Guo Xinbo , Brennan Charles Stephen
Published: June 2020

The impacts of black tea infusion on physicochemical properties, antioxidant capacity and microstructure of stirred acidified dairy gel (ADG) system have not been fully explored. These impacts were studied during a 28-day cold storage (4 °C) period to explore the feasibility and technical boundaries of making acidified dairy gels in which black tea infusion (BTI) is incorporated. Reconstituted skim milks containing different proportions of BTI were acidified by GDL (glucono-δ-lactone) at 35 °C for making ADG systems. Both textural properties and structural features were characterized; antioxidant capacity was determined through three assays. They are (1) free radical scavenging ability by DPPH (2,2-diphenyl-1-picrylhydrazyl) assay; (2) ABTS [2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid)] assay and (3) ferric reducing antioxidant power (FRAP) assay. The microstructure of the ADGs was observed using SEM (scanning electron microscopy) and CLSM (confocal laser scanning microscopy). Results showed that BTI significantly increased the antioxidant capacity of the gel systems and the gel containing 15% BTI was as stable as the control gel in terms of syneresis rate. However lower phase stability (higher syneresis rate) was observed in the ADG with a higher portion of BTI (30% to 60%). The microstructure of the ADGs observed may explain to the phase stability and textural attributes. The results suggested that tea polyphenols (TPs) improved antioxidant capacity in all samples and the interactions between BTI and dairy components significantly altered the texture of ADGs. Such alterations were more pronounced in the samples with higher proportion of BTI (60%) and/or longer storage time (28 days).
Effect of Buckwheat Groats Processing on the Content and Bioaccessibility of Selected Minerals
Authors: Klepacka Joanna , Najda Agnieszka , Klimek Kamila
Published: June 2020

Adequate supply of minerals in the diet is necessary for the proper functioning of the human body. In recent years gluten-free diet, which rigorous forms may lead to deficiencies of mineral components (especially Mg, Mn, Zn and Cu), is becoming more and more popular. Buckwheat grains do not contain gluten, and their nutritional value is very high. They are often consumed in the form of groats, which are obtained from roasted and dehulled seeds. The purpose of the work was to determine how conducting the buckwheat groats production in industrial conditions affects the content and availability of magnesium, manganese, zinc and copper. The results indicated that husk removal had a particularly adverse effect on the total manganese content and its amount released by enzymatic digestion, whereas it had a positive effect on the post-digestion zinc level by increasing it by nearly half. Hydrothermal processes especially affected the release of analysed elements simulated by the in vitro method, and the extent of changes depended on the processing parameters. It was shown that bioaccessibility of minerals may be increased by treating buckwheat at a lower temperature for a short time, which has a particularly beneficial effect on the manganese and magnesium. Treating grains at a higher temperature reduces the bioaccessibility of all analysed elements, which was particularly noted for zinc and copper. Based on the obtained results, it should be stated that buckwheat groats should be a regular part of human diet, because they are a good source of easily digestible mineral compounds. Their consumption should be especially considered by people on a rigorous gluten-free diet, as they can prevent mineral deficiencies associated with its use.
Chemical and Cellular Antioxidant Activities of In Vitro Digesta of Tilapia Protein and Its Hydrolysates
Authors: Zhang Xiaogang , Noisa Parinya , Yongsawatdigul Jirawat
Published: June 2020

Production of protein hydrolysate as nutraceuticals is typically based on the activity of the hydrolysate, which might not yield the optimal activity under physiological condition due to structural modification of peptides upon gastrointestinal (GI) digestion. This study systematically compared the chemical and cellular antioxidant activities of the in vitro digesta of tilapia protein and its hydrolysates prepared with various degree of hydrolysis (DH) by Alcalase. The enzymes used in the in vitro GI digestion analysis significantly contributed to the peptide content, Trolox equivalent antioxidant capacity (TEAC), and oxygen radical absorbance capacity (ORAC). Proteins and all hydrolysates were slightly digested by pepsin but hydrolyzed extensively by pancreatin. Both hydrolysate and digesta predominantly scavenged free radicals via hydrogen atom transfer (HAT). The antioxidant activities of the hydrolysates increased with the increasing DH up to 16 h of hydrolysis. However, the digesta of 10-h hydrolysate displayed the highest chemical and HepG2 cellular antioxidant activities, while the protein digesta displayed the lowest. Principal component analysis (PCA) showed that the TEAC of the digesta was positively correlated with the cellular antioxidant activity (CAA). Therefore, the production of protein hydrolysate should be optimized based on the activity of the hydrolysate digesta rather than that of hydrolysates.
Utilization of Bioelectrical Impedance to Predict Intramuscular Fat and Physicochemical Traits of the Beef Longissimus Thoracis et Lumborum Muscle
Authors: Afonso João , Guedes Cristina , Santos Virgínia , Morais Raul , Silva José , Teixeira Alfredo , Silva Severiano
Published: June 2020

