bluuebunny/crossref_metadata_2025 huggingface dataset:
Antidiabetic Food-Derived Peptides for Functional Feeding: Production, Functionality and In Vivo Evidences
Authors: Rivero-Pino Fernando , Espejo-Carpio F. Javier , Guadix Emilia M.
Published: July 2020

Bioactive peptides released from the enzymatic hydrolysis of food proteins are currently a trending topic in the scientific community. Their potential as antidiabetic agents, by regulating the glycemic index, and thus to be employed in food formulation, is one of the most important functions of these peptides. In this review, we aimed to summarize the whole process that must be considered when talking about including these molecules as a bioactive ingredient. In this regard, at first, the production, purification and identification of bioactive peptides is summed up. The detailed metabolic pathways described included carbohydrate hydrolases (glucosidase and amylase) and dipeptidyl-peptidase IV inhibition, due to their importance in the food-derived peptides research field. Then, their characterization, concerning bioavailability in vitro and in situ, stability and functionality in food matrices, and ultimately, the in vivo evidence (from invertebrate animals to humans), was described. The future applicability that these molecules have due to their biological potential as functional ingredients makes them an important field of research, which could help the world population avoid suffering from several diseases, such as diabetes.
Mantle-Derived Corundum-Bearing Felsic Dykes May Survive Only within the Lower (Refractory/Inert) Crust: Evidence from Zircon Geochemistry and Geochronology (Ivrea–Verbano Zone, Southern Alps, Italy)
Authors: Bonazzi Mattia , Langone Antonio , Tumiati Simone , Dellarole Edoardo , Mazzucchelli Maurizio , Giovanardi Tommaso , Zanetti Alberto
Published: July 2020

Corundum-rich (up to 55 vol.%) felsic dykes formed with albite, ±K-feldspar, ±hercynite and ±biotite-siderophyllite cut the lower crustal rocks exposed in the Ivrea–Verbano Zone (NW Italy). Zircon is an abundant accessory mineral and its investigation through laser ablation-inductively coupled plasma (multi-collector)-mass spectrometer (LA-ICP-(MC)MS) has allowed results to directly constrain the timing of emplacement, as well as petrology and geochemistry of parental melts. Zircons are characterized by very large concentration in rare earth elements (REE), Th, U, Nb and Ta, and negative Eu anomaly. U–Pb analysis points to Norian emplacement ages (223 ± 7 Ma and 224 ± 6 Ma), whereas large positive εHf(t) values (+13 on average) indicate a derivation from depleted to mildly enriched mantle source. The mantle signature and the corundum oversaturation were preserved thanks to limited crustal contamination of the host, high-temperature refractory granulites and mafic intrusives. According to the geochemical data and to the evidence of the development of violent explosions into the conduits, it is proposed that dykes segregated from peraluminous melts produced by exsolution processes affecting volatile-rich differentiates during alkaline magmatism. This work provides robust evidence about the transition of the geochemical affinity of Southern Alps magmatism from orogenic-like to anorogenic during Norian time, linked to a regional uprising of the asthenosphere and change of tectonic regime.
Impact of South Korea’s Comprehensive Nursing Service Policy on Nurse and Patient Outcomes
Authors: Lee Seon Heui , Yu Soyoung , Kim Miok , Kim Hee Sun
Published: July 2020

In some Asian and African countries, caregivers of patients are permitted to reside in hospital rooms and support the daily tasks of patient care. To solve the various problems that this system could cause, the Korean government has established a comprehensive nursing service, whereby caregivers are no longer permitted in the hospital and, instead, nurses provide all the patient care. This study aimed to identify and evaluate the effectiveness of the comprehensive nursing service, by surveying 1348 nurses to evaluate nursing outcomes—specifically, the Nurses’ Assessment of Quality Scale, job satisfaction, and turnover intention. A total of 396 patients were also surveyed to determine patient outcome, in particular patient satisfaction. In the comprehensive nursing service ward, the total score on the Nurses’ Assessment of Quality Scale, job satisfaction, and patient satisfaction scores were higher than in the non-comprehensive nursing service ward. Moreover, turnover intention was lower. All differences were statistically significant. The results of this study demonstrate that the decision to implement policy-based comprehensive nursing services has thus far been beneficial. In the future, the government should revise and supplement its policies through various socioeconomic assessments.
Quadrupling the N95 Supply during the COVID-19 Crisis with an Innovative 3D-Printed Mask Adaptor
Authors: Imbrie-Moore Annabel M. , Park Matthew H. , Zhu Yuanjia , Paulsen Michael J. , Wang Hanjay , Woo Y. Joseph
Published: July 2020

