bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the Impacts of Environmental Factors on Adolescents’ Daily Participation: A Structural Equation Modelling Approach
Authors: Fogel Yael , Josman Naomi , Rosenblum Sara
Published: December 2020

Adolescents with neurodevelopmental difficulties struggle to perform daily activities, reflecting the significant impact of executive functions on their participation. This research examines an integrated conceptual model wherein supportive environmental factors in the community, school and home settings explain the children’s participation (involvement and frequency) with their daily activities performance as a mediator. Parents of 81 10- to 14-year-old adolescents with and without executive function deficit profiles completed the Participation and Environment Measure for Children and Youth and the Child Evaluation Checklist. A secondary analysis was conducted to examine the structural equation model using AMOS software. The results demonstrated support for the hypothesised model. Supportive environmental demands in school predicted 32% of home participation, and the adolescents’ daily performance reflected that executive functions mediated the relationship between them. Together, these findings highlight the school environment as the primary contributor that affects the children’s functioning according to their parents’ reports and as a predictor of high participation at home in terms of frequency and involvement. This study has implications for multidisciplinary practitioners working with adolescents in general, and in the school setting specifically, to understand meaningful effects of executive functions on adolescents’ daily functioning and to provide accurate assistance and intervention.
Correction: Xiao, H., et al. Social Distancing among Medical Students during the 2019 Coronavirus Disease Pandemic in China: Disease Awareness, Anxiety Disorder, Depression, and Behavioral Activities. Int. J. Environ. Res. Public Health 2020, 17, 5047
Authors: Xiao Huidi , Shu Wen , Li Menglong , Li Ziang , Tao Fangbiao , Wu Xiaoyan , Yu Yizhen , Meng Heng , Vermund Sten H. , Hu Yifei
Published: December 2020

In our recently published article [...]
Parental Stress, Anxiety and Depression Symptoms Associated with Self-Efficacy in Paediatric Type 1 Diabetes: A Literature Review
Authors: Bassi Giulia , Mancinelli Elisa , Di Riso Daniela , Salcuni Silvia
Published: December 2020

Background: Parents play a significant role in the management and monitoring of their children’s Type 1 diabetes mellitus (T1DM), being considered a family disease. The current review intends to investigate parental stress, depression and anxiety symptoms associated with self-efficacy referred to paediatric diabetes management. Method: A literature review was carried out using PsycINFO, Web of Science and PubMed where the following terms were considered: diabetes mellitus, paediatric, parent-child relationship, self-efficacy, parenting stress, perceived stress, stress, depression, anxiety. Standing a defined list of inclusion and exclusion criteria, a total of 33 papers were finally included. Results: Findings have shown that parents experience relatively high levels of anxiety, depression and stress symptoms related to managing a child with T1DM and are associated with parental self-efficacy. Parental stress predicts a worsening in the control of HbA1c levels, while parental diabetes-specific distress predicts an increase in children depression symptoms. High parental self-efficacy associates with better monitoring, allowing better adherence and more balanced HbA1c levels in the children. Conclusions: Interventions aimed at fostering social support, improving diabetes management, and decreasing perceived stress, might alleviate parents’ psychological symptoms by focusing on increasing their self-efficacy. Digital interventions might also represent valuable solutions to support parents in the management of paediatric diabetes not presented and substantiated in the main text and should not exaggerate the main conclusions.
Variability Matters
Authors: Wensink Maarten Jan , Ahrenfeldt Linda Juel , Möller Sören
Published: December 2020

Much of science, including public health research, focuses on means (averages). The purpose of the present paper is to reinforce the idea that variability matters just as well. At the hand of four examples, we highlight four classes of situations where the conclusion drawn on the basis of the mean alone is qualitatively altered when variability is also considered. We suggest that some of the more serendipitous results have their origin in variability.
Comparison of Subjective Responses of Low Back Pain Patients and Asymptomatic Controls to Use of Spinal Exoskeleton during Simple Load Lifting Tasks: A Pilot Study
Authors: Kozinc Žiga , Babič Jan , Šarabon Nejc
Published: December 2020

Spinal exoskeletons have been suggested as an approach for the prevention and rehabilitation of occupational low back pain (LBP). While the state-of-the-art exoskeletons were shown to substantially unload the back, user acceptance is still limited. Perceived discomfort and restriction of freedom of movement are commonly reported. In this pilot study, we explored the differences in subjective responses and user impressions to using passive spinal exoskeleton during a set of simple lifting tasks between LBP patients (n = 12) and asymptomatic individuals (n = 10). Visual analog scales (0–10) were used for all assessments. Overall, the results showed mostly similar responses or slightly more positive responses to the exoskeleton from LBP patients. Most notably, the LBP patients reported a statistically significant (p = 0.048) higher willingness to use the device daily (5.36 ± 4.05) compared to the control group (2.00 ± 1.85) and also gave the device a higher overall grade (6.58 ± 1.98 vs. 4.30 ± 2.26; p = 0.021). This study has demonstrated that individuals with current LBP responded more favorably to the use of the spinal exoskeleton for simple lifting tasks. This implies that current exoskeletons could be appropriate for LBP rehabilitation, but not preventions, as pain-free individuals are less willing to use such devices. Future studies should explore whether different exoskeleton designs could be more appropriate for people with no LBP issues.
Sounds Stimulation on In Vitro HL1 Cells: A Pilot Study and a Theoretical Physical Model
Authors: Dal Lin Carlo , Radu Claudia Maria , Vitiello Giuseppe , Romano Paola , Polcari Albino , Iliceto Sabino , Simioni Paolo , Tona Francesco
Published: December 2020