The bioelectrical impedance analysis (BIA) is a non-destructive technique that has been successfully used to assess the body and carcass composition of farm species. This study aimed to predict intramuscular fat (IMF) and physicochemical traits in the longissimus thoracis et lumborum muscle (LM) of beef, using BIA. These traits were evaluated in LM samples of 52 crossbred heifer carcasses. The BIA was performed in LM, using a 50 Hz frequency high precision impedance converter system. A correlation analysis of the studied variables was performed. Then a stepwise with a k-folds cross validation procedure was used to modelling the prediction of IMF and physicochemical traits from BIA parameters (24.5% ≤ CV ≤ 47.3%). Wide variation was found for IMF and BIA parameters. In general, correlations of BIA parameters with IMF and physicochemical traits were moderate to high and were similar for all BIA parameters (−0.50 ≤ r ≤ 0.50 only for total pigments, a* and pH48). It was possible to predict IMF and physicochemical traits from BIA. The best fit explained 79.3% of the variation in IMF, while for physicochemical traits the best fits were for sarcomere length and shear force (64.4% and 60.5%, respectively). The results confirmed the potential of BIA for objective measurement of meat quality.
Cross-Species BAC Mapping Highlights Conservation of Chromosome Synteny across Dragon Lizards (Squamata: Agamidae)
Authors: Alam Shayer Mahmood Ibney , Altmanová Marie , Prasongmaneerut Tulyawat , Georges Arthur , Sarre Stephen D. , Nielsen Stuart V. , Gamble Tony , Srikulnath Kornsorn , Rovatsos Michail , Kratochvíl Lukáš , Ezaz Tariq
Published: June 2020

Dragon lizards (Squamata: Agamidae) comprise about 520 species in six subfamilies distributed across Asia, Australasia and Africa. Only five species are known to have sex chromosomes. All of them possess ZZ/ZW sex chromosomes, which are microchromosomes in four species from the subfamily Amphibolurinae, but much larger in Phrynocephalus vlangalii from the subfamily Agaminae. In most previous studies of these sex chromosomes, the focus has been on Australian species from the subfamily Amphibolurinae, but only the sex chromosomes of the Australian central bearded dragon (Pogona vitticeps) are well-characterized cytogenetically. To determine the level of synteny of the sex chromosomes of P. vitticeps across agamid subfamilies, we performed cross-species two-colour FISH using two bacterial artificial chromosome (BAC) clones from the pseudo-autosomal regions of P. vitticeps. We mapped these two BACs across representative species from all six subfamilies as well as two species of chameleons, the sister group to agamids. We found that one of these BAC sequences is conserved in macrochromosomes and the other in microchromosomes across the agamid lineages. However, within the Amphibolurinae, there is evidence of multiple chromosomal rearrangements with one of the BACs mapping to the second-largest chromosome pair and to the microchromosomes in multiple species including the sex chromosomes of P. vitticeps. Intriguingly, no hybridization signal was observed in chameleons for either of these BACs, suggesting a likely agamid origin of these sequences. Our study shows lineage-specific evolution of sequences/syntenic blocks and successive rearrangements and reveals a complex history of sequences leading to their association with important biological processes such as the evolution of sex chromosomes and sex determination.
Arabidopsis V-ATPase d2 Subunit Plays a Role in Plant Responses to Oxidative Stress
Authors: Feng Shuang , Peng Yun , Liu Enhui , Ma Hongping , Qiao Kun , Zhou Aimin , Liu Shenkui , Bu Yuanyuan
Published: June 2020