The need for personal protective equipment during the COVID-19 pandemic is far outstripping our ability to manufacture and distribute these supplies to hospitals. In particular, the medical N95 mask shortage is resulting in healthcare providers reusing masks or utilizing masks with filtration properties that do not meet medical N95 standards. We developed a solution for immediate use: a mask adaptor, outfitted with a quarter section of an N95 respirator that maintains the N95 seal standard, thereby quadrupling the N95 supply. A variety of designs were 3D-printed and optimized based on the following criteria: seal efficacy, filter surface area and N95 respirator multiplicity. The final design is reusable and features a 3D-printed soft silicone base as well as a rigid 3D-printed cartridge to seal one-quarter of a 3M 1860 N95 mask. Our mask passed the computerized N95 fit test for six individuals. All files are publicly available with this publication. Our design can provide immediate support for healthcare professionals in dire need of medical N95 masks by extending the current supply by a factor of four.
Barriers to and Facilitators of Physical Activity among Korean Female Adults with Knee Osteoarthritis and Comorbidity: A Qualitative Study
Authors: Park Eunyoung , Park Hyung-Ran , Choi Eui-Sung
Published: July 2020

When knee osteoarthritis is combined with comorbidity, it is associated with limited physical activity. This study aimed to identify barriers to and facilitators of physical activity among Korean female adults with knee osteoarthritis and comorbidity, such as hypertension, diabetes, and dyslipidemia. A qualitative content analysis study was conducted. Ten female knee osteoarthritis participants with comorbidity were recruited at an orthopedic outpatient center in South Korea. Data were collected using in-depth interviews and were analyzed using a conventional content analysis method. Ten participants with a mean age of 70.7 years participated in this study. Four categories of barriers and three of facilitators were identified. Barriers to physical activity were physical hardships, lack of motivation, environmental restrictions, and lack of knowledge. Categories of facilitators were pain management, self-control in physical activity, and understanding the importance of physical activity. Participants did not express any social or environmental facilitators of physical exercise. Healthcare professionals should include social support and environmental facilities to achieve medical and institutional compliance. Understanding female adults with knee osteoarthritis and comorbidity would support provision of appropriately tailored interventions that account for the characteristics of the comorbidity.
Spatial Mismatch between the Supply and Demand of Urban Leisure Services with Multisource Open Data
Authors: Deng Yue , Liu Jiping , Luo An , Wang Yong , Xu Shenghua , Ren Fu , Su Fenzhen
Published: July 2020

Understanding the balance between the supply and demand of leisure services (LSs) in urban areas can benefit urban spatial planning and improve the quality of life of residents. In cities in developing countries, the pursuit of rapid economic growth has ignored residents’ demand for LSs, thereby leading to a high demand for and short supply of these services. However, due to the lack of relevant research data, few studies have focused on the spatial mismatch in the supply and demand of LSs in urban areas. As typical representatives of multisource geographic data, social sensing data are readily available at various temporal and spatial scales, thus making social sensing data ideal for quantitative urban research. The objectives of this study are to use openly accessible datasets to explore the spatial pattern of the supply and demand of LSs in urban areas and then to depict the relationship between the supply and demand by using correlation analysis. Therefore, taking Beijing, China, as an example, the LS supply index (SI) and societal needs index (SNI) are proposed based on open data to reflect the supply and demand of LSs. The results show that the spatial distribution of the LS supply and demand in Beijing varies with a concentric pattern from the urban center to suburban areas. There is a strong correlation between the supply and demand of commercial and multifunctional services in Chaoyang, Fengtai, Haidian and Shijingshan, but there is no obvious correlation between the supply and demand of ecological and cultural services in Beijing. Especially in Dongcheng and Xicheng, there is no obvious correlation between the supply and demand of all services. The proposed approach provides an effective urban LS supply and demand evaluation method. In addition, the research results can provide a reference for the construction of “happy cities” in China.
The CCL20-CCR6 Axis in Cancer Progression
Authors: Kadomoto Suguru , Izumi Kouji , Mizokami Atsushi
Published: July 2020

Chemokines, which are basic proteins that exert their effects via G protein-coupled receptors and a subset of the cytokine family, are mediators deeply involved in leukocyte migration during an inflammatory reaction. Chemokine (C-C motif) ligand 20 (CCL20), also known as macrophage inflammatory protein (MIP)-3α, liver activation regulated chemokine (LARC), and Exodus-1, is a small protein that is physiologically expressed in the liver, colon, and skin, is involved in tissue inflammation and homeostasis, and has a specific receptor C-C chemokine receptor 6 (CCR6). The CCL20-CCR6 axis has long been known to be involved in inflammatory and infectious diseases, such as rheumatoid arthritis and human immunodeficiency virus infections. Recently, however, reports have shown that the CCL20-CCR6 axis is associated with several cancers, including hepatocellular carcinoma, colorectal cancer, breast cancer, pancreatic cancer, cervical cancer, and kidney cancer. The CCL20-CCR6 axis promotes cancer progression directly by enhancing migration and proliferation of cancer cells and indirectly by remodeling the tumor microenvironment through immune cell control. The present article reviewed the role of the CCL20-CCR6 axis in cancer progression and its potential as a therapeutic target.
Optimization of the Preparation of Magnetic Liposomes for the Combined Use of Magnetic Hyperthermia and Photothermia in Dual Magneto-Photothermal Cancer Therapy
Authors: T. S. Anilkumar , Lu Yu-Jen , Chen Jyh-Ping
Published: July 2020

