bluuebunny/crossref_metadata_2025 huggingface dataset:
Filling the Antibody Pipeline in Allergy: PIPE Cloning of IgE, IgG1 and IgG4 against the Major Birch Pollen Allergen Bet v 1
Authors: Köhler Verena K. , Crescioli Silvia , Fazekas-Singer Judit , Bax Heather J. , Hofer Gerhard , Pranger Christina L. , Hufnagl Karin , Bianchini Rodolfo , Flicker Sabine , Keller Walter , Karagiannis Sophia N. , Jensen-Jarolim Erika
Published: August 2020

Birch pollen allergy is among the most prevalent pollen allergies in Northern and Central Europe. This IgE-mediated disease can be treated with allergen immunotherapy (AIT), which typically gives rise to IgG antibodies inducing tolerance. Although the main mechanisms of allergen immunotherapy (AIT) are known, questions regarding possible Fc-mediated effects of IgG antibodies remain unanswered. This can mainly be attributed to the unavailability of appropriate tools, i.e., well-characterised recombinant antibodies (rAbs). We hereby aimed at providing human rAbs of several classes for mechanistic studies and as possible candidates for passive immunotherapy. We engineered IgE, IgG1, and IgG4 sharing the same variable region against the major birch pollen allergen Bet v 1 using Polymerase Incomplete Primer Extension (PIPE) cloning. We tested IgE functionality and IgG blocking capabilities using appropriate model cell lines. In vitro studies showed IgE engagement with FcεRI and CD23 and Bet v 1-dependent degranulation. Overall, we hereby present fully functional, human IgE, IgG1, and IgG4 sharing the same variable region against Bet v 1 and showcase possible applications in first mechanistic studies. Furthermore, our IgG antibodies might be useful candidates for passive immunotherapy of birch pollen allergy.
Nutritional Indices for Assessing Fatty Acids: A Mini-Review
Authors: Chen Jiapeng , Liu Hongbing
Published: August 2020

Dietary fats are generally fatty acids that may play positive or negative roles in the prevention and treatment of diseases. In nature, fatty acids occur in the form of mixtures of saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA), so their nutritional and/or medicinal values must be determined. Herein, we do not consider the classic indices, such as ∑SFA, ∑MUFA, ∑PUFA, ∑n-6 PUFA, ∑n-3 PUFA, and n-6 PUFA/n-3 PUFA; instead, we summarize and review the definitions, implications, and applications of indices used in recent years, including the PUFA/SFA, index of atherogenicity (IA), the index of thrombogenicity (IT), the hypocholesterolemic/hypercholesterolemic ratio (HH), the health-promoting index (HPI), the unsaturation index (UI), the sum of eicosapentaenoic acid and docosahexaenoic acid (EPA + DHA), fish lipid quality/flesh lipid quality (FLQ), the linoleic acid/α-linolenic acid (LA/ALA) ratio, and trans fatty acid (TFA). Of these nutritional indices, IA and IT are the most commonly used to assess the composition of fatty acids as they outline significant implications and provide clear evidence. EPA + DHA is commonly used to assess the nutritional quality of marine animal products. All indices have their advantages and disadvantages; hence, a rational choice of which to use is critical.
Biotechnological Approaches: Gene Overexpression, Gene Silencing, and Genome Editing to Control Fungal and Oomycete Diseases in Grapevine
Authors: Capriotti Luca , Baraldi Elena , Mezzetti Bruno , Limera Cecilia , Sabbadini Silvia
Published: August 2020

Downy mildew, powdery mildew, and grey mold are some of the phytopathological diseases causing economic losses in agricultural crops, including grapevine, worldwide. In the current scenario of increasing global warming, in which the massive use of agrochemicals should be limited, the management of fungal disease has become a challenge. The knowledge acquired on candidate resistant (R) genes having an active role in plant defense mechanisms has allowed numerous breeding programs to integrate these traits into selected cultivars, even though with some limits in the conservation of the proper qualitative characteristics of the original clones. Given their gene-specific mode of action, biotechnological techniques come to the aid of breeders, allowing them to generate simple and fast modifications in the host, without introducing other undesired genes. The availability of efficient gene transfer procedures in grapevine genotypes provide valid tools that support the application of new breeding techniques (NBTs). The expertise built up over the years has allowed the optimization of these techniques to overexpress genes that directly or indirectly limit fungal and oomycetes pathogens growth or silence plant susceptibility genes. Furthermore, the downregulation of pathogen genes which act as virulence effectors by exploiting the RNA interference mechanism, represents another biotechnological tool that increases plant defense. In this review, we summarize the most recent biotechnological strategies optimized and applied on Vitis species, aimed at reducing their susceptibility to the most harmful fungal and oomycetes diseases. The best strategy for combating pathogenic organisms is to exploit a holistic approach that fully integrates all these available tools.
Polyethylene Glycol 35 as a Perfusate Additive for Mitochondrial and Glycocalyx Protection in HOPE Liver Preservation
Authors: Panisello Rosello Arnau , Teixeira da Silva Rui , Castro Carlos , G. Bardallo Raquel , Calvo Maria , Folch-Puy Emma , Carbonell Teresa , Palmeira Carlos , Roselló Catafau Joan , Adam René
Published: August 2020