Mechanical vibrations seem to affect the behaviour of different cell types and the functions of different organs. Pressure waves, including acoustic waves (sounds), could affect cytoskeletal molecules via coherent changes in their spatial organization and mechano-transduction signalling. We analyzed the sounds spectra and their fractal features. Cardiac muscle HL1 cells were exposed to different sounds, were stained for cytoskeletal markers (phalloidin, beta-actin, alpha-tubulin, alpha-actinin-1), and studied with multifractal analysis (using FracLac for ImageJ). A single cell was live-imaged and its dynamic contractility changes in response to each different sound were analysed (using Musclemotion for ImageJ). Different sound stimuli seem to influence the contractility and the spatial organization of HL1 cells, resulting in a different localization and fluorescence emission of cytoskeletal proteins. Since the cellular behaviour seems to correlate with the fractal structure of the sound used, we speculate that it can influence the cells by virtue of the different sound waves’ geometric properties that we have photographed and filmed. A theoretical physical model is proposed to explain our results, based on the coherent molecular dynamics. We stress the role of the systemic view in the understanding of the biological activity.
Chemical Evaluation of Eumelanin Maturation by ToF-SIMS and Alkaline Peroxide Oxidation HPLC Analysis
Authors: Jarenmark Martin , Sjövall Peter , Ito Shosuke , Wakamatsu Kazumasa , Lindgren Johan
Published: December 2020

Residual melanins have been detected in multimillion-year-old animal body fossils; however, confident identification and characterization of these natural pigments remain challenging due to loss of chemical signatures during diagenesis. Here, we simulate this post-burial process through artificial maturation experiments using three synthetic and one natural eumelanin exposed to mild (100 °C/100 bar) and harsh (250 °C/200 bar) environmental conditions, followed by chemical analysis employing alkaline hydrogen peroxide oxidation (AHPO) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Our results show that AHPO is sensitive to changes in the melanin molecular structure already during mild heat and pressure treatment (resulting, e.g., in increased C-C cross-linking), whereas harsh maturation leads to extensive loss of eumelanin-specific chemical markers. In contrast, negative-ion ToF-SIMS spectra are considerably less affected by mild maturation conditions, and eumelanin-specific features remain even after harsh treatment. Detailed analysis of ToF-SIMS spectra acquired prior to experimental treatment revealed significant differences between the investigated eumelanins. However, systematic spectral changes upon maturation reduced these dissimilarities, indicating that intense heat and pressure treatment leads to the formation of a common, partially degraded, eumelanin molecular structure. Our findings elucidate the complementary nature of AHPO and ToF-SIMS during chemical characterization of eumelanin traces in fossilized organismal remains.
The Interfacial Interactions of Glycine and Short Glycine Peptides in Model Membrane Systems
Authors: Doucette Kaitlin A. , Chaiyasit Prangthong , Calkins Donn L. , Martinez Kayli N. , Van Cleave Cameron , Knebel Callan A. , Tongraar Anan , Crans Debbie C.
Published: December 2020

The interactions of amino acids and peptides at model membrane interfaces have considerable implications for biological functions, with the ability to act as chemical messengers, hormones, neurotransmitters, and even as antibiotics and anticancer agents. In this study, glycine and the short glycine peptides diglycine, triglycine, and tetraglycine are studied with regards to their interactions at the model membrane interface of Aerosol-OT (AOT) reverse micelles via 1H NMR spectroscopy, dynamic light scattering (DLS), and Langmuir trough measurements. It was found that with the exception of monomeric glycine, the peptides prefer to associate between the interface and bulk water pool of the reverse micelle. Monomeric glycine, however, resides with the N-terminus in the ordered interstitial water (stern layer) and the C-terminus located in the bulk water pool of the reverse micelle.
Systems Approach to Pathogenic Mechanism of Type 2 Diabetes and Drug Discovery Design Based on Deep Learning and Drug Design Specifications
Authors: Chang Shen , Chen Jian-You , Chuang Yung-Jen , Chen Bor-Sen
Published: December 2020

In this study, we proposed a systems biology approach to investigate the pathogenic mechanism for identifying significant biomarkers as drug targets and a systematic drug discovery strategy to design a potential multiple-molecule targeting drug for type 2 diabetes (T2D) treatment. We first integrated databases to construct the genome-wide genetic and epigenetic networks (GWGENs), which consist of protein–protein interaction networks (PPINs) and gene regulatory networks (GRNs) for T2D and non-T2D (health), respectively. Second, the relevant “real GWGENs” are identified by system identification and system order detection methods performed on the T2D and non-T2D RNA-seq data. To simplify network analysis, principal network projection (PNP) was thereby exploited to extract core GWGENs from real GWGENs. Then, with the help of KEGG pathway annotation, core signaling pathways were constructed to identify significant biomarkers. Furthermore, in order to discover potential drugs for the selected pathogenic biomarkers (i.e., drug targets) from the core signaling pathways, not only did we train a deep neural network (DNN)-based drug–target interaction (DTI) model to predict candidate drug’s binding with the identified biomarkers but also considered a set of design specifications, including drug regulation ability, toxicity, sensitivity, and side effects to sieve out promising drugs suitable for T2D.
Induction of Oxidative Stress and Mitochondrial Dysfunction by Juglone Affects the Development of Bovine Oocytes
Authors: Mesalam Ahmed Atef , El-Sheikh Marwa , Joo Myeong-Don , Khalil Atif Ali Khan , Mesalam Ayman , Ahn Mi-Jeong , Kong Il-Keun
Published: December 2020