Vacuolar-type H+-ATPase (V-ATPase), a multisubunit proton pump located on the endomembrane, plays an important role in plant growth. The Arabidopsis thaliana V-ATPase d subunit (VHA-d) consists of two isoforms; AtVHA-d1 and AtVHA-d2. In this study, the function of AtVHA-d2 was investigated. Histochemical analysis revealed that the expression of AtVHA-d1 and AtVHA-d2 was generally highly overlapping in multiple tissues at different developmental stages of Arabidopsis. Subcellular localization revealed that AtVHA-d2 was mainly localized to the vacuole. AtVHA-d2 expression was significantly induced by oxidative stress. Analysis of phenotypic and H2O2 content showed that the atvha-d2 mutant was sensitive to oxidative stress. The noninvasive microtest monitoring demonstrated that the net H+ influx in the atvha-d2 roots was weaker than that in the wild-type under normal conditions. However, oxidative stress resulted in the H+ efflux in atvha-d2 roots, which was significantly different from that in the wild-type. RNA-seq combined with qPCR analysis showed that the expression of several members of the plasma membrane H+-ATPase gene (AtAHA) family in atvha-d2 was significantly different from that in the wild-type. Overall, our results indicate that AtVHA-d2 plays a role in Arabidopsis in response to oxidative stress by affecting H+ flux and AtAHA gene expression.
Blockade of PD-1, PD-L1, and TIM-3 Altered Distinct Immune- and Cancer-Related Signaling Pathways in the Transcriptome of Human Breast Cancer Explants
Authors: Saleh Reem , Toor Salman M. , Al-Ali Dana , Sasidharan Nair Varun , Elkord Eyad
Published: June 2020

Immune checkpoint inhibitors (ICIs) are yet to have a major advantage over conventional therapies, as only a fraction of patients benefit from the currently approved ICIs and their response rates remain low. We investigated the effects of different ICIs—anti-programmed cell death protein 1 (PD-1), anti-programmed death ligand-1 (PD-L1), and anti-T cell immunoglobulin and mucin-domain containing-3 (TIM-3)—on human primary breast cancer explant cultures using RNA-Seq. Transcriptomic data revealed that PD-1, PD-L1, and TIM-3 blockade follow unique mechanisms by upregulating or downregulating distinct pathways, but they collectively enhance immune responses and suppress cancer-related pathways to exert anti-tumorigenic effects. We also found that these ICIs upregulated the expression of other IC genes, suggesting that blocking one IC can upregulate alternative ICs, potentially giving rise to compensatory mechanisms by which tumor cells evade anti-tumor immunity. Overall, the transcriptomic data revealed some unique mechanisms of the action of monoclonal antibodies (mAbs) targeting PD-1, PD-L1, and TIM-3 in human breast cancer explants. However, further investigations and functional studies are warranted to validate these findings.
Consistency of Medical Data Using Intelligent Neuron Faster R-CNN Algorithm for Smart Health Care Application
Authors: Kim Seong-Kyu , Huh Jun-Ho
Published: June 2020

The purpose of this study is to increase interest in health as human life is extended in modern society. Hence, many people in hospitals produce much medical data (EMR, PACS, OCS, EHR, MRI, X-ray) after treatment. Medical data are stored as structured and unstructured data. However, many medical data are causing errors, omissions and mistakes in the process of reading. This behavior is very important in dealing with human life and sometimes leads to medical accidents due to physician errors. Therefore, this research is conducted through the CNN intelligent agent cloud architecture to verify errors in reading existing medical image data. To reduce the error rule when reading medical image data, a faster R-CNN intelligent agent cloud architecture is proposed. It shows the result of increasing errors of existing error reading by more than 1.4 times (140%). In particular, it is an algorithm that analyses data stored by actual existing medical data through Conv feature map using deep ConvNet and ROI Projection. The data were verified using about 120,000 databases. It uses data to examine human lungs. In addition, the experimental environment established an environment that can handle GPU’s high performance and NVIDIA SLI multi-OS and multiple Quadro GPUs were used. In this experiment, the verification data composition was verified and randomly extracted from about 120,000 medical records and the similarity compared to the original data were measured by comparing about 40% of the extracted images. Finally, we want to reduce and verify the error rate of medical data reading.
On-Site VIS-NIR Spectral Reflectance and Colour Measurements—A Fast and Inexpensive Alternative for Delineating Sediment Layers Quantitatively? A Case Study from a Monumental Bronze Age Burial Mound (Seddin, Germany)
Authors: Haburaj Vincent , Nykamp Moritz , May Jens , Hoelzmann Philipp , Schütt Brigitta
Published: June 2020