In this work, we aimed to develop liposomal nanocomposites containing citric-acid-coated iron oxide magnetic nanoparticles (CMNPs) for dual magneto-photothermal cancer therapy induced by alternating magnetic field (AMF) and near-infrared (NIR) lasers. Toward this end, CMNPs were encapsulated in cationic liposomes to form nano-sized magnetic liposomes (MLs) for simultaneous magnetic hyperthermia (MH) in the presence of AMF and photothermia (PT) induced by NIR laser exposure, which amplified the heating efficiency for dual-mode cancer cell killing and tumor therapy. Since the heating capability is directly related to the amount of entrapped CMNPs in MLs, while the liposome size is important to allow internalization by cancer cells, response surface methodology was utilized to optimize the preparation of MLs by simultaneously maximizing the encapsulation efficiency (EE) of CMNPs in MLs and minimizing the size of MLs. The experimental design was performed based on the central composite rotatable design. The accuracy of the model was verified from the validation experiments, providing a simple and effective method for fabricating the best MLs, with an EE of 87% and liposome size of 121 nm. The CMNPs and the optimized MLs were fully characterized from chemical and physical perspectives. In the presence of dual AMF and NIR laser treatment, a suspension of MLs demonstrated amplified heat generation from dual hyperthermia (MH)–photothermia (PT) in comparison with single MH or PT. In vitro cell culture experiments confirmed the efficient cellular uptake of the MLs from confocal laser scanning microscopy due to passive accumulation in human glioblastoma U87 cells originated from the cationic nature of MLs. The inducible thermal effects mediated by MLs after endocytosis also led to enhanced cytotoxicity and cumulative cell death of cancer cells in the presence of AMF–NIR lasers. This functional nanocomposite will be a potential candidate for bimodal MH–PT dual magneto-photothermal cancer therapy.
Sulforaphane Elicits Protective Effects in Intestinal Ischemia Reperfusion Injury
Authors: Chen Zhiquan , Mohr Annika , Heitplatz Barbara , Hansen Uwe , Pascher Andreas , Brockmann Jens G. , Becker Felix
Published: July 2020

Intestinal ischemia reperfusion injury (IRI) is an inherent, unavoidable event of intestinal transplantation, contributing to allograft failure and rejection. The inflammatory state elicited by intestinal IRI is characterized by heightened leukocyte recruitment to the gut, which is amplified by a cross-talk with platelets at the endothelial border. Sulforaphane (SFN), a naturally occurring isothiocyanate, exhibits anti-inflammatory characteristics and has been shown to reduce platelet activation and block leukocyte adhesion. Thus, the aim of this study was to investigate protective effects and mechanism of action of SFN in a murine model of intestinal IRI. Intestinal IRI was induced by superior mesenteric artery occlusion for 30 min, followed by reperfusion for 2 h, 8 h or 24 h. To investigate cellular interactions, leukocytes were in vivo stained with rhodamine and platelets were harvested from donor animals and ex vivo stained. Mice (C57BL/6J) were divided into three groups: (1) control, (2) SFN treatment 24 h prior to reperfusion and (3) SFN treatment 24 h prior to platelet donation. Leukocyte and platelet recruitment was analyzed via intravital microscopy. Tissue was analyzed for morphological alterations in intestinal mucosa, barrier permeability, and leukocyte infiltration. Leukocyte rolling and adhesion was significantly reduced 2 h and 8 h after reperfusion. Mice receiving SFN treated platelets exhibited significantly decreased leukocyte and platelet recruitment. SFN showed protection for intestinal tissue with less damage observed in histopathological and ultrastructural evaluation. In summary, the data presented provide evidence for SFN as a potential therapeutic strategy against intestinal IRI.
Molecular and Functional Analysis of Choline Transporters and Antitumor Effects of Choline Transporter-Like Protein 1 Inhibitors in Human Pancreatic Cancer Cells
Authors: Hirai Kaho , Watanabe Saiichiro , Nishijima Nozomi , Shibata Kaoru , Hase Akane , Yamanaka Tsuyoshi , Inazu Masato
Published: July 2020

Choline, an organic cation, is one of the biofactors that play an important role in the structure and the function of biological membranes, and it is essential for the synthesis of phospholipids. Choline positron emission tomography-computed tomography (PET/CT) provides useful information for the imaging diagnosis of cancers, and increased choline accumulation has been identified in a variety of tumors. However, the molecular mechanisms of choline uptake and choline transporters in pancreatic cancer have not been elucidated. Here, we examined molecular and functional analyses of choline transporters in human pancreatic-cancer cell line MIA PaCa-2 and the elucidation of the action mechanism behind the antitumor effect of novel choline-transporter-like protein 1 (CTL1) inhibitors, Amb4269951 and its derivative Amb4269675. CTL1 and CTL2 mRNAs were highly expressed in MIA PaCa-2 cells, and CTL1 and CTL2 proteins were localized in the plasma membrane and the intracellular compartments, respectively. Choline uptake was characterized by Na+-independence, a single-uptake mechanism, and inhibition by choline-uptake inhibitor HC-3, similar to the function of CTL1. These results suggest that the uptake of extracellular choline in MIA PaCa-2 cells is mediated by CTL1. Choline deficiency and HC-3 treatment inhibited cell viability and increased caspase 3/7 activity, suggesting that the inhibition of CTL1 function, which is responsible for choline transport, leads to apoptosis-induced cell death. Both Amb4269951 and Amb4269675 inhibited choline uptake and cell viability and increased caspase-3/7 activity. Ceramide, which is increased by inhibiting choline uptake, also inhibited cell survival and increased caspase-3/7 activity. Lastly, both Amb4269951 and Amb4269675 significantly inhibited tumor growth in a mouse-xenograft model without any adverse effects such as weight loss. CTL1 is a target molecule for the treatment of pancreatic cancer, and its inhibitors Amb4269951 and Amb4269675 are novel lead compounds.
B-Cell Maturation Antigen (BCMA) as a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma
Authors: Abramson Hanley N.
Published: July 2020