Juglone, a major naphthalenedione component of walnut trees, has long been used in traditional medicine as an antimicrobial and antitumor agent. Nonetheless, its impact on oocyte and preimplantation embryo development has not been entirely clarified. Using the bovine model, we sought to elucidate the impact of juglone treatment during the in vitro maturation (IVM) of oocytes on their maturation and development of embryos. Results showed a severe reduction in oocyte nuclear maturation and cumulus expansion and a significant increase in mitochondrial dysfunction and reactive oxygen species (ROS) levels in cumulus–oocyte complexes (COCs) treated with juglone (12.5, 25.0, and 50.0 µM). In addition, RT–qPCR showed downregulation of the expansion-related (HAS2, TNFAIP6, PTX3, and PTGS2) and mitochondrial (ATPase6 and ATP5F1E) genes in juglone-treated COCs. Moreover, the development rates of day 4 total cleavage and 8–16 cell stage embryos, as well as day 8 blastocysts, were significantly reduced following exposure to juglone. Using immunofluorescence, the apoptotic marker caspase-9 was overexpressed in oocytes exposed to juglone (25.0 µM) compared to the untreated control. In conclusion, our study reports that exposing bovine oocytes to 12.5–50.0 µM of juglone can reduce their development through the direct induction of ROS accumulation, apoptosis, and mitochondrial dysfunction.
Pathophysiology and Treatment of Pruritus in Elderly
Authors: Chung Bo Young , Um Ji Young , Kim Jin Cheol , Kang Seok Young , Park Chun Wook , Kim Hye One
Published: December 2020

Pruritus is a relatively common symptom that anyone can experience at any point in their life and is more common in the elderly. Pruritus in elderly can be defined as chronic pruritus in a person over 65 years old. The pathophysiology of pruritus in elderly is still unclear, and the quality of life is reduced. Generally, itch can be clinically classified into six types: Itch caused by systemic diseases, itch caused by skin diseases, neuropathic pruritus, psychogenic pruritus, pruritus with multiple factors, and from unknown causes. Senile pruritus can be defined as a chronic pruritus of unknown origin in elderly people. Various neuronal mediators, signaling mechanisms at neuronal terminals, central and peripheral neurotransmission pathways, and neuronal sensitizations are included in the processes causing itch. A variety of therapies are used and several novel drugs are being developed to relieve itch, including systemic and topical treatments.
In Vitro Photodynamic Effects of the Inclusion Nanocomplexes of Glucan and Chlorin e6 on Atherogenic Foam Cells
Authors: Ahn Jae Won , Kim Jin Hyuk , Park Kyeongsoon
Published: December 2020

Macrophage-derived foam cells play critical roles in the initiation and progression of atherosclerosis. Activated macrophages and foam cells are important biomarkers for targeted imaging and inflammatory disease therapy. Macrophages also express the dectin-1 receptor, which specifically recognizes β-glucan (Glu). Here, we prepared photoactivatable nanoagents (termed Glu/Ce6 nanocomplexes) by encapsulating hydrophobic chlorin e6 (Ce6) within the triple-helix structure of Glu in aqueous condition. Glu/Ce6 nanocomplexes generate singlet oxygen upon laser irradiation. The Glu/Ce6 nanocomplexes were internalized into foam cells and delivered Ce6 molecules into the cytoplasm of foam cells. Upon laser irradiation, they induced significant membrane damage and apoptosis of foam cells. These results suggest that Glu/Ce6 nanocomplexes can be a photoactivatable material for treating atherogenic foam cells.
The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy
Authors: Yun Chul Won , Jeon Juhee , Go Gyeongyun , Lee Jun Hee , Lee Sang Hun
Published: December 2020

Autophagy is a delicate intracellular degradation process that occurs due to diverse stressful conditions, including the accumulation of damaged proteins and organelles as well as nutrient deprivation. The mechanism of autophagy is initiated by the creation of autophagosomes, which capture and encapsulate abnormal components. Afterward, autophagosomes assemble with lysosomes to recycle or remove degradative cargo. The regulation of autophagy has bipolar roles in cancer suppression and promotion in diverse cancers. Furthermore, autophagy modulates the features of tumorigenesis, cancer metastasis, cancer stem cells, and drug resistance against anticancer agents. Some autophagy regulators are used to modulate autophagy for anticancer therapy but the dual roles of autophagy limit their application in anticancer therapy, and present as the main reason for therapy failure. In this review, we summarize the mechanisms of autophagy, tumorigenesis, metastasis, cancer stem cells, and resistance against anticancer agents. Finally, we discuss whether targeting autophagy is a promising and effective therapeutic strategy in anticancer therapy.
Finely-Tuned Calcium Oscillations in Osteoclast Differentiation and Bone Resorption
Authors: Okada Hiroyuki , Okabe Koji , Tanaka Sakae
Published: December 2020