Organ transplantation is a multifactorial process in which proper graft preservation is a mandatory step for the success of the transplantation. Hypothermic preservation of abdominal organs is mostly based on the use of several commercial solutions, including UW, Celsior, HTK and IGL-1. The presence of the oncotic agents HES (in UW) and PEG35 (in IGL-1) characterize both solution compositions, while HTK and Celsior do not contain any type of oncotic agent. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic and water-soluble polymers, which present a combination of properties of particular interest in the clinical context of ischemia-reperfusion injury (IRI): they limit edema and nitric oxide induction and modulate immunogenicity. Besides static cold storage (SCS), there are other strategies to preserve the organ, such as the use of machine perfusion (MP) in dynamic preservation strategies, which increase graft function and survival as compared to the conventional static hypothermic preservation. Here we report some considerations about using PEG35 as a component of perfusates for MP strategies (such as hypothermic oxygenated perfusion, HOPE) and its benefits for liver graft preservation. Improved liver preservation is closely related to mitochondria integrity, making this organelle a good target to increase graft viability, especially in marginal organs (e.g., steatotic livers). The final goal is to increase the pool of suitable organs, and thereby shorten patient waiting lists, a crucial problem in liver transplantation.
Dominant-Negative Attenuation of cAMP-Selective Phosphodiesterase PDE4D Action Affects Learning and Behavior
Authors: Bolger Graeme B. , Smoot Lisa High Mitchell , van Groen Thomas
Published: August 2020

PDE4 cyclic nucleotide phosphodiesterases reduce 3′, 5′ cAMP levels in the CNS and thereby regulate PKA activity and the phosphorylation of CREB, fundamental to depression, cognition, and learning and memory. The PDE4 isoform PDE4D5 interacts with the signaling proteins β-arrestin2 and RACK1, regulators of β2-adrenergic and other signal transduction pathways. Mutations in PDE4D in humans predispose to acrodysostosis, associated with cognitive and behavioral deficits. To target PDE4D5, we developed mice that express a PDE4D5-D556A dominant-negative transgene in the brain. Male transgenic mice demonstrated significant deficits in hippocampus-dependent spatial learning, as assayed in the Morris water maze. In contrast, associative learning, as assayed in a fear conditioning assay, appeared to be unaffected. Male transgenic mice showed augmented activity in prolonged (2 h) open field testing, while female transgenic mice showed reduced activity in the same assay. Transgenic mice showed no demonstrable abnormalities in prepulse inhibition. There was also no detectable difference in anxiety-like behavior, as measured in the elevated plus-maze. These data support the use of a dominant-negative approach to the study of PDE4D5 function in the CNS and specifically in learning and memory.
Patterns of Expansion and Expression Divergence of the Polygalacturonase Gene Family in Brassica oleracea
Authors: Lyu Meiling , Iftikhar Junaid , Guo Rongfang , Wu Binghua , Cao Jiashu
Published: August 2020

Plant polygalacturonases (PGs) are closely related to cell-separation events during plant growth and development by degrading pectin. Identifying and investigating their diversification of evolution and expression could shed light on research on their function. We conducted sequence, molecular evolution, and gene expression analyses of PG genes in Brassica oleracea. Ninety-nine B. oleracea PGs (BoPGs) were identified and divided into seven clades through phylogenetic analysis. The exon/intron structures and motifs were conserved within, but divergent between, clades. The second conserved domain (GDDC) may be more closely related to the identification of PGs. There were at least 79 common ancestor PGs between Arabidopsis thaliana and B. oleracea. The event of whole genome triplication and tandem duplication played important roles in the rapid expansion of the BoPG gene family, and gene loss may be an important mechanism in the generation of the diversity of BoPGs. By evaluating the expression in five tissues, we found that most of the expressed BoPGs in clades A, B, and E showed ubiquitous expression characteristics, and the expressed BoPGs in clades C, D, and F were mainly responsible for reproduction development. Most of the paralogous gene pairs (76.2%) exhibited divergent expression patterns, indicating that they may have experienced neofunctionalization or subfunctionalization. The cis-elements analysis showed that up to 96 BoPGs contained the hormone response elements in their promoters. In conclusion, our comparative analysis may provide a valuable data foundation for the further functional analysis of BoPGs during the development of B. oleracea.
SARS-CoV-2 Entry Inhibitors: Small Molecules and Peptides Targeting Virus or Host Cells
Authors: Cannalire Rolando , Stefanelli Irina , Cerchia Carmen , Beccari Andrea R. , Pelliccia Sveva , Summa Vincenzo
Published: August 2020

The pandemic evolution of SARS-CoV-2 infection is forcing the scientific community to unprecedented efforts to explore all possible approaches against COVID-19. In this context, targeting virus entry is a promising antiviral strategy for controlling viral infections. The main strategies pursued to inhibit the viral entry are considering both the virus and the host factors involved in the process. Primarily, direct-acting antivirals rely on inhibition of the interaction between ACE2 and the receptor binding domain (RBD) of the Spike (S) protein or targeting the more conserved heptad repeats (HRs), involved in the membrane fusion process. The inhibition of host TMPRSS2 and cathepsins B/L may represent a complementary strategy to be investigated. In this review, we discuss the development entry inhibitors targeting the S protein, as well as the most promising host targeting strategies involving TMPRSS2 and CatB/L, which have been exploited so far against CoVs and other related viruses.
Autophagy Declines with Premature Skin Aging resulting in Dynamic Alterations in Skin Pigmentation and Epidermal Differentiation
Authors: Murase Daiki , Kusaka-Kikushima Ayumi , Hachiya Akira , Fullenkamp Rachel , Stepp Anita , Imai Asuka , Ueno Mizuki , Kawabata Keigo , Takahashi Yoshito , Hase Tadashi , Ohuchi Atsushi , Nakamura Shuhei , Yoshimori Tamotsu
Published: August 2020