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, has approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.
Epigenetic Regulation of Verticillium dahliae Virulence: Does DNA Methylation Level Play A Role?
Authors: Ramírez-Tejero Jorge A. , Cabanás Carmen Gómez-Lama , Valverde-Corredor Antonio , Mercado-Blanco Jesús , Luque Francisco
Published: July 2020

Verticillium dahliae is the etiological agent of Verticillium wilt of olive. The virulence of Defoliating V. dahliae isolates usually displays differences and high plasticity. This work studied whether an epigenetic mechanism was involved in this plasticity. An inverse correlation between virulence and DNA methylation of protein-coding genes was found. A set of 831 genes was selected for their highly consistent inverse methylation profile and virulence in the five studied isolates. Of these genes, ATP-synthesis was highly represented, which indicates that the more virulent D isolates are, the more energy requirements they may have. Furthermore, there were numerous genes in the protein biosynthesis process: genes coding for the chromatin structure, which suggests that epigenetic changes may also affect chromatin condensation; many transmembrane transporter genes, which is consistent with denser compounds, traffic through membranes in more virulent isolates; a fucose-specific lectin that may play a role in the attachment to plant cell walls during the host infection process; and pathogenic cutinases that facilitate plant invasion and sporulation genes for rapid spreading alongside plants. Our findings support the notion that differences in the virulence of the Defoliating V. dahliae isolates may be controlled, at least to some extent, by an epigenetic mechanism.
The In Vitro Effect of Prostaglandin E2 and F2α on the Chemerin System in the Porcine Endometrium during Gestation
Authors: Dobrzyn Kamil , Kiezun Marta , Zaobidna Ewa , Kisielewska Katarzyna , Rytelewska Edyta , Gudelska Marlena , Kopij Grzegorz , Bors Kinga , Szymanska Karolina , Kaminska Barbara , Kaminski Tadeusz , Smolinska Nina
Published: July 2020

Chemerin belongs to the group of adipocyte-derived hormones known as adipokines, which are responsible mainly for the control of energy homeostasis. Adipokine exerts its influence through three receptors: Chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C motif chemokine receptor-like 2 (CCRL2). A growing body of evidence indicates that chemerin participates in the regulation of the female reproductive system. According to the literature, the expression of chemerin and its receptors in reproductive structures depends on the local hormonal milieu. The aim of this study was to investigate the in vitro effect of prostaglandins E2 (PGE2) and F2α (PGF2α) on chemerin and chemerin receptor (chemerin system) mRNAs (qPCR) and proteins (ELISA, Western blotting) in endometrial tissue explants collected from early-pregnant gilts. Both PGE2 and PGF2α significantly influenced the expression of the chemerin gene, hormone secretion, and the expression of chemerin receptor genes and proteins. The influence of both prostaglandins on the expression of the chemerin system varied between different stages of gestation. This is the first study to describe the modulatory effect of PGE2 and PGF2α on the expression of the chemerin system in the porcine uterus during early gestation.
A Tissue-Engineered Human Psoriatic Skin Model to Investigate the Implication of cAMP in Psoriasis: Differential Impacts of Cholera Toxin and Isoproterenol on cAMP Levels of the Epidermis
Authors: Simard Mélissa , Morin Sophie , Rioux Geneviève , Séguin Rachelle , Loing Estelle , Pouliot Roxane
Published: July 2020

Pathological and healthy skin models were reconstructed using similar culture conditions according to well-known tissue engineering protocols. For both models, cyclic nucleotide enhancers were used as additives to promote keratinocytes’ proliferation. Cholera toxin (CT) and isoproterenol (ISO), a beta-adrenergic agonist, are the most common cAMP stimulators recommended for cell culture. The aim of this study was to evaluate the impact of either CT or ISO on the pathological characteristics of the dermatosis while producing a psoriatic skin model. Healthy and psoriatic skin substitutes were produced according to the self-assembly method of tissue engineering, using culture media supplemented with either CT (10−10 M) or ISO (10−6 M). Psoriatic substitutes produced with CT exhibited a more pronounced psoriatic phenotype than those produced with ISO. Indeed, the psoriatic substitutes produced with CT had the thickest epidermis, as well as contained the most proliferating cells and the most altered expression of involucrin, filaggrin, and keratin 10. Of the four conditions under study, psoriatic substitutes produced with CT had the highest levels of cAMP and enhanced expression of adenylate cyclase 9. Taken together, these results suggest that high levels of cAMP are linked to a stronger psoriatic phenotype.
Characteristics of Circular RNA Expression Profiles of Porcine Granulosa Cells in Healthy and Atretic Antral Follicles
Authors: Meng Li , Teerds Katja , Tao Jian , Wei Hengxi , Jaklofsky Marcel , Zhao Zhihong , Liang Yaodi , Li Li , Wang Chi Chiu , Zhang Shouquan
Published: July 2020