Calcium (Ca2+) plays an important role in regulating the differentiation and function of osteoclasts. Calcium oscillations (Ca oscillations) are well-known phenomena in receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption via calcineurin. Many modifiers are involved in the fine-tuning of Ca oscillations in osteoclasts. In addition to macrophage colony-stimulating factors (M-CSF; CSF-1) and RANKL, costimulatory signaling by immunoreceptor tyrosine-based activation motif-harboring adaptors is important for Ca oscillation generation and osteoclast differentiation. DNAX-activating protein of 12 kD is always necessary for osteoclastogenesis. In contrast, Fc receptor gamma (FcRγ) works as a key controller of osteoclastogenesis especially in inflammatory situation. FcRγ has a cofactor in fine-tuning of Ca oscillations. Some calcium channels and transporters are also necessary for Ca oscillations. Transient receptor potential (TRP) channels are well-known environmental sensors, and TRP vanilloid channels play an important role in osteoclastogenesis. Lysosomes, mitochondria, and endoplasmic reticulum (ER) are typical organelles for intracellular Ca2+ storage. Ryanodine receptor, inositol trisphosphate receptor, and sarco/endoplasmic reticulum Ca2+ ATPase on the ER modulate Ca oscillations. Research on Ca oscillations in osteoclasts has still many problems. Surprisingly, there is no objective definition of Ca oscillations. Causality between Ca oscillations and osteoclast differentiation and/or function remains to be examined.
Terminal Mono- and Bis-Conjugates of Oligonucleotides with Closo-Dodecaborate: Synthesis and Physico-Chemical Properties
Authors: Novopashina Darya S. , Vorobyeva Mariya A. , Lomzov Alexander A. , Silnikov Vladimir N. , Venyaminova Alya G.
Published: December 2020

Oligonucleotide conjugates with boron clusters have found applications in different fields of molecular biology, biotechnology, and biomedicine as potential agents for boron neutron capture therapy, siRNA components, and antisense agents. Particularly, the closo-dodecaborate anion represents a high-boron-containing residue with remarkable chemical stability and low toxicity, and is suitable for the engineering of different constructs for biomedicine and molecular biology. In the present work, we synthesized novel oligonucleotide conjugates of closo-dodecaborate attached to the 5′-, 3′-, or both terminal positions of DNA, RNA, 2′-O-Me RNA, and 2′-F-Py RNA oligomers. For their synthesis, we employed click reaction with the azido derivative of closo-dodecaborate. The key physicochemical characteristics of the conjugates have been investigated using high-performance liquid chromatography, gel electrophoresis, UV thermal melting, and circular dichroism spectroscopy. Incorporation of closo-dodecaborate residues at the 3′-end of all oligomers stabilized their complementary complexes, whereas analogous 5′-modification decreased duplex stability. Two boron clusters attached to the opposite ends of the oligomer only slightly influence the stability of complementary complexes of RNA oligonucleotide and its 2′-O-methyl and 2′-fluoro analogs. On the contrary, the same modification of DNA oligonucleotides significantly destabilized the DNA/DNA duplex but gave a strong stabilization of the duplex with an RNA target. According to circular dichroism spectroscopy results, two terminal closo-dodecaborate residues cause a prominent structural rearrangement of complementary complexes with a substantial shift from the B-form to the A-form of the double helix. The revealed changes of key characteristics of oligonucleotides caused by incorporation of terminal boron clusters, such as the increase of hydrophobicity, change of duplex stability, and prominent structural changes for DNA conjugates, should be taken into account for the development of antisense oligonucleotides, siRNAs, or aptamers bearing boron clusters. These features may also be used for engineering of developing NA constructs with pre-defined properties.
Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors
Authors: Renault Pedro , Giraldo Jesús
Published: December 2020

G protein-coupled Receptors (GPCRs) play a central role in many physiological processes and, consequently, constitute important drug targets. In particular, the search for allosteric drugs has recently drawn attention, since they could be more selective and lead to fewer side effects. Accordingly, computational tools have been used to estimate the druggability of allosteric sites in these receptors. In spite of many successful results, the problem is still challenging, particularly the prediction of hydrophobic sites in the interface between the protein and the membrane. In this work, we propose a complementary approach, based on dynamical correlations. Our basic hypothesis was that allosteric sites are strongly coupled to regions of the receptor that undergo important conformational changes upon activation. Therefore, using ensembles of experimental structures, normal mode analysis and molecular dynamics simulations we calculated correlations between internal fluctuations of different sites and a collective variable describing the activation state of the receptor. Then, we ranked the sites based on the strength of their coupling to the collective dynamics. In the β2 adrenergic (β2AR), glucagon (GCGR) and M2 muscarinic receptors, this procedure allowed us to correctly identify known allosteric sites, suggesting it has predictive value. Our results indicate that this dynamics-based approach can be a complementary tool to the existing toolbox to characterize allosteric sites in GPCRs.
Challenges in Bone Tissue Regeneration: Stem Cell Therapy, Biofunctionality and Antimicrobial Properties of Novel Materials and Its Evolution
Authors: Riester Oliver , Borgolte Max , Csuk René , Deigner Hans-Peter
Published: December 2020