Autophagy is a membrane traffic system that provides sustainable degradation of cellular components for homeostasis, and is thus considered to promote health and longevity, though its activity declines with aging. The present findings show deterioration of autophagy in association with premature skin aging. Autophagy flux was successfully determined in skin tissues, which demonstrated significantly decreased autophagy in hyperpigmented skin such as that seen in senile lentigo. Furthermore, an exacerbated decline in autophagy was confirmed in xerotic hyperpigmentation areas, accompanied by severe dehydration and a barrier defect, which showed correlations with skin physiological conditions. The enhancement of autophagy in skin ex vivo ameliorated skin integrity, including pigmentation and epidermal differentiation. The present results indicate that the restoration of autophagy can contribute to improving premature skin aging by various intrinsic and extrinsic factors via the normalization of protein homeostasis.
The Evolution of Duplicated Genes of the Cpi-17/Phi-1 (ppp1r14) Family of Protein Phosphatase 1 Inhibitors in Teleosts
Authors: Lang Irene , Virk Guneet , Zheng Dale C. , Young Jason , Nguyen Michael J. , Amiri Rojin , Fong Michelle , Arata Alisa , Chadaideh Katia S. , Walsh Susan , Weiser Douglas C.
Published: August 2020

The Cpi-17 (ppp1r14) gene family is an evolutionarily conserved, vertebrate specific group of protein phosphatase 1 (PP1) inhibitors. When phosphorylated, Cpi-17 is a potent inhibitor of myosin phosphatase (MP), a holoenzyme complex of the regulatory subunit Mypt1 and the catalytic subunit PP1. Myosin phosphatase dephosphorylates the regulatory myosin light chain (Mlc2) and promotes actomyosin relaxation, which in turn, regulates numerous cellular processes including smooth muscle contraction, cytokinesis, cell motility, and tumor cell invasion. We analyzed zebrafish homologs of the Cpi-17 family, to better understand the mechanisms of myosin phosphatase regulation. We found single homologs of both Kepi (ppp1r14c) and Gbpi (ppp1r14d) in silico, but we detected no expression of these genes during early embryonic development. Cpi-17 (ppp1r14a) and Phi-1 (ppp1r14b) each had two duplicate paralogs, (ppp1r14aa and ppp1r14ab) and (ppp1r14ba and ppp1r14bb), which were each expressed during early development. The spatial expression pattern of these genes has diverged, with ppp1r14aa and ppp1r14bb expressed primarily in smooth muscle and skeletal muscle, respectively, while ppp1r14ab and ppp1r14ba are primarily expressed in neural tissue. We observed that, in in vitro and heterologous cellular systems, the Cpi-17 paralogs both acted as potent myosin phosphatase inhibitors, and were indistinguishable from one another. In contrast, the two Phi-1 paralogs displayed weak myosin phosphatase inhibitory activity in vitro, and did not alter myosin phosphorylation in cells. Through deletion and chimeric analysis, we identified that the difference in specificity for myosin phosphatase between Cpi-17 and Phi-1 was encoded by the highly conserved PHIN (phosphatase holoenzyme inhibitory) domain, and not the more divergent N- and C- termini. We also showed that either Cpi-17 paralog can rescue the knockdown phenotype, but neither Phi-1 paralog could do so. Thus, we provide new evidence about the biochemical and developmental distinctions of the zebrafish Cpi-17 protein family.
Chronic Administration of Fipronil Heterogeneously Alters the Neurochemistry of Monoaminergic Systems in the Rat Brain
Authors: Bharatiya Rahul , Chagraoui Abdeslam , De Deurwaerdere Salomé , Argiolas Antonio , Melis Maria Rosaria , Sanna Fabrizio , De Deurwaerdere Philippe
Published: August 2020

Fipronil (FPN), a widely used pesticide for agricultural and non-agricultural pest control, is possibly neurotoxic for mammals. Brain monoaminergic systems, involved in virtually all brain functions, have been shown to be sensitive to numerous pesticides. Here, we addressed the hypothesis that chronic exposure to FPN could modify brain monoamine neurochemistry. FPN (10 mg/kg) was chronically administered for 21 days through oral gavage in rats. Thereafter, the tissue concentrations of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid; serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA); and noradrenaline (NA) were measured in 30 distinct brain regions. FPN significantly decreased DA and its metabolite levels in most striatal territories, including the nucleus accumbens and the substantia nigra (SN). FPN also diminished 5-HT levels in some striatal regions and the SN. The indirect index of the turnovers, DOPAC/DA and 5-HIAA/5-HT ratios, was increased in numerous brain regions. FPN reduced the NA content only in the nucleus accumbens core. Using the Bravais–Pearson test to study the neurochemical organization of monoamines through multiple correlative analyses across the brain, we found fewer correlations for NA, DOPAC/DA, and 5-HIAA/5-HT ratios, and an altered pattern of correlations within and between monoamine systems. We therefore conclude that the chronic administration of FPN in rats induces massive and inhomogeneous changes in the DA and 5-HT systems in the brain.
Cinnamic Acid Derivatives and Their Biological Efficacy
Authors: Ruwizhi Ngonidzashe , Aderibigbe Blessing Atim
Published: August 2020