Quantitative sediment analyses performed in the laboratory are often used throughout archaeological excavations to critically reflect on-site stratigraphic delineation. Established methods are, however, often time-consuming and expensive. Recent studies suggest that systematic image analysis can objectivise the delineation of stratigraphic layers based on fast quantitative spectral measurements. The presented study examines how these assumptions prevail when compared to modern techniques of sediment analysis. We examine an archaeological cross-section at a Bronze Age burial mound near Seddin (administrative district Prignitz, Brandenburg, Germany), consisting of several layers of construction-related material. Using detailed on-site descriptions supported by quantitatively measured sediment properties as a measure of quality, we compare clustering results of (i) extensive colour measurements conducted with an RGB and a multispectral camera during fieldwork, as well as (ii) selectively sampled sedimentological data and (iii) visible and near infrared (VIS-NIR) hyperspectral data, both acquired in the laboratory. Furthermore, the influence of colour transformation to the CIELAB colour space (Commission Internationale de l’Eclairage) and the possibilities of predicting soil organic carbon (SOC) based on image data are examined. Our results indicate that quantitative spectral measurements, while still experimental, can be used to delineate stratigraphic layers in a similar manner to traditional sedimentological data. The proposed processing steps further improved our results. Quantitative colour measurements should therefore be included in the current workflow of archaeological excavations.
Spousal Concordance of Physical Frailty in Older Korean Couples
Authors: Kang Suah , Kim Miji , Won Chang Won
Published: June 2020

Marital status is an important risk factor for physical frailty. However, there are limited data on spousal concordance of physical frailty among married couples. Here, we evaluate the spousal concordance of frailty as defined by the Fried frailty phenotype and specific phenotype components that contribute to this association. Data on 315 married couples (630 individuals) aged between 70 and 84 years were obtained from the Korean Frailty and Aging Cohort Study (KFACS). Multivariate logistic regressions were used for the analysis. After adjusting for covariates (age, body mass index, education, house ownership, comorbidity, cognition, depressive symptoms, cohabitation with adult children for both partners), a husband’s frailty was positively associated with his wife’s frailty (odds ratio (OR) 3.34, 95% confidence interval (CI) 1.04–10.73, p < 0.05), and a wife’s frailty was significantly associated with her husband’s frailty (OR 4.62, 95% CI 1.31–16.33, p < 0.05), indicating a greater effect of the frailty status of the spouse among women than among men. Among the five components of the Fried frailty phenotype, weight loss, slowness, and exhaustion were the main contributing factors to the spousal association for frailty. In conclusion, having a frail spouse is a strong and independent risk factor for frailty among community-living older adults.
Brief Psychological Intervention Through Mobile App and Conference Calls for the Prevention of Depression in Non-Professional Caregivers: A Pilot Study
Authors: Otero Patricia , Hita Isabel , Torres Ángela J. , Vázquez Fernando L.
Published: June 2020

Despite its potential, no intervention aimed at non-professional caregivers administered through a smartphone app has been proven to prevent depression. The objective of this pilot study was to evaluate the efficacy and feasibility of an indicated depression-prevention intervention for non-professional caregivers administered through an app with the addition of conference-call contact. The intervention was administered to 31 caregivers (Mean age = 54.0 years, 93.5% women). An independent evaluation determined the incidence of depression, depressive symptoms, risk of developing depression, and the variables in the theoretical model (positive environmental reinforcement, negative automatic thoughts) at the pre-intervention and post-intervention, as well as the one- and three-month follow-ups. The incidence of depression at 3 months of follow-up was 6.5%. There was a significant reduction in depressive symptoms (p < 0.001) and in the risk of developing depression (p < 0.001) at the post-intervention and at the one- and three-month follow-ups. The model’s variables improved significantly after the intervention and were associated with post-intervention depressive symptoms. The intervention was more effective in caregivers who had a lower level of depressive symptoms at the pre-intervention. Adherence and satisfaction with the intervention were high. The results encourage future research using a randomized controlled clinical trial.
Swedish Tennis Coaches’ Everyday Practices for Creating Athlete Development Environments
Authors: Gerdin Göran , Fahlström Per Göran , Glemne Mats , Linnér Susanne
Published: June 2020

Finding and describing the optimal path to elite athletic performance has, for a long time, been a challenge for researchers. This study examined Swedish tennis coaches’ everyday practices for creating athlete development environments and the environmental factors that promote or hinder athlete development. The study was conducted in 2018–2019 and included in-depth focus groups with 13 Swedish full-time tennis coaches. Data were analyzed using thematic analysis and by drawing on models for studying athlete development environments. The results highlight how the coaches’ everyday work involves a range of administrative tasks, which ultimately means that there is little to no time left for focusing on athlete development. These results also draw attention to concerns about these professional coaches’ health, with increasing demands in their roles to manage administrative tasks in addition to the coaching and time spent on the court with their athletes. The results further reveal how the tennis clubs’ boards are increasingly interested in sound economy and high participation levels rather than focusing on performance outcomes and developing elite athletes. Finally, the results from this study emphasize the importance of increased collaboration and communication between clubs, coaches, regions, and the national association to create common and clearer guidelines for long-term athlete development. Future studies could engage in longitudinal and ethnographic work with tennis clubs of varying size and geographical locations, involving different stakeholders (e.g., coaches, management, parents, players) in order to further explore the environmental factors that promote or hinder athlete development.
Characterizing #Backwoods on Instagram: “The Number One Selling All Natural Cigar”
Authors: Smiley Sabrina L. , Kim Stephanie , Mourali Alia , Allem Jon-Patrick , Unger Jennifer B. , Boley Cruz Tess
Published: June 2020