An aging population leads to increasing demand for sustained quality of life with the aid of novel implants. Patients expect fast healing and few complications after surgery. Increased biofunctionality and antimicrobial behavior of implants, in combination with supportive stem cell therapy, can meet these expectations. Recent research in the field of bone implants and the implementation of autologous mesenchymal stem cells in the treatment of bone defects is outlined and evaluated in this review. The article highlights several advantages, limitations and advances for metal-, ceramic- and polymer-based implants and discusses the future need for high-throughput screening systems used in the evaluation of novel developed materials and stem cell therapies. Automated cell culture systems, microarray assays or microfluidic devices are required to efficiently analyze the increasing number of new materials and stem cell-assisted therapies. Approaches described in the literature to improve biocompatibility, biofunctionality and stem cell differentiation efficiencies of implants range from the design of drug-laden nanoparticles to chemical modification and the selection of materials that mimic the natural tissue. Combining suitable implants with mesenchymal stem cell treatment promises to shorten healing time and increase treatment success. Most research studies focus on creating antibacterial materials or modifying implants with antibacterial coatings in order to address the increasing number of complications after surgeries that are mostly caused by bacterial infections. Moreover, treatment of multiresistant pathogens will pose even bigger challenges in hospitals in the future, according to the World Health Organization (WHO). These antibacterial materials will help to reduce infections after surgery and the number of antibiotic treatments that contribute to the emergence of new multiresistant pathogens, whilst the antibacterial implants will help reduce the amount of antibiotics used in clinical treatment.
Theanine, Antistress Amino Acid in Tea Leaves, Causes Hippocampal Metabolic Changes and Antidepressant Effects in Stress-Loaded Mice
Authors: Unno Keiko , Muguruma Yoshio , Inoue Koichi , Konishi Tomokazu , Taguchi Kyoko , Hasegawa-Ishii Sanae , Shimada Atsuyoshi , Nakamura Yoriyuki
Published: December 2020

By comprehensively measuring changes in metabolites in the hippocampus of stress-loaded mice, we investigated the reasons for stress vulnerability and the effect of theanine, i.e., an abundant amino acid in tea leaves, on the metabolism. Stress sensitivity was higher in senescence-accelerated mouse prone 10 (SAMP10) mice than in normal ddY mice when these mice were loaded with stress on the basis of territorial consciousness in males. Group housing was used as the low-stress condition reference. Among the statistically altered metabolites, depression-related kynurenine and excitability-related histamine were significantly higher in SAMP10 mice than in ddY mice. In contrast, carnosine, which has antidepressant-like activity, and ornithine, which has antistress effects, were significantly lower in SAMP10 mice than in ddY mice. The ingestion of theanine, an excellent antistress amino acid, modulated the levels of kynurenine, histamine, and carnosine only in the stress-loaded SAMP10 mice and not in the group-housing mice. Depression-like behavior was suppressed in mice that had ingested theanine only under stress loading. Taken together, changes in these metabolites, such as kynurenine, histamine, carnosine, and ornithine, were suggested to be associated with the stress vulnerability and depression-like behavior of stressed SAMP10 mice. It was also shown that theanine action appears in the metabolism of mice only under stress loading.
Pyrrolizidine Alkaloids Induce Cell Death in Human HepaRG Cells in a Structure-Dependent Manner
Authors: Glück Josephin , Waizenegger Julia , Braeuning Albert , Hessel-Pras Stefanie
Published: December 2020

Pyrrolizidine alkaloids (PAs) are a group of secondary metabolites produced in various plant species as a defense mechanism against herbivores. PAs consist of a necine base, which is esterified with one or two necine acids. Humans are exposed to PAs by consumption of contaminated food. PA intoxication in humans causes acute and chronic hepatotoxicity. It is considered that enzymatic PA toxification in hepatocytes is structure-dependent. In this study, we aimed to elucidate the induction of PA-induced cell death associated with apoptosis activation. Therefore, 22 structurally different PAs were analyzed concerning the disturbance of cell viability in the metabolically competent human hepatoma cell line HepaRG. The chosen PAs represent the main necine base structures and the different esterification types. Open-chained and cyclic heliotridine- and retronecine-type diesters induced strong cytotoxic effects, while treatment of HepaRG with monoesters did not affect cell viability. For more detailed investigation of apoptosis induction, comprising caspase activation and gene expression analysis, 14 PA representatives were selected. The proapoptotic effects were in line with the potency observed in cell viability studies. In vitro data point towards a strong structure–activity relationship whose effectiveness needs to be investigated in vivo and can then be the basis for a structure-associated risk assessment.
Coiled-Coil N21 of Hpa1 in Xanthomonas oryzae pv. oryzae Promotes Plant Growth, Disease Resistance and Drought Tolerance in Non-Hosts via Eliciting HR and Regulation of Multiple Defense Response Genes
Authors: Ji Zhao-Lin , Yu Mei-Hui , Ding Ya-Yan , Li Jian , Zhu Feng , He Jun-Xian , Yang Li-Na
Published: December 2020