The role played by cinnamic acid derivatives in treating cancer, bacterial infections, diabetes and neurological disorders, among many, has been reported. Cinnamic acid is obtained from cinnamon bark. Its structure is composed of a benzene ring, an alkene double bond and an acrylic acid functional group making it possible to modify the aforementioned functionalities with a variety of compounds resulting in bioactive agents with enhanced efficacy. The nature of the substituents incorporated into cinnamic acid has been found to play a huge role in either enhancing or decreasing the biological efficacy of the synthesized cinnamic acid derivatives. Some of the derivatives have been reported to be more effective when compared to the standard drugs used to treat chronic or infectious diseases in vitro, thus making them very promising therapeutic agents. Compound 20 displayed potent anti-TB activity, compound 27 exhibited significant antibacterial activity on S. aureus strain of bacteria and compounds with potent antimalarial activity are 35a, 35g, 35i, 36i, and 36b. Furthermore, compounds 43d, 44o, 55g–55p, 59e, 59g displayed potent anticancer activity and compounds 86f–h were active against both hAChE and hBuChE. This review will expound on the recent advances on cinnamic acid derivatives and their biological efficacy.
Human Lymph Node Stromal Cells Have the Machinery to Regulate Peripheral Tolerance during Health and Rheumatoid Arthritis
Authors: Hähnlein Janine S. , Nadafi Reza , Jong Tineke A. de , Semmelink Johanna F. , Remmerswaal Ester B. M. , Safy Mary , Lienden Krijn P. van , Maas Mario , Gerlag Danielle M. , Tak Paul P. , Mebius Reina E. , Wähämaa Heidi , Catrina Anca I. , G. M. van Baarsen Lisa
Published: August 2020

Background: In rheumatoid arthritis (RA) the cause for loss of tolerance and anti-citrullinated protein antibody (ACPA) production remains unidentified. Mouse studies showed that lymph node stromal cells (LNSCs) maintain peripheral tolerance through presentation of peripheral tissue antigens (PTAs). We hypothesize that dysregulation of peripheral tolerance mechanisms in human LNSCs might underlie pathogenesis of RA. Method: Lymph node (LN) needle biopsies were obtained from 24 RA patients, 23 individuals positive for RA-associated autoantibodies but without clinical disease (RA-risk individuals), and 14 seronegative healthy individuals. Ex vivo human LNs from non-RA individuals were used to directly analyze stromal cells. Molecules involved in antigen presentation and immune modulation were measured in LNSCs upon interferon γ (IFNγ) stimulation (n = 15). Results: Citrullinated targets of ACPAs were detected in human LN tissue and in cultured LNSCs. Human LNSCs express several PTAs, transcription factors autoimmune regulator (AIRE) and deformed epidermal autoregulatory factor 1 (DEAF1), and molecules involved in citrullination, antigen presentation, and immunomodulation. Overall, no clear differences between donor groups were observed with exception of a slightly lower induction of human leukocyte antigen-DR (HLA-DR) and programmed cell death 1 ligand (PD-L1) molecules in LNSCs from RA patients. Conclusion: Human LNSCs have the machinery to regulate peripheral tolerance making them an attractive target to exploit in tolerance induction and maintenance.
Genetics and Epigenetics of Atrial Fibrillation
Authors: Lozano-Velasco Estefanía , Franco Diego , Aranega Amelia , Daimi Houria
Published: August 2020

Atrial fibrillation (AF) is known to be the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence exponentially increases with age and could reach up to 8% in the elderly population. The management of AF is a complex issue that is addressed by extensive ongoing basic and clinical research. AF centers around different types of disturbances, including ion channel dysfunction, Ca2+-handling abnormalities, and structural remodeling. Genome-wide association studies (GWAS) have uncovered over 100 genetic loci associated with AF. Most of these loci point to ion channels, distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Recently, the discovery of post-transcriptional regulatory mechanisms, involving non-coding RNAs (especially microRNAs), DNA methylation, and histone modification, has allowed to decipher how a normal heart develops and which modifications are involved in reshaping the processes leading to arrhythmias. This review aims to provide a current state of the field regarding the identification and functional characterization of AF-related epigenetic regulatory networks
Biological Evaluation of Polyvinyl Alcohol Hydrogels Enriched by Hyaluronic Acid and Hydroxyapatite
Authors: Chocholata Petra , Kulda Vlastimil , Dvorakova Jana , Kolaja Dobra Jana , Babuska Vaclav
Published: August 2020