We sought to assess the proportion of Backwoods (Imperial Tobacco Group Brands LLC) cigar-related posts to Instagram that may contain misleading claims, nature-evoking imagery, and appealing flavors. Inclusion criteria for this study included an Instagram post with the hashtag “#backwoods” from 30 August to 12 September 2018. Rules were established to content analyze (n = 1206) posts. Categories included misleading packaging (i.e., the post contained an image of a Backwoods product with the descriptor “natural” on the packaging), misleading promo (i.e., the corresponding caption to the post contained hashtag(s) like “#natural”, “#authentic”, “#alwaystrue”), nature-evoking imagery (i.e., the post contained images of grass, water, and pastural views along with a Backwoods product), flavors (i.e., the post contained a Backwoods product with brand-specific flavors on the packaging), flavor promo (i.e., the corresponding caption to the post contained hashtag(s) of Backwoods’ brand-specific flavors), marijuana-related (i.e., the post contained an image of marijuana next to a Backwoods pack, rolled cigars visibly contained marijuana, or hollowed-out cigars next to marijuana), smoking (the post contained an image of smoke or a lit cigar), brand-specific promo (i.e., the post contained an image of a Backwoods t-shirt, sweatshirt, hat, etc.), and perceived gender. Among the posts analyzed, 645 (53.5%) were marijuana-related, 564 (46.8%) were flavors, 463 (38.4%) were misleading packaging, 335 (27.8%) were flavor promo, 309 (25.6%) were misleading promo, 188 (15.6%) were nature-evoking imagery, 165 (13.7%) were smoking, 157 (13.0%) were brand-specific promo, and 239 (19.8%) were perceived male gender. Backwoods cigar-related posts to Instagram often contained misleading images and promotions of a “natural” tobacco product, images of marijuana use (in the form of blunt-making), brand-specific flavors, smoking, and promotional merchandise. Misleading images and the depictions of marijuana use in addition to the variety of flavor options may increase product appeal to consumers. These results underscore the need for comprehensive regulation of cigar products similar to cigarettes.
The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling
Authors: Shorning Boris Y. , Dass Manisha S. , Smalley Matthew J. , Pearson Helen B.
Published: June 2020

Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.
Distinct Local and Systemic Molecular Signatures in the Esophageal and Gastric Cancers: Possible Therapy Targets and Biomarkers for Gastric Cancer
Authors: Bednarz-Misa Iwona , Fortuna Paulina , Diakowska Dorota , Jamrozik Natalia , Krzystek-Korpacka Małgorzata
Published: June 2020

Gastric (GC) and esophageal (EC) cancers are highly lethal. Better understanding of molecular abnormalities is needed for new therapeutic targets and biomarkers to be found. Expression of 18 cancer-related genes in 31 paired normal-tumor samples was quantified by reversely-transcribed quantitative polymerase chain reaction (RTqPCR) and systemic concentration of 27 cytokines/chemokines/growth factors in 195 individuals was determined using Luminex xMAP technology. Only Ki67, CLDN2, and BCLxL were altered in GC while Ki67, CDKN1A, ODC1, SLC2A1, HIF1A, VEGFA, NOS2, CCL2, PTGS2, IL10, IL10Ra, and ACTA2 were changed in EC. The relatively unaltered molecular GC landscape resulted from high expression of BCLxL, CDKN1A, BCL2, Ki67, HIF1A, VEGFA, ACTA2, TJP1, CLDN2, IL7Ra, ODC1, PTGS2, and CCL2 in non-cancerous tissue. The NOS2 expression and IL-4, IL-9, FGF2, and RANTES secretion were higher in cardiac than non-cardiac GC. Four-cytokine panels (interleukin (IL)-1β/IL-1ra/IL-6/RANTES or IL-1β/IL-6/IL-4/IL-13) differentiated GC from benign conditions with 87–89% accuracy. Our results showed increased proliferative, survival, inflammatory and angiogenic capacity in gastric tumor-surrounding tissue, what might contribute to GC aggressiveness and facilitate cancer recurrence. Further studies are needed to determine the CLDN2 and NOS2 suitability as candidate molecular targets in GC and cardiac GC, respectively, and discern the role of CLDN2 or to verify IL-1β/IL-1ra/IL-6/RANTES or IL-1β/IL-6/IL-4/IL-13 usefulness as differential biomarkers.
Sharing Marks: H3K4 Methylation and H2B Ubiquitination as Features of Meiotic Recombination and Transcription
Authors: Serrano-Quílez Joan , Roig-Soucase Sergi , Rodríguez-Navarro Susana
Published: June 2020