Acting as a typical harpin protein, Hpa1 of Xanthomonas oryzae pv. oryzae is one of the pathogenic factors in hosts and can elicit hypersensitive responses (HR) in non-hosts. To further explain the underlying mechanisms of its induced resistance, we studied the function of the most stable and shortest three heptads in the N-terminal coiled-coil domain of Hpa1, named N21Hpa1. Proteins isolated from N21-transgenic tobacco elicited HR in Xanthi tobacco, which was consistent with the results using N21 and full-length Hpa1 proteins expressed in Escherichia coli. N21-expressing tobacco plants showed enhanced resistance to tobacco mosaic virus (TMV) and Pectobacterium carotovora subsp. carotovora (Pcc). Spraying of a synthesized N21 peptide solution delayed the disease symptoms caused by Botrytis cinerea and Monilinia fructicola and promoted the growth and drought tolerance of plants. Further analysis indicated that N21 upregulated the expression of multiple plant defense-related genes, such as genes mediated by salicylic acid (SA), jasmonic acid (JA) and ethylene (ET) signaling, and genes related to reactive oxygen species (ROS) biosynthesis. Further, the bioavailability of N21 peptide was better than that of full-length Hpa1Xoo. Our studies support the broad application prospects of N21 peptide as a promising succedaneum to biopesticide Messenger or Illite or other biological pharmaceutical products, and provide a basis for further development of biopesticides using proteins with similar structures.
Fabry Disease Therapy: State-of-the-Art and Current Challenges
Authors: Azevedo Olga , Gago Miguel Fernandes , Miltenberger-Miltenyi Gabriel , Sousa Nuno , Cunha Damião
Published: December 2020

Fabry disease (FD) is a lysosomal storage disorder caused by mutations of the GLA gene that lead to a deficiency of the enzymatic activity of α-galactosidase A. Available therapies for FD include enzyme replacement therapy (ERT) (agalsidase alfa and agalsidase beta) and the chaperone migalastat. Despite the large body of literature published about ERT over the years, many issues remain unresolved, such as the optimal dose, the best timing to start therapy, and the clinical impact of anti-drug antibodies. Migalastat was recently approved for FD patients with amenable GLA mutations; however, recent studies have raised concerns that “in vitro” amenability may not always reflect “in vivo” amenability, and some findings on real-life studies have contrasted with the results of the pivotal clinical trials. Moreover, both FD specific therapies present limitations, and the attempt to correct the enzymatic deficiency, either by enzyme exogenous administration or enzyme stabilization with a chaperone, has not shown to be able to fully revert FD pathology and clinical manifestations. Therefore, several new therapies are under research, including new forms of ERT, substrate reduction therapy, mRNA therapy, and gene therapy. In this review, we provide an overview of the state-of-the-art on the currently approved and emerging new therapies for adult patients with FD.
Possible Adverse Effects of Food Additive E171 (Titanium Dioxide) Related to Particle Specific Human Toxicity, Including the Immune System
Authors: Bischoff Nicolaj S. , de Kok Theo M. , Sijm Dick T.H.M. , van Breda Simone G. , Briedé Jacco J. , Castenmiller Jacqueline J.M. , Opperhuizen Antoon , Chirino Yolanda I. , Dirven Hubert , Gott David , Houdeau Eric , Oomen Agnes G. , Poulsen Morten , Rogler Gerhard , van Loveren Henk
Published: December 2020

Titanium dioxide (TiO2) is used as a food additive (E171) and can be found in sauces, icings, and chewing gums, as well as in personal care products such as toothpaste and pharmaceutical tablets. Along with the ubiquitous presence of TiO2 and recent insights into its potentially hazardous properties, there are concerns about its application in commercially available products. Especially the nano-sized particle fraction (<100 nm) of TiO2 warrants a more detailed evaluation of potential adverse health effects after ingestion. A workshop organized by the Dutch Office for Risk Assessment and Research (BuRO) identified uncertainties and knowledge gaps regarding the gastrointestinal absorption of TiO2, its distribution, the potential for accumulation, and induction of adverse health effects such as inflammation, DNA damage, and tumor promotion. This review aims to identify and evaluate recent toxicological studies on food-grade TiO2 and nano-sized TiO2 in ex-vivo, in-vitro, and in-vivo experiments along the gastrointestinal route, and to postulate an Adverse Outcome Pathway (AOP) following ingestion. Additionally, this review summarizes recommendations and outcomes of the expert meeting held by the BuRO in 2018, in order to contribute to the hazard identification and risk assessment process of ingested TiO2.
Regenerative Therapies to Restore Interneuron Disturbances in Experimental Models of Encephalopathy of Prematurity
Authors: Vaes Josine E. G. , Kosmeijer Chantal M. , Kaal Marthe , van Vliet Rik , Brandt Myrna J. V. , Benders Manon J. N. L. , Nijboer Cora H.
Published: December 2020