This study aimed to develop polyvinyl alcohol (PVA) -based scaffold enriched with hyaluronic acid (HA) and hydroxyapatite (HAp) using physical crosslinking by freezing–thawing method. We accomplished biological evaluation of scaffolds, swelling degree, bioactivity assessment, and hemolytic test. The results showed that all types of scaffolds should be safe for use in the human body. The culturing of human osteoblast-like cells MG-63 and their proliferation showed better adhesion of cells due to the presence of HA and confirmed better proliferation depending on the amount of HAp. This paper gives the optimal composition of the scaffold and the optimal amount of the particular components of the scaffold. Based on our results we concluded that the best PVA/HA/HAp combination is in the ratio 3:1:2.
Glucagon-Like Peptide-1 Receptor Agonist Prevented the Progression of Hepatocellular Carcinoma in a Mouse Model of Nonalcoholic Steatohepatitis
Authors: Kojima Motoyasu , Takahashi Hirokazu , Kuwashiro Takuya , Tanaka Kenichi , Mori Hitoe , Ozaki Iwata , Kitajima Yoichiro , Matsuda Yayoi , Ashida Kenji , Eguchi Yuichiro , Anzai Keizo
Published: August 2020

Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their effects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma (HCC) remain unclear. In this study, mice with streptozotocin- and high-fat diet-induced diabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks. Glycemic control, hepatocarcinogenesis, and liver histology were compared between the groups. Fasting blood glucose levels were significantly lower in the liraglutide group than in the control group (210.0 ± 17.3 mg/dL vs. 601.8 ± 123.6 mg/dL), and fasting insulin levels were significantly increased by liraglutide (0.18 ± 0.06 ng/mL vs. 0.09 ± 0.03 ng/mL). Liraglutide completely suppressed hepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 ± 3.87; average tumor size, 8.1 ± 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and hepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and insulin-positive β-cells were observed in the pancreas in liraglutide-treated mice but not in control mice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic mice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes.
PPARs and Angiogenesis—Implications in Pathology
Authors: Wagner Nicole , Wagner Kay-Dietrich
Published: August 2020

Peroxisome proliferator-activated receptors (PPARs) belong to the family of ligand-activated nuclear receptors. The PPAR family consists of three subtypes encoded by three separate genes: PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3). PPARs are critical regulators of metabolism and exhibit tissue and cell type-specific expression patterns and functions. Specific PPAR ligands have been proposed as potential therapies for a variety of diseases such as metabolic syndrome, cancer, neurogenerative disorders, diabetes, cardiovascular diseases, endometriosis, and retinopathies. In this review, we focus on the knowledge of PPAR function in angiogenesis, a complex process that plays important roles in numerous pathological conditions for which therapeutic use of PPAR modulation has been suggested.
The Role of Alpha-Synuclein and Other Parkinson’s Genes in Neurodevelopmental and Neurodegenerative Disorders
Authors: Morato Torres C. Alejandra , Wassouf Zinah , Zafar Faria , Sastre Danuta , Outeiro Tiago Fleming , Schüle Birgitt
Published: August 2020

Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson’s disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes, which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.
Alzheimer’s Disease Mouse as a Model of Testis Degeneration
Authors: Szegeczki Vince , Horváth Gabriella , Perényi Helga , Tamás Andrea , Radák Zsolt , Ábrahám Dóra , Zákány Róza , Reglodi Dora , Juhász Tamás
Published: August 2020

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with protective functions in the central nervous system and various peripheral organs. PACAP has the highest expression level in the testes, among the peripheral organs, and has a positive regulative role in spermatogenesis and in sperm motility. In the present study, we explored testicular degenerative alterations in a mouse model of Alzheimer’s disease (AD) (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) and demonstrated changes in PACAP-regulated signaling pathways. In addition, the effects of increased physical activity of AD (trained AD (TAD)) mice on testis were also followed. Reduced cell number and decreased thickness of basement membrane were detected in AD samples. These changes were compensated by physical activity. Expression of PACAP receptors and canonical signaling elements such as PKA, P-PKA, PP2A significantly decreased in AD mice, and altered Sox transcription factor expression was also detected. Via this signaling mechanism, physical activity compensated the negative effects of AD on the expression of type IV collagen. Our findings suggest that the testes of AD mice can be a good model of testis degeneration. Moreover, it can be an appropriate organ to follow the effects of various interventions such as physical activity on tissue regeneration and signaling alterations.
AcoMYB4, an Ananas comosus L. MYB Transcription Factor, Functions in Osmotic Stress through Negative Regulation of ABA Signaling
Authors: Chen Huihuang , Lai Linyi , Li Lanxin , Liu Liping , Jakada Bello Hassan , Huang Youmei , He Qing , Chai Mengnan , Niu Xiaoping , Qin Yuan
Published: August 2020

Drought and salt stress are the main environmental cues affecting the survival, development, distribution, and yield of crops worldwide. MYB transcription factors play a crucial role in plants’ biological processes, but the function of pineapple MYB genes is still obscure. In this study, one of the pineapple MYB transcription factors, AcoMYB4, was isolated and characterized. The results showed that AcoMYB4 is localized in the cell nucleus, and its expression is induced by low temperature, drought, salt stress, and hormonal stimulation, especially by abscisic acid (ABA). Overexpression of AcoMYB4 in rice and Arabidopsis enhanced plant sensitivity to osmotic stress; it led to an increase in the number stomata on leaf surfaces and lower germination rate under salt and drought stress. Furthermore, in AcoMYB4 OE lines, the membrane oxidation index, free proline, and soluble sugar contents were decreased. In contrast, electrolyte leakage and malondialdehyde (MDA) content increased significantly due to membrane injury, indicating higher sensitivity to drought and salinity stresses. Besides the above, both the expression level and activities of several antioxidant enzymes were decreased, indicating lower antioxidant activity in AcoMYB4 transgenic plants. Moreover, under osmotic stress, overexpression of AcoMYB4 inhibited ABA biosynthesis through a decrease in the transcription of genes responsible for ABA synthesis (ABA1 and ABA2) and ABA signal transduction factor ABI5. These results suggest that AcoMYB4 negatively regulates osmotic stress by attenuating cellular ABA biosynthesis and signal transduction pathways.
Structural Complexity and Plasticity of Signaling Regulation at the Melanocortin-4 Receptor
Authors: Kleinau Gunnar , Heyder Nicolas A. , Tao Ya-Xiong , Scheerer Patrick
Published: August 2020