Meiosis is a specialized cell division that gives raise to four haploid gametes from a single diploid cell. During meiosis, homologous recombination is crucial to ensure genetic diversity and guarantee accurate chromosome segregation. Both the formation of programmed meiotic DNA double-strand breaks (DSBs) and their repair using homologous chromosomes are essential and highly regulated pathways. Similar to other processes that take place in the context of chromatin, histone posttranslational modifications (PTMs) constitute one of the major mechanisms to regulate meiotic recombination. In this review, we focus on specific PTMs occurring in histone tails as driving forces of different molecular events, including meiotic recombination and transcription. In particular, we concentrate on the influence of H3K4me3, H2BK123ub, and their corresponding molecular machineries that write, read, and erase these histone marks. The Spp1 subunit within the Complex of Proteins Associated with Set1 (COMPASS) is a critical regulator of H3K4me3-dependent meiotic DSB formation. On the other hand, the PAF1c (RNA polymerase II associated factor 1 complex) drives the ubiquitination of H2BK123 by Rad6-Bre1. We also discuss emerging evidence obtained by cryo-electron microscopy (EM) structure determination that has provided new insights into how the “cross-talk” between these two marks is accomplished.
Single Exon Skipping Can Address a Multi-Exon Duplication in the Dystrophin Gene
Authors: Greer Kane , Johnsen Russell , Nevo Yoram , Fellig Yakov , Fletcher Susan , Wilton Steve D.
Published: June 2020

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease typically caused by protein-truncating mutations that preclude synthesis of a functional dystrophin. Exonic deletions are the most common type of DMD lesion, however, whole exon duplications account for between 10–15% of all reported mutations. Here, we describe in vitro evaluation of antisense oligonucleotide-induced splice switching strategies to re-frame the transcript disrupted by a multi-exon duplication within the DMD gene. Phosphorodiamidate morpholino oligomers and phosphorodiamidate morpholino oligomers coupled to a cell penetrating peptide were evaluated in a Duchenne muscular dystrophy patient cell strain carrying an exon 14–17 duplication. Two strategies were employed; the conventional approach was to remove both copies of exon 17 in addition to exon 18, and the second strategy was to remove only the first copy of exon 17. Both approaches result in a larger than normal but in-frame DMD transcript, but surprisingly, the removal of only the first exon 17 appeared to be more efficient in restoring dystrophin, as determined using western blotting. The emergence of a normal sized DMD mRNA transcript that was not apparent in untreated samples may have arisen from back splicing and could also account for some of the dystrophin protein being produced.
Pulmonary Involvement in a Mouse Model of Sjögren’s Syndrome Induced by STING Activation
Authors: Papinska Joanna , Bagavant Harini , Gmyrek Grzegorz B. , Deshmukh Umesh S.
Published: June 2020

Sjögren’s Syndrome (SS), a chronic autoimmune disorder affecting multiple organ systems, is characterized by an elevated type I interferon (IFN) response. Activation of Stimulator of Interferon Genes (STING) protein induces type I IFN and in mice, several features of SS, including anti-nuclear antibodies, sialadenitis, and salivary gland dysfunction. Since lung involvement occurs in one-fifth of SS patients, we investigated whether systemic activation of STING also leads to lung inflammation. Lungs from female C57BL/6 mice injected with the STING agonist 5, 6-Dimethylxanthenone-4-acetic acid (DMXAA), were evaluated for acute and chronic inflammatory responses. Within 4h of DMXAA injection, the expression of Ifnb1, Il6, Tnf, Ifng, and Mx1 was significantly upregulated. At 1 and 2 months post-treatment, lungs showed lymphocytic infiltration in the peri-bronchial regions. The lungs from DMXAA treated mice showed an increased expression of multiple chemokines and an increase in lymphatic endothelial cells. Despite STING expression in bronchial epithelium and cells lining the alveolar wall, bone marrow chimeras between STING knockout and wild type mice showed that STING expression in hematopoietic cells was critical for lung inflammation. Our results suggest that activation of the STING pathway might be involved in SS patients with concomitant salivary gland and lung disease.
Linking the Peptidoglycan Synthesis Protein Complex with Asymmetric Cell Division during Bacillus subtilis Sporulation
Authors: Muchová Katarína , Chromiková Zuzana , Barák Imrich
Published: June 2020