Encephalopathy of Prematurity (EoP) is a major cause of morbidity in (extreme) preterm neonates. Though the majority of EoP research has focused on failure of oligodendrocyte maturation as an underlying pathophysiological mechanism, recent pioneer work has identified developmental disturbances in inhibitory interneurons to contribute to EoP. Here we investigated interneuron abnormalities in two experimental models of EoP and explored the potential of two promising treatment strategies, namely intranasal mesenchymal stem cells (MSCs) or insulin-like growth factor I (IGF1), to restore interneuron development. In rats, fetal inflammation and postnatal hypoxia led to a transient increase in total cortical interneuron numbers, with a layer-specific deficit in parvalbumin (PV)+ interneurons. Additionally, a transient excess of total cortical cell density was observed, including excitatory neuron numbers. In the hippocampal cornu ammonis (CA) 1 region, long-term deficits in total interneuron numbers and PV+ subtype were observed. In mice subjected to postnatal hypoxia/ischemia and systemic inflammation, total numbers of cortical interneurons remained unaffected; however, subtype analysis revealed a global, transient reduction in PV+ cells and a long-lasting layer-specific increase in vasoactive intestinal polypeptide (VIP)+ cells. In the dentate gyrus, a long-lasting deficit of somatostatin (SST)+ cells was observed. Both intranasal MSC and IGF1 therapy restored the majority of interneuron abnormalities in EoP mice. In line with the histological findings, EoP mice displayed impaired social behavior, which was partly restored by the therapies. In conclusion, induction of experimental EoP is associated with model-specific disturbances in interneuron development. In addition, intranasal MSCs and IGF1 are promising therapeutic strategies to aid interneuron development after EoP.
Hepatitis B Virus Cure: Targets and Future Therapies
Authors: Lee Hye Won , Lee Jae Seung , Ahn Sang Hoon
Published: December 2020

Chronic hepatitis B virus (HBV) infection is a major global health problem. It can cause progressive liver fibrosis leading to cirrhosis with end-stage liver disease, and a markedly increased risk of hepatocellular carcinoma. In the last two decades, substantial progress has been made in the treatment of chronic hepatitis, B. However, HBV is often reactivated after stopping nucloes(t)ide analogues because antivirals alone do not directly target covalently closed circular DNA, which is the template for all viral RNAs. Therefore, although currently available antiviral therapies achieve suppression of HBV replication in the majority of patients, hepatitis B surface antigen (HBsAg) loss and seroconversion is rarely achieved despite long-term antiviral treatment (HBsAg loss of less than 10% in 5 years). Various clinical trials of agents that interrupt the HBV life cycle in hepatocytes have been conducted. Potential treatment strategies and new agents are emerging as HBV cure. A combination of current and new anti-HBV agents may increase the rate of HBsAg seroclearance; thus, optimized regimens must be validated. Here, we review the newly investigated therapeutic compounds and the results of preclinical and/or clinical trials.
Yeast Translation Elongation Factor eIF5A Expression Is Regulated by Nutrient Availability through Different Signalling Pathways
Authors: Barba-Aliaga Marina , Villarroel-Vicente Carlos , Stanciu Alice , Corman Alba , Martínez-Pastor María Teresa , Alepuz Paula
Published: December 2020

Translation elongation factor eIF5A binds to ribosomes to promote peptide bonds between problematic amino acids for the reaction like prolines. eIF5A is highly conserved and essential in eukaryotes, which usually contain two similar but differentially expressed paralogue genes. The human eIF5A-1 isoform is abundant and implicated in some cancer types; the eIF5A-2 isoform is absent in most cells but becomes overexpressed in many metastatic cancers. Several reports have connected eIF5A and mitochondria because it co-purifies with the organelle or its inhibition reduces respiration and mitochondrial enzyme levels. However, the mechanisms of eIF5A mitochondrial function, and whether eIF5A expression is regulated by the mitochondrial metabolism, are unknown. We analysed the expression of yeast eIF5A isoforms Tif51A and Tif51B under several metabolic conditions and in mutants. The depletion of Tif51A, but not Tif51B, compromised yeast growth under respiration and reduced oxygen consumption. Tif51A expression followed dual positive regulation: by high glucose through TORC1 signalling, like other translation factors, to promote growth and by low glucose or non-fermentative carbon sources through Snf1 and heme-dependent transcription factor Hap1 to promote respiration. Upon iron depletion, Tif51A was down-regulated and Tif51B up-regulated. Both were Hap1-dependent. Our results demonstrate eIF5A expression regulation by cellular metabolic status.
Investigating the Diffusion of Workload-Induced Stress—A Simulation Approach
Authors: Ogunbiyi Niyi , Basukoski Artie , Chaussalet Thierry
Published: December 2020