The melanocortin-4 receptor (MC4R) is a class A G protein-coupled receptor (GPCR), essential for regulation of appetite and metabolism. Pathogenic inactivating MC4R mutations are the most frequent cause of monogenic obesity, a growing medical and socioeconomic problem worldwide. The MC4R mediates either ligand-independent or ligand-dependent signaling. Agonists such as α-melanocyte-stimulating hormone (α-MSH) induce anorexigenic effects, in contrast to the endogenous inverse agonist agouti-related peptide (AgRP), which causes orexigenic effects by suppressing high basal signaling activity. Agonist action triggers the binding of different subtypes of G proteins and arrestins, leading to concomitant induction of diverse intracellular signaling cascades. An increasing number of experimental studies have unraveled molecular properties and mechanisms of MC4R signal transduction related to physiological and pathophysiological aspects. In addition, the MC4R crystal structure was recently determined at 2.75 Å resolution in an inactive state bound with a peptide antagonist. Underpinned by structural homology models of MC4R complexes simulating a presumably active-state conformation compared to the structure of the inactive state, we here briefly summarize the current understanding and key players involved in the MC4R switching process between different activity states. Finally, these perspectives highlight the complexity and plasticity in MC4R signaling regulation and identify gaps in our current knowledge.
Metabolic and Molecular Mechanisms of Macrophage Polarisation and Adipose Tissue Insulin Resistance
Authors: Orliaguet Lucie , Ejlalmanesh Tina , Alzaid Fawaz
Published: August 2020

Inflammation plays a key role in the development and progression of type-2 diabetes (T2D), a disease characterised by peripheral insulin resistance and systemic glucolipotoxicity. Visceral adipose tissue (AT) is the main source of inflammation early in the disease course. Macrophages are innate immune cells that populate all peripheral tissues, including AT. Dysregulated AT macrophage (ATM) responses to microenvironmental changes are at the root of aberrant inflammation and development of insulin resistance, locally and systemically. The inflammatory activation of macrophages is regulated at multiple levels: cell surface receptor stimulation, intracellular signalling, transcriptional and metabolic levels. This review will cover the main mechanisms involved in AT inflammation and insulin resistance in T2D. First, we will describe the physiological and pathological changes in AT that lead to inflammation and insulin resistance. We will next focus on the transcriptional and metabolic mechanisms described that lead to the activation of ATMs. We will discuss more novel metabolic mechanisms that influence macrophage polarisation in other disease or tissue contexts that may be relevant to future work in insulin resistance and T2D.
Collagen 24 α1 Is Increased in Insulin-Resistant Skeletal Muscle and Adipose Tissue
Authors: Weng Xiong , Lin De , Huang Jeffrey T. J. , Stimson Roland H. , Wasserman David H. , Kang Li
Published: August 2020

Aberrant extracellular matrix (ECM) remodelling in muscle, liver and adipose tissue is a key characteristic of obesity and insulin resistance. Despite its emerging importance, the effective ECM targets remain largely undefined due to limitations of current approaches. Here, we developed a novel ECM-specific mass spectrometry-based proteomics technique to characterise the global view of the ECM changes in the skeletal muscle and liver of mice after high fat (HF) diet feeding. We identified distinct signatures of HF-induced protein changes between skeletal muscle and liver where the ECM remodelling was more prominent in the muscle than liver. In particular, most muscle collagen isoforms were increased by HF diet feeding whereas the liver collagens were differentially but moderately affected highlighting a different role of the ECM remodelling in different tissues of obesity. Moreover, we identified a novel association between collagen 24α1 and insulin resistance in the skeletal muscle. Using quantitative gene expression analysis, we extended this association to the white adipose tissue. Importantly, collagen 24α1 mRNA was increased in the visceral adipose tissue, but not the subcutaneous adipose tissue of obese diabetic subjects compared to lean controls, implying a potential pathogenic role of collagen 24α1 in obesity and type 2 diabetes.
Is Green Marketing a Label for Ecotourism? The Romanian Experience
Authors: Nistoreanu Puiu , Aluculesei Alina-Cerasela , Avram Daniel
Published: August 2020