Circular RNAs (circRNAs) are thought to play essential roles in multiple biological processes, including apoptosis, an important process in antral follicle atresia. We aimed to investigate the potential involvement of circRNAs in granulosa cell apoptosis and thus antral follicle atresia. CircRNA expression profiles were generated from porcine granulosa cells isolated from healthy antral (HA) and atretic antral (AA) follicles. Over 9632 circRNAs were identified, of which 62 circRNAs were differentially expressed (DE-circRNAs). Back-splicing, RNase R resistance, and stability of DE-circRNAs were validated, and miRNA binding sites and related target genes were predicted. Two exonic circRNAs with low false discovery rate (FDR) high fold change, miRNA binding sites, and relevant biological functions—circ_CBFA2T2 and circ_KIF16B—were selected for further characterization. qRT-PCR and linear regression analysis confirmed expression and correlation of the targeted genes—the antioxidant gene GCLC (potential target of circ_CBFA2T2) and the apoptotic gene TP53 (potential target of circ_KIF16B). Increased mRNA content of TP53 in granulosa cells of AA follicles was further confirmed by strong immunostaining of both p53 and its downstream target pleckstrin homology like domain family a member 3 (PHLDA3) in AA follicles compared to negligible staining in granulosa cells of HA follicles. Therefore, we concluded that aberrantly expressed circRNAs presumably play a potential role in antral follicular atresia.
Investigation of Strand-Selective Interaction of SNA-Modified siRNA with AGO2-MID
Authors: Kamiya Yukiko , Takeyama Yuuki , Mizuno Tomonari , Satoh Fuminori , Asanuma Hiroyuki
Published: July 2020

Small interfering RNA (siRNA) has been recognized as a powerful gene-silencing tool. For therapeutic application, chemical modification is often required to improve the properties of siRNA, including its nuclease resistance, activity, off-target effects, and tissue distribution. Careful siRNA guide strand selection in the RNA-induced silencing complex (RISC) is important to increase the RNA interference (RNAi) activity as well as to reduce off-target effects. The passenger strand-mediated off-target activity was previously reduced and on-target activity was enhanced by substitution with acyclic artificial nucleic acid, namely serinol nucleic acid (SNA). In the present study, the reduction of off-target activity caused by the passenger strand was investigated by modifying siRNAs with SNA. The interactions of SNA-substituted mononucleotides, dinucleotides, and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)-labeled double-stranded RNA (dsRNA) with the MID domain of the Argonaute 2 (AGO2) protein, which plays a pivotal role in strand selection by accommodation of the 5’-terminus of siRNA, were comprehensively analyzed. The obtained nuclear magnetic resonance (NMR) data revealed that AGO2-MID selectively bound to the guide strand of siRNA due to the inhibitory effect of the SNA backbone located at the 5’ end of the passenger strand.
Primary Humoral Immune Deficiencies: Overlooked Mimickers of Chronic Immune-Mediated Gastrointestinal Diseases in Adults
Authors: Malesza Ida Judyta , Malesza Michał , Krela-Kaźmierczak Iwona , Zielińska Aleksandra , Souto Eliana B. , Dobrowolska Agnieszka , Eder Piotr
Published: July 2020

In recent years, the incidence of immune-mediated gastrointestinal disorders, including celiac disease (CeD) and inflammatory bowel disease (IBD), is increasingly growing worldwide. This generates a need to elucidate the conditions that may compromise the diagnosis and treatment of such gastrointestinal disorders. It is well established that primary immunodeficiencies (PIDs) exhibit gastrointestinal manifestations and mimic other diseases, including CeD and IBD. PIDs are often considered pediatric ailments, whereas between 25 and 45% of PIDs are diagnosed in adults. The most common PIDs in adults are the selective immunoglobulin A deficiency (SIgAD) and the common variable immunodeficiency (CVID). A trend to autoimmunity occurs, while gastrointestinal disorders are common in both diseases. Besides, the occurrence of CeD and IBD in SIgAD/CVID patients is significantly higher than in the general population. However, some differences concerning diagnostics and management between enteropathy/colitis in PIDs, as compared to idiopathic forms of CeD/IBD, have been described. There is an ongoing discussion whether CeD and IBD in CVID patients should be considered a true CeD and IBD or just CeD-like and IBD-like diseases. This review addresses the current state of the art of the most common primary immunodeficiencies in adults and co-occurring CeD and IBD.
Chronic Carbon Tetrachloride Applications Induced Hepatocyte Apoptosis in Lipocalin 2 Null Mice through Endoplasmic Reticulum Stress and Unfolded Protein Response
Authors: Borkham-Kamphorst Erawan , Haas Ute , Van de Leur Eddy , Trevanich Anothai , Weiskirchen Ralf
Published: July 2020