Work-induced stress is widely acknowledged as harming physical and psychosocial health and has been linked with adverse outcomes such as a decrease in productivity. Recently, workplace stressors have increased due to the COVID-19 pandemic. This study aims to contribute to the literature base in a couple of areas. First, it extends the current knowledge base by utilising generative additive modelling (GAMs) to uncover the nature of the relationship between workload (a key workplace stressor) and productivity based on real-world event logs. Additionally, it uses recursive partitioning modelling to shed light on the factors that drive the relationship between these variables. Secondly, it utilises a simulation-based approach to investigate the diffusion of workload-induced stress in the workplace. Simulation is a valuable tool for exploring the effect of changes in a risk-free manner as it provides the ability to run multiple scenarios in a safe and virtual environment with a view to making recommendations to stakeholders. However, there are several recognised issues with traditional simulation approaches, such as inadequate resource modelling and the limited use of simulations for operational decision making. In this study, we propose an approach which extracts the required parameters from an event log and subsequently utilises them to initialise a workload-induced stress diffusion simulation model accurately. We also explore the effects of varying the parameters to control the spread of workload-induced stress within the network. With suitable amendments, this approach can be extended to model the spread of disease (e.g., COVID-19), diffusion of ideas, among other things, in the workplace.
Risk Assessment for Tomato Fruitworm in Processing Tomato Crop-Egg Location and Sequential Sampling
Authors: Figueiredo Elisabete , Gonçalves Catarina , Duarte Sónia , Godinho Maria C. , Mexia António , Torres Laura
Published: December 2020

Helicoverpa armigera is one of the key pests affecting processing tomatoes and many other crops. A three-year study was conducted to describe the oviposition preferences of this species on determinate tomato plants (mainly the stratum, leaf, leaflet, and leaf side) and the spatial pattern of the eggs in the field, to form a sequential sampling plan. Eggs were found mainly in the exposed canopy, on leaves a (upper stratum) and b (upper-middle stratum) and significantly fewer eggs on leaf c (middle-lower stratum) below flower clusters. This vertical pattern in the plant was found in all phenological growth stages. The spatial pattern was found to be aggregated, with a trend towards a random pattern at lower densities. A sequential sampling plan was developed, based on Iwao’s method with the parameters of Taylor’s power law, with minimum and maximum sample size of 20 and 80 sample units (plants), respectively (two leaves/plant). For its validation, operating characteristic (OC) and average sample number (ASN) curves were calculated by means of simulation with independent data sets. The β-error was higher than desirable in the vicinity of the economic threshold, but this sampling plan is regarded as an improvement both in effort and precision, compared with the fixed sample plan, and further improvements are discussed.
Recommendations for Patients with High Return to Sports Expectations after TKA Remain Controversial
Authors: Vu-Han Tu-Lan , Gwinner Clemens , Perka Carsten , Hardt Sebastian
Published: December 2020

(1) Background: Improved surgical techniques and implants in total knee arthroplasty (TKA) have led to broader indications for surgical interventions of osteoarthritis of the knee. There is a growing young and active patient subgroup with high return to sports (RTS) expectations after TKA. The current lack of evidence regarding RTS capacity in this patient cohort, requires the consolidation of experts’ opinions and experiences to address the special needs among these patients. The aim of this study was to assess current expert opinions in regard to preoperative patient assessment, surgical technique and decision-making and patient counseling for these patients. (2) Methods: We performed a survey among surgeons specialized in arthroplasty with a questionnaire designed to assess current recommendations, surgical techniques, and implant preferences as well as patient counseling in patients with high expectations for RTS after TKA. (3) Results: The majority of surgeons are in favor of return to low-impact sports after TKA within 3 to 6 months. Some even recommend return to high-impact sports. Despite improvement of surgical techniques and implants, we observed no clear preference for a single surgical technique or implant specification in active patients. (4) Conclusions: Current evidence for sports-associated complications after TKA is scarce. Despite a growing array of surgical techniques and implants, the available literature is still controversial with no single surgical technique or TKA design distinguishing itself clearly from others. Surgeons’ recommendations are mostly based on their experience and training. Nonetheless, we observed growing faith in modern implants with some surgeons even recommending high-impact sports after TKA.
Comparison of Blood Flow Restriction Training versus Non-Occlusive Training in Patients with Anterior Cruciate Ligament Reconstruction or Knee Osteoarthritis: A Systematic Review
Authors: Bobes Álvarez Cristina , Issa-Khozouz Santamaría Paloma , Fernández-Matías Rubén , Pecos-Martín Daniel , Achalandabaso-Ochoa Alexander , Fernández-Carnero Samuel , Martínez-Amat Antonio , Gallego-Izquierdo Tomás
Published: December 2020

Patients undergoing anterior cruciate ligament (ACL) reconstruction and patients suffering from knee osteoarthritis (KOA) have been shown to have quadriceps muscle weakness and/or atrophy in common. The physiological mechanisms of blood flow restriction (BFR) training could facilitate muscle hypertrophy. The purpose of this systematic review is to investigate the effects of BFR training on quadriceps cross-sectional area (CSA), pain perception, function and quality of life on these patients compared to a non-BFR training. A literature research was performed using Web of Science, PEDro, Scopus, MEDLINE, Dialnet, CINAHL and The Cochrane Library databases. The main inclusion criteria were that papers were English or Spanish language reports of randomized controlled trials involving patients with ACL reconstruction or suffering from KOA. The initial research identified 159 publications from all databases; 10 articles were finally included. The search was conducted from April to June 2020. Four of these studies found a significant improvement in strength. A significant increase in CSA was found in two studies. Pain significantly improved in four studies and only one study showed a significant improvement in functionality/quality of life. Low-load training with BFR may be an effective option treatment for increasing quadriceps strength and CSA, but more research is needed.