The focus on sustainability represents the key to the tourism industry today. Green marketing was constantly on the agenda of local authorities and started to be a subject of interest for Academia too, but it was very little approached in the Eastern European countries, especially in the tourism studies. This article describes the presence of green marketing in Romanian ecotourism and its impact on tourist’s perception. Due to its natural landscapes and tourist attractions, Romanian ecotourism can take advantage of green marketing practices and promote tourism products based on the new preference of the tourists for sustainable activities. However, there is a lack of legislative framework regarding green labeling that can effect in the long term the destination brand. The main objective of the present article is to give an overview image of the online presence of the Romanian ecotourist accommodation units that applied for the Eco-label provided by the ECO-Romania Association. The study describes how these establishments use green marketing practices and if their guests perceive the green image too. The methodology of the study consists of a qualitative analysis of the primary data obtained by the authors from the websites of ECO Romania Association, TripAdvisor platform and accommodation units. The results show a high interest of the accommodation units from the ecotourism field for green marketing practices which is also perceived by tourists. The tendency of tourism stakeholders to apply for an accreditation system provided by non-governmental organization instead of choosing a European accreditation shows the impact of such a national initiative and emphasizes the need to develop a legal framework for green ecotourism practices.
Measuring Drivers’ Physiological Response to Different Vehicle Controllers in Highly Automated Driving (HAD): Opportunities for Establishing Real-Time Values of Driver Discomfort
Authors: Radhakrishnan Vishnu , Merat Natasha , Louw Tyron , Lenné Michael G. , Romano Richard , Paschalidis Evangelos , Hajiseyedjavadi Foroogh , Wei Chongfeng , Boer Erwin R.
Published: August 2020

This study investigated how driver discomfort was influenced by different types of automated vehicle (AV) controllers, compared to manual driving, and whether this response changed in different road environments, using heart-rate variability (HRV) and electrodermal activity (EDA). A total of 24 drivers were subjected to manual driving and four AV controllers: two modelled to depict “human-like” driving behaviour, one conventional lane-keeping assist controller, and a replay of their own manual drive. Each drive lasted for ~15 min and consisted of rural and urban environments, which differed in terms of average speed, road geometry and road-based furniture. Drivers showed higher skin conductance response (SCR) and lower HRV during manual driving, compared to the automated drives. There were no significant differences in discomfort between the AV controllers. SCRs and subjective discomfort ratings showed significantly higher discomfort in the faster rural environments, when compared to the urban environments. Our results suggest that SCR values are more sensitive than HRV-based measures to continuously evolving situations that induce discomfort. Further research may be warranted in investigating the value of this metric in assessing real-time driver discomfort levels, which may help improve acceptance of AV controllers.
Quantitative Cluster Headache Analysis for Neurological Diagnosis Support Using Statistical Classification
Authors: El-Yaagoubi Mohammed , Mora-Jiménez Inmaculada , Jabrane Younes , Muñoz-Romero Sergio , Rojo-Álvarez José Luis , Pareja-Grande Juan Antonio
Published: August 2020

Cluster headache (CH) belongs to the group III of The International Classification of Headaches. It is characterized by attacks of severe pain in the ocular/periocular area accompanied by cranial autonomic signs, including parasympathetic activation and sympathetic hypofunction on the symptomatic side. Iris pigmentation occurs in the neonatal period and depends on the sympathetic tone in each eye. We hypothesized that the presence of visible or subtle color iris changes in both eyes could be used as a quantitative biomarker for screening and early detection of CH. This work scrutinizes the scope of an automatic diagnosis-support system for early detection of CH, by using as indicator the error rate provided by a statistical classifier designed to identify the eye (left vs. right) from iris pixels in color images. Systematic tests were performed on a database with images of 11 subjects (four with CH, four with other ophthalmic diseases affecting the iris pigmentation, and three control subjects). Several aspects were addressed to design the classifier, including: (a) the most convenient color space for the statistical classifier; (b) whether the use of features associated to several color spaces is convenient; (c) the robustness of the classifier to iris spatial subregions; (d) the contribution of the pixels neighborhood. Our results showed that a reduced value for the error rate (lower than 0.25) can be used as CH marker, whereas structural regions of the iris image need to be taken into account. The iris color feature analysis using statistical classification is a potentially useful technique to investigate disorders affecting the autonomous nervous system in CH.
‘Candidatus Liberibacter Solanacearum’ Is Unlikely to Be Transmitted Spontaneously from Infected Carrot Plants to Citrus Plants by Trioza Erytreae
Authors: Quintana-González de Chaves María , Teresani Gabriela R. , Hernández-Suárez Estrella , Bertolini Edson , Moreno Aránzazu , Fereres Alberto , Cambra Mariano , Siverio Felipe
Published: August 2020

Bacteria belonging to ‘Candidatus Liberibacter spp.’ are associated with various severe diseases in the five continents. The African citrus psyllid Trioza erytreae (Hemiptera: Triozidae) is an efficient vector of citrus huanglongbing-HLB disease, absent in the Mediterranean basin. This psyllid is currently present in the islands and mainland Portugal and Spain, where the prevalence of ‘Ca. Liberibacter solanacearum’ (CaLsol) associated to a carrot disease is high. Trioza erytreae normally feeds on citrus plants but has also been observed on other crops. It would be a great concern to the Mediterranean citrus industry if T. erytreae could transmit this bacterium from carrots to citrus and cause disease; therefore, the transmission of CaLsol from carrot plants to citrus plants was experimentally assessed. Although CaLsol was initially detected on receptor citrus plants in transmission assays by dodder and budding, the infection was not established. The feeding behavior by electrical penetration graphs and oviposition of T. erytreae on carrot plants versus citrus plants was evaluated. Trioza erytreae only reached the phloem in citrus plants. However, it was able to acquire CaLsol from infected carrots but unable to transmit it to citrus plants. CaLsol was detected in some carrot plants immediately after 7 and 14 days (inoculation access period), but it was not detected after one month. Trioza erytreae was unable to complete its life cycle on carrot plants. In conclusion, the efficient vector of bacteria associated to huanglongbing was unable to transmit CaLsol from carrot to citrus plants, but it acquired and transmitted the bacterium from carrot to carrot plants with low efficiency.
The Gut–Brain–Microbiome Axis in Bumble Bees
Authors: Leger Laura , McFrederick Quinn S.
Published: August 2020