Peptidoglycan is generally considered one of the main determinants of cell shape in bacteria. In rod-shaped bacteria, cell elongation requires peptidoglycan synthesis to lengthen the cell wall. In addition, peptidoglycan is synthesized at the division septum during cell division. Sporulation of Bacillus subtilis begins with an asymmetric cell division. Formation of the sporulation septum requires almost the same set of proteins as the vegetative septum; however, these two septa are significantly different. In addition to their differences in localization, the sporulation septum is thinner and it contains SpoIIE, a crucial sporulation specific protein. Here we show that peptidoglycan biosynthesis is linked to the cell division machinery during sporulation septum formation. We detected a direct interaction between SpoIIE and GpsB and found that both proteins co-localize during the early stages of asymmetric septum formation. We propose that SpoIIE is part of a multi-protein complex which includes GpsB, other division proteins and peptidoglycan synthesis proteins, and could provide a link between the peptidoglycan synthesis machinery and the complex morphological changes required for forespore formation during B. subtilis sporulation.
Heterogenous Nuclear Ribonucleoprotein H1 Promotes Colorectal Cancer Progression through the Stabilization of mRNA of Sphingosine-1-Phosphate Lyase 1
Authors: Takahashi Keitaro , Fujiya Mikihiro , Konishi Hiroaki , Murakami Yuki , Iwama Takuya , Sasaki Takahiro , Kunogi Takehito , Sakatani Aki , Ando Katsuyoshi , Ueno Nobuhiro , Kashima Shin , Moriichi Kentaro , Tanabe Hiroki , Okumura Toshikatsu
Published: June 2020

The oncogenic properties of heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) have been reported, although the tumor-promoting mechanism remains unclear. We herein report the mechanism underlying colorectal cancer cell progression mediated by hnRNP H1. The growth of colorectal cancer cells was suppressed by hnRNP H1 downregulation. A terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed the anti-apoptotic effect of hnRNP H1 in colorectal cancer cells. An RNA immunoprecipitation assay revealed that hnRNP H1 bound to sphingosine-1-phosphate lyase 1 (SGPL1). Reverse transcription-polymerase chain reaction revealed the high expression of hnRNP H1 mRNA in colorectal cancer cells and Spearman’s rank correlation coefficient showed a strong positive correlation between hnRNP H1 mRNA and SGPL1 mRNA. An siRNA of hnRNP H1 decreased SGPL1 mRNA expression in colorectal cancer cells, but not in non-tumorous cells. These findings suggested that hnRNP H1 increased SGPL1 mRNA expression specifically in cancer cells through direct binding. Targeted knockdown of hnRNP H1 or SGPL1 with siRNAs upregulated p53 phosphorylation and p53-associated molecules, resulting in cell growth inhibition, while hnRNP H1 upregulated the mRNA of SGPL1 and inhibited p53 activation, thereby promoting tumor cell growth. This is a novel mechanism underlying colorectal cancer cell progression mediated by hnRNP H1–SGPL1 mRNA stabilization.
IPSC-Derived Neuronal Cultures Carrying the Alzheimer’s Disease Associated TREM2 R47H Variant Enables the Construction of an Aβ-Induced Gene Regulatory Network
Authors: Martins Soraia , Müller-Schiffmann Andreas , Erichsen Lars , Bohndorf Martina , Wruck Wasco , Sleegers Kristel , Van Broeckhoven Christine , Korth Carsten , Adjaye James
Published: June 2020

Genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer´s disease (LOAD). The rare R47H variant within triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to increase the risk for developing Alzheimer’s disease (AD) 2–3-fold. Here, we report the generation and characterization of a model of late-onset Alzheimer’s disease (LOAD) using lymphoblast-derived induced pluripotent stem cells (iPSCs) from patients carrying the TREM2 R47H mutation, as well as from control individuals without dementia. All iPSCs efficiently differentiated into mature neuronal cultures, however AD neuronal cultures showed a distinct gene expression profile. Furthermore, manipulation of the iPSC-derived neuronal cultures with an Aβ-S8C dimer highlighted metabolic pathways, phagosome and immune response as the most perturbed pathways in AD neuronal cultures. Through the construction of an Aβ-induced gene regulatory network, we were able to identify an Aβ signature linked to protein processing in the endoplasmic reticulum (ER), which emphasized ER-stress, as a potential causal role in LOAD. Overall, this study has shown that our AD-iPSC based model can be used for in-depth studies to better understand the molecular mechanisms underlying the etiology of LOAD and provides new opportunities for screening of potential therapeutic targets.
Post-Treatment M2BPGi Level and the Rate of Autotaxin Reduction are Predictive of Hepatocellular Carcinoma Development after Antiviral Therapy in Patients with Chronic Hepatitis C
Authors: Takemura Kazuya , Takizawa Etsuko , Tamori Akihiro , Nakamae Mika , Kubota Hiroshi , Uchida-Kobayashi Sawako , Enomoto Masaru , Kawada Norifumi , Hino Masayuki
Published: June 2020