The lack of Lipocalin (LCN2) provokes overwhelming endoplasmic reticulum (ER) stress responses in vitro and in acute toxic liver injury models, resulting in hepatocyte apoptosis. LCN2 is an acute phase protein produced in hepatocytes in response to acute liver injuries. In line with these findings we investigated ER stress responses of Lcn2−/− mice in chronic ER stress using a long-term repetitive carbon tetrachloride (CCl4) injection model. We found chronic CCl4 application to enhance ER stress and unfolded protein responses (UPR), including phosphorylation of eukaryotic initiation factor 2α (eIF2α), increased expression of binding immunoglobulin protein (BiP) and glucose-regulated protein 94 (GRP94). IRE1α/TRAF2/JNK signaling enhanced mitochondrial apoptotic pathways, and showed slightly higher in Lcn2−/− mice compared to the wild type counterparts, leading to increased hepatocyte apoptosis well evidenced by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Hepatocyte injuries were confirmed by significant high serum alanine transaminase (ALT) levels in CCl4-treated Lcn2−/− mice. Lcn2−/− mice furthermore developed mild hepatic steatosis, supporting our finding that ER stress promotes lipogenesis. In a previous report we demonstrated that the pharmacological agent tunicamycin (TM) induced ER stress through altered protein glycosylation and induced high amounts of C/EBP-homologous protein (CHOP), resulting in hepatocyte apoptosis. We compared TM-induced ER stress in wild type, Lcn2−/−, and Chop null (Chop−/−) primary hepatocytes and found Chop−/− hepatocytes to attenuate ER stress responses and resist ER stress-induced hepatocyte apoptosis through canonical eIF2α/GADD34 signaling, inhibiting protein synthesis. Unexpectedly, in later stages of TM incubation, Chop−/− hepatocytes resumed activation of IRE1α/JNK/c-Jun and p38/ATF2 signaling, leading to late hepatocyte apoptosis. This interesting observation indicates Chop−/− mice to be unable to absolutely prevent all types of liver injury, while LCN2 protects the hepatocytes by maintaining homeostasis under ER stress conditions.
(Phospho)proteomic Profiling of Microsatellite Unstable CRC Cells Reveals Alterations in Nuclear Signaling and Cholesterol Metabolism Caused by Frameshift Mutation of NMD Regulator UPF3A
Authors: Michalak Malwina , Katzenmaier Eva-Maria , Roeckel Nina , Woerner Stefan M. , Fuchs Vera , Warnken Uwe , Yuan Yan P. , Bork Peer , Neu-Yilik Gabriele , Kulozik Andreas , von Knebel Doeberitz Magnus , Kloor Matthias , Kopitz Jürgen , Gebert Johannes
Published: July 2020

DNA mismatch repair-deficient colorectal cancers (CRCs) accumulate numerous frameshift mutations at repetitive sequences recognized as microsatellite instability (MSI). When coding mononucleotide repeats (cMNRs) are affected, tumors accumulate frameshift mutations and premature termination codons (PTC) potentially leading to truncated proteins. Nonsense-mediated RNA decay (NMD) can degrade PTC-containing transcripts and protect from such faulty proteins. As it also regulates normal transcripts and cellular physiology, we tested whether NMD genes themselves are targets of MSI frameshift mutations. A high frequency of cMNR frameshift mutations in the UPF3A gene was found in MSI CRC cell lines (67.7%), MSI colorectal adenomas (55%) and carcinomas (63%). In normal colonic crypts, UPF3A expression was restricted to single chromogranin A-positive cells. SILAC-based proteomic analysis of KM12 CRC cells revealed UPF3A-dependent down-regulation of several enzymes involved in cholesterol biosynthesis. Furthermore, reconstituted UPF3A expression caused alterations of 85 phosphosites in 52 phosphoproteins. Most of them (38/52, 73%) reside in nuclear phosphoproteins involved in regulation of gene expression and RNA splicing. Since UPF3A mutations can modulate the (phospho)proteomic signature and expression of enzymes involved in cholesterol metabolism in CRC cells, UPF3A may influence other processes than NMD and loss of UPF3A expression might provide a growth advantage to MSI CRC cells.
Role of Age-Related Mitochondrial Dysfunction in Sarcopenia
Authors: Ferri Evelyn , Marzetti Emanuele , Calvani Riccardo , Picca Anna , Cesari Matteo , Arosio Beatrice
Published: July 2020

Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main factors leading to negative health outcomes in geriatric patients. Notwithstanding the exact mechanisms responsible for sarcopenia are not fully understood, mitochondria have emerged as one of the central regulators of sarcopenia. In fact, there is a wide consensus on the assumption that the loss of mitochondrial integrity in myocytes is the main factor leading to muscle degeneration. Mitochondria are also key players in senescence. It has been largely proven that the modulation of mitochondrial functions can induce the death of senescent cells and that removal of senescent cells improves musculoskeletal health, quality, and function. In this review, the crosstalk among mitochondria, cellular senescence, and sarcopenia will be discussed with the aim to elucidate the role that the musculoskeletal cellular senescence may play in the onset of sarcopenia through the mediation of mitochondria.
Interleukin-6 in Rheumatoid Arthritis
Authors: Pandolfi Franco , Franza Laura , Carusi Valentina , Altamura Simona , Andriollo Gloria , Nucera Eleonora
Published: July 2020