The brain-gut–microbiome axis is an emerging area of study, particularly in vertebrate systems. Existing evidence suggests that gut microbes can influence basic physiological functions and that perturbations to the gut microbiome can have deleterious effects on cognition and lead to neurodevelopmental disorders. While this relationship has been extensively studied in vertebrate systems, little is known about this relationship in insects. We hypothesized that because of its importance in bee health, the gut microbiota influences learning and memory in adult bumble bees. As an initial test of whether there is a brain-gut–microbiome axis in bumble bees, we reared microbe-inoculated and microbe-depleted bees from commercial Bombus impatiens colonies. We then conditioned experimental bees to associate a sucrose reward with a color and tested their ability to learn and remember the rewarding color. We found no difference between microbe-inoculated and microbe-depleted bumble bees in performance during the behavioral assay. While these results suggest that the brain-gut–microbiome axis is not evident in Bombus impatiens, future studies with different invertebrate systems are needed to further investigate this phenomenon.
Extra-Esophageal Presentation of Gastroesophageal Reflux Disease: 2020 Update
Authors: Durazzo Marilena , Lupi Giulia , Cicerchia Francesca , Ferro Arianna , Barutta Federica , Beccuti Guglielmo , Gruden Gabriella , Pellicano Rinaldo
Published: August 2020

Gastroesophageal reflux disease (GERD) is defined by the presence of symptoms induced by the reflux of the stomach contents into the esophagus. Although clinical manifestations of GERD typically involve the esophagus, extra-esophageal manifestations are widespread and less known. In this review, we discuss extra-esophageal manifestations of GERD, focusing on clinical presentations, diagnosis, and treatment. Common extra-esophageal manifestations of GERD include chronic cough, asthma, laryngitis, dental erosions, and gingivitis. Extra-esophageal involvement can be present also when classic GERD symptoms are absent, making the diagnosis more challenging. Although available clinical studies are heterogeneous and frequently of low quality, a trial with proton pump inhibitors can be suggested as a first-line diagnostic strategy in case of suspected extra-esophageal manifestations of GERD.
Prevalence of Myofascial Trigger Points in Patients with Mild to Moderate Painful Knee Osteoarthritis: A Secondary Analysis
Authors: Sánchez Romero Eleuterio A. , Fernández Carnero Josué , Villafañe Jorge Hugo , Calvo-Lobo César , Ochoa Sáez Victoria , Burgos Caballero Verónica , Laguarta Val Sofia , Pedersini Paolo , Pecos Martín Daniel
Published: August 2020

Objective: To determine the prevalence of myofascial trigger points (MTrPs) and the correlation between the number of MTrPs and pain and function in patients presenting knee pain osteoarthritis (OA). Methods: This was a secondary analysis of data from a cross-sectional study. The prevalence of MTrPs located in tensor fasciae latae, hip adductors, hamstrings, quadriceps, gastrocnemius, and popliteus muscles was studied in 114 patients (71 men and 43 women) with knee OA. Pain and functionality were assessed with a numerical pain rating scale (NPRS), the Western Ontario, McMaster Universities Osteoarthritis Index (WOMAC) score, the Barthel Index, and the timed up and go test. Results: The prevalence of latent MTrPs was detected via palpation and was estimated to be 50%, 35%, 25%, 29%, 33%, and 12% for tensor fasciae latae, hip adductors, hamstrings, quadriceps, gastrocnemius, and popliteus muscles, respectively. The prevalence of active MTrPs was estimated to be 11%, 17%, 30%, 18%, 25%, and 17% for tensor fasciae latae, hip adductors, hamstrings, quadriceps, gastrocnemius, and popliteus muscles, respectively. Pain was measured with the NPRS scale and was poorly correlated with the prevalence of latent MTrPs (r = 0.2; p = 0.03) and active MTrPs (r = 0.23; p = 0.01) in the hamstrings. Disability was moderately correlated with the number of latent MTrPs in the tensor fasciae latae muscle (Barthel, r = 0.26; p = 0.01 and WOMAC, r = 0.19; p = 0.04). Conclusions: This secondary analysis found that the prevalence of the MTrPs varied from 11% to 50% in different muscles of patients with mild to moderate painful knee osteoarthritis. Pain was correlated poorly with the prevalence of latent and active MTrPs in the hamstring muscles, and disability correlated moderately with the number of latent MTrPs in tensor fasciae latae.
Rheumatoid Arthritis from Pathogenesis to Therapeutic Strategies
Authors: Mueller Ruediger B. , Hasler Paul
Published: August 2020

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint destruction [...]