Patients with chronic hepatitis C virus (HCV) develop hepatocellular carcinoma (HCC) regardless of achieving a sustained viral response (SVR). Because advanced liver fibrosis is a powerful risk factor for HCC, we analyzed the association between autotaxin (ATX), a liver fibrosis marker, and post-SVR HCC development within 3 years after antiviral treatment. We included 670 patients with HCV who received direct-acting antivirals, achieved SVR and were followed up for at least 6 months (270 of them were followed up for 3 years or more). We measured serum ATX levels before treatment and 12/24 weeks after treatment. The diagnosis of HCC was based on imaging modalities, such as dynamic computed tomography and dynamic magnetic resonance imaging and/or liver biopsy. The present study revealed that high levels of serum ATX predicted post-SVR HCC development (area under the receiver operating characteristic: 0.70–0.76). However, Wisteria floribunda agglutinin positive Mac-2 binding protein (M2BPGi), another liver fibrosis marker, was a more useful predictive marker especially post-treatment according to a multivariate analysis. Patients with a high rate of ATX reduction before and after antiviral treatment did not develop HCC regardless of high pretreatment ATX levels. In conclusion, post-treatment M2BPGi level and the combination of pretreatment ATX levels and rate of ATX reduction were useful predictive markers for post-SVR HCC development in patients with chronic HCV infection.
In Vivo Analysis of the Biocompatibility and Immune Response of Jellyfish Collagen Scaffolds and its Suitability for Bone Regeneration
Authors: Flaig Iris , Radenković Milena , Najman Stevo , Pröhl Annica , Jung Ole , Barbeck Mike
Published: June 2020

Jellyfish collagen, which can be defined as “collagen type 0” due to its homogeneity to the mammalian types I, II, III, V, and IX and its batch-to-batch consistent producibility, is of special interest for different medical applications related to (bone) tissue regeneration as an alternative to mammalian collagen-based biomaterials. However, no in vivo studies regarding the induction of M1- and M2-macrophages and their time-dependent ration as well as the analysis of the bone regeneration capacity of jellyfish collagen scaffolds have been conducted until now. Thus, the goal of this study was to determine the nature of the immune response to jellyfish collagen scaffolds and their bone healing capacities. Two in vivo studies using established implantation models, i.e., the subcutaneous and the calvarian implantation model in Wistar rats, were conducted. Furthermore, specialized histological, histopathological, and histomorphometrical methods have been used. As a control biomaterial, a collagen scaffold, originating from porcine pericardium, which has already been stated as biocompatible, was used for the subcutaneous study. The results of the present study show that jellyfish collagen scaffolds are nearly completely resorbed until day 60 post implantation by stepwise integration within the subcutaneous connective tissue mediated mainly by macrophages and single multinucleated giant cells. Interestingly, the degradation process ended in a vessel rich connective tissue that is understood to be an optimal basis for tissue regeneration. The study results showed an overall weaker immune response to jellyfish collagen than to porcine pericardium matrices by the induction of significantly lower numbers of macrophages together with a more balanced occurrence of M1- and M2-macrophages. However, both collagen-based biomaterials induced balanced numbers of both macrophage subtypes, which supports their good biocompatibility. Moreover, the histomorphometrical results for the calvarial implantation of the jellyfish scaffolds revealed an average of 46.20% de novo bone formation at day 60, which was significantly higher compared to the control group. Thereby, the jellyfish collagen scaffolds induced also significantly higher numbers of anti-inflammatory macrophages within the bony implantation beds. Altogether, the results show that the jellyfish collagen scaffolds allowed for a directed integration behavior, which is assumed to be in accordance with the concept of Guided Bone Regeneration (GBR). Furthermore, the jellyfish collagen scaffolds induced a long-term anti-inflammatory macrophage response and an optimal vascularization pattern within their implant beds, thus showing excellent biocompatibility and (bone) tissue healing properties.