The role of interleukin (IL)-6 in health and disease has been under a lot of scrutiny in recent years, particularly during the recent COVID-19 pandemic. The inflammatory pathways in which IL-6 is involved are also partly responsible of the development and progression of rheumatoid arthritis (RA), opening interesting perspectives in terms of therapy. Anti-IL-6 drugs are being used with variable degrees of success in other diseases and are being tested in RA. Results have been encouraging, particularly when anti-IL-6 has been used with other drugs, such as metothrexate (MTX). In this review we discuss the main immunologic aspects that make anti-IL-6 a good candidate in RA, but despite the main therapeutic options available to target IL-6, no gold standard treatment has been established so far.
Implementation of Gamification in Polish Companies—Stages, Elements, Ethics
Authors: Witoszek-Kubicka Aleksandra
Published: July 2020

Business gamification has been gaining in popularity in Poland in recent years and is indeed appearing in companies, especially large ones. However, the implementation of game-based solutions is still not sufficiently described. The technology allows the use of solutions such as AI or Machine Learning, but gamification is not only an IT project. The aim of the article is to determine the stages of implementation of business gamification according to various models, describe the existing differences and confront the results with business practice in Poland. To this end, a scoping review on the subject was carried out in terms of the existing methodologies for the implementation of gamification solutions. In the next stage, a scenario was created to conduct individual in-depth interviews (IDI) with companies implementing gamification projects in business. As a result of the research, the practice of implementing business gamification in Poland was described against the background of the methodologies proposed in the literature. This has led to the identification of several significant differences in implementation stages both between theory and practice and among the implementations proposed by the companies participating in the interviews. An attempt was made to explain these differences by taking the type of IT solution as a criterion.
Honeydew Deposition by the Giant Willow Aphid (Tuberolachnus salignus) Affects Soil Biota and Soil Biochemical Properties
Authors: Tun Kyaw Min , Clavijo McCormick Andrea , Jones Trevor , Garbuz Stanislav , Minor Maria
Published: July 2020

Infestation of willow plants by the giant willow aphid Tuberolachnus salignus (Hemiptera: Aphididae) is associated with copious deposition of sugar-rich honeydew under the plant canopy. We explored the effect of aphid honeydew on the soil biota and biochemical indicators in a two-year field trial. Soil samples from under aphid-infested and control willow trees, as well as samples from black sooty mould spots under the aphid-infested willows were compared; soil samples before aphid inoculation were used as a baseline. The honeydew deposition had a positive effect on the total soil carbon (C), but not on the total soil nitrogen content or soil pH. Microbial biomass C, basal respiration, number of yeast colony forming units, and the geometric mean of activities for six enzymes were significantly higher in honeydew-affected soils than in the control treatment on both years. The honeydew deposition also increased soil meso-fauna abundance, especially in the black sooty mould spots. The soil biochemical properties, which differed before and after aphid infestation, showed considerable overlap between the first and second year post-infestation. The results highlight the cascading effects of T. salignus on soil biological activity and the importance of using a multitrophic approach to explore similar scenarios.
Identification and Expression of Inward-Rectifying Potassium Channel Subunits in Plutella xylostella
Authors: Lai Xiaoyi , Xu Jie , Ma Haihao , Liu Zheming , Zheng Wei , Liu Jia , Zhu Hang , Zhou Yong , Zhou Xiaomao
Published: July 2020

In insects, inward-rectifying potassium (Kir) channels regulate vital physiological functions, such as feeding behavior, silk secretion, renal excretion, and immune function. Therefore, they offer promising potential as targets for insecticides. Three types of Kir subunits have been identified in Diptera and Hemiptera, but the Kir subunits of Lepidoptera still remain unclear. This study identified five Kir subunit genes (pxkir1, pxkir2, pxkir3A, pxkir3B, and pxkir4) in the transcriptome of Plutella xylostella. Phylogenetic analysis identified pxkir1, pxkir2, pxkir3A, and pxkir3B as orthologous genes of kir1–3 in other insects. Interestingly, pxkir4 may be encoding a new class of Kir subunit in Lepidoptera that has not been reported to date. To identify further Kir channel subunits of P. xylostella, the gene expression profiles of five pxkir genes were studied by quantitative real-time PCR. These pxkir genes are expressed throughout the development of P. xylostella. pxkir1 and pxkir2 were highly expressed in thoraxes and legs, while pxkir3 (3A and 3B) and pxkir4 had high expression levels in the midgut and Malpighian tubules. This study identified the composition and distribution of Kir subunits in P. xylostella for the first time, and provides useful information for the further study of Kir channel subunits in Lepidoptera.
Essential Oil Headspace Volatiles Prevent Invasive Box Tree Moth (Cydalima perspectalis) Oviposition—Insights from Electrophysiology and Behaviour
Authors: Szelényi Magdolna Olívia , Erdei Anna Laura , Jósvai Júlia Katalin , Radványi Dalma , Sümegi Bence , Vétek Gábor , Molnár Béla Péter , Kárpáti Zsolt
Published: July 2020

The box tree moth (Cydalima perspectalis Walker) is an invasive species in Europe causing severe damage both in natural and ornamental boxwood (Buxus spp.) vegetation. Pest management tactics are often based on the use of chemical insecticides, whereas environmentally-friendly control solutions are not available against this insect. The application of essential oils may provide effective protection against oviposition and subsequent larval damage. Oviposition deterrence of cinnamon, eucalyptus and lavender essential oils was tested on female C. perspectalis in behavioural bioassays. Our results indicate that all the studied essential oils may be adequate deterrents; however, cinnamon oil exhibited the strongest effect. To determine the physiologically active compounds in the headspace of the essential oils, gas chromatography coupled with electroantennography recordings were performed in parallel with gas chromatography-mass spectrometry to identify the volatile constituents. In addition, the release rates of various components from vial-wick dispensers were measured during the oviposition bioassay. These results may serve as a basis for the development of a practical and insecticide-free plant protection method against this invasive moth species.
Cost Analysis of Demand-Side Generating Assets Contribution to Ancillary Services of Island Power Systems
Authors: Fiorentzis Konstantinos , Karapidakis Emmanuel , Tsikalakis Antonios
Published: July 2020

Demand-Side Generating Assets (DSGAs) relate to existing small diesel Gensets serving the critical loads of infrastructures in unexpected electrical network interruptions. This paper investigates the exploitation of DSGA as potential suppliers of ancillary services (AS), especially in the case of isolated or weak interconnected island power systems such as in Crete. In this regard, their impact on substations’ loading reductions and associated copper losses is presented, using a substation as a case study with a typical touristic load in Crete. DSGA’s impact on such a significant part of reliability enhancement in distribution systems is evaluated, examining different scenarios of DSGA installed capacity. Subsequently, extensive research is carried out regarding the cost analysis for their access to the electrical grid providing AS, in combination with their operating cost analysis. The calculations on fuel consumption cost show that DSGA are comparable with the most expensive gas turbines of the Cretan power system. Finally, considering the capital cost for their required configurations and their fuel consumption cost, a proposal for their remuneration prices is made. The prices that arise are lower than the actual remuneration prices of other similar services such as Genset rentals for the case of the Cretan power system.
Early Embryonic Expression of AP-2α Is Critical for Cardiovascular Development
Authors: Johnson Amy-Leigh , Schneider Jürgen E. , Mohun Timothy J. , Williams Trevor , Bhattacharya Shoumo , Henderson Deborah J. , Phillips Helen M. , Bamforth Simon D.
Published: July 2020

Congenital cardiovascular malformation is a common birth defect incorporating abnormalities of the outflow tract and aortic arch arteries, and mice deficient in the transcription factor AP-2α (Tcfap2a) present with complex defects affecting these structures. AP-2α is expressed in the pharyngeal surface ectoderm and neural crest at mid-embryogenesis in the mouse, but the precise tissue compartment in which AP-2α is required for cardiovascular development has not been identified. In this study we describe the fully penetrant AP-2α deficient cardiovascular phenotype on a C57Bl/6J genetic background and show that this is associated with increased apoptosis in the pharyngeal ectoderm. Neural crest cell migration into the pharyngeal arches was not affected. Cre-expressing transgenic mice were used in conjunction with an AP-2α conditional allele to examine the effect of deleting AP-2α from the pharyngeal surface ectoderm and the neural crest, either individually or in combination, as well as the second heart field. This, surprisingly, was unable to fully recapitulate the global AP-2α deficient cardiovascular phenotype. The outflow tract and arch artery phenotype was, however, recapitulated through early embryonic Cre-mediated recombination. These findings indicate that AP-2α has a complex influence on cardiovascular development either being required very early in embryogenesis and/or having a redundant function in many tissue layers.
New Treatment Options for Hyperkalemia in Patients with Chronic Kidney Disease
Authors: Esposito Pasquale , Conti Novella Evelina , Falqui Valeria , Cipriani Leda , Picciotto Daniela , Costigliolo Francesca , Garibotto Giacomo , Saio Michela , Viazzi Francesca
Published: July 2020

Hyperkalemia may cause life-threatening cardiac and neuromuscular alterations, and it is associated with high mortality rates. Its treatment includes a multifaceted approach, guided by potassium levels and clinical presentation. In general, treatment of hyperkalemia may be directed towards stabilizing cell membrane potential, promoting transcellular potassium shift and lowering total K+ body content. The latter can be obtained by dialysis, or by increasing potassium elimination by urine or the gastrointestinal tract. Until recently, the only therapeutic option for increasing fecal K+ excretion was represented by the cation-exchanging resin sodium polystyrene sulfonate. However, despite its common use, the efficacy of this drug has been poorly studied in controlled studies, and concerns about its safety have been reported. Interestingly, new drugs, namely patiromer and sodium zirconium cyclosilicate, have been developed to treat hyperkalemia by increasing gastrointestinal potassium elimination. These medications have proved their efficacy and safety in large clinical trials, involving subjects at high risk of hyperkalemia, such as patients with heart failure and chronic kidney disease. In this review, we discuss the mechanisms of action and the updated data of patiromer and sodium zirconium cyclosilicate, considering that the availability of these new treatment options offers the possibility of improving the management of both acute and chronic hyperkalemia.