bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Light Condition-Dependent Differences in the Accumulation and Subcellular Localization of Glutathione in Arabidopsis and Wheat
Authors: Gasperl Anna , Balogh Eszter , Boldizsár Ákos , Kemeter Nadine , Pirklbauer Richard , Möstl Stefan , Kalapos Balázs , Szalai Gabriella , Müller Maria , Zellnig Günther , Kocsy Gábor
Published: January 2021

This study aimed to clarify whether the light condition-dependent changes in the redox state and subcellular distribution of glutathione were similar in the dicotyledonous model plant Arabidopsis (wild-type, ascorbate- and glutathione-deficient mutants) and the monocotyledonous crop species wheat (Chinese Spring variety). With increasing light intensity, the amount of its reduced (GSH) and oxidized (GSSG) form and the GSSG/GSH ratio increased in the leaf extracts of both species including all genotypes, while far-red light increased these parameters only in wheat except for GSH in the GSH-deficient Arabidopsis mutant. Based on the expression changes of the glutathione metabolism-related genes, light intensity influences the size and redox state of the glutathione pool at the transcriptional level in wheat but not in Arabidopsis. In line with the results in leaf extracts, a similar inducing effect of both light intensity and far-red light was found on the total glutathione content at the subcellular level in wheat. In contrast to the leaf extracts, the inducing influence of light intensity on glutathione level was only found in the cell compartments of the GSH-deficient Arabidopsis mutant, and far-red light increased it in both mutants. The observed general and genotype-specific, light-dependent changes in the accumulation and subcellular distribution of glutathione participate in adjusting the redox-dependent metabolism to the actual environmental conditions.
Antioxidant, Cytotoxic, Genotoxic, and DNA-Protective Potential of 2,3-Substituted Quinazolinones: Structure—Activity Relationship Study
Authors: Hricovíniová Jana , Hricovíniová Zuzana , Kozics Katarína
Published: January 2021

The evaluation of antioxidant compounds that counteract the mutagenic effects caused by the direct action of reactive oxygen species on DNA molecule is of considerable interest. Therefore, a series of 2,3-substituted quinazolinone derivatives (Q1–Q8) were investigated by different assays, and the relationship between their biological properties and chemical structure was examined. Genotoxicity and the potential DNA-protective effects of Q1–Q8 were evaluated by comet assay and DNA topology assay. Antioxidant activity was examined by DPPH-radical-scavenging, reducing-power, and total antioxidant status (TAS) assays. The cytotoxic effect of compounds was assessed in human renal epithelial cells (TH-1) and renal carcinoma cells (Caki-1) by MTT assay. Analysis of the structure–activity relationship disclosed significant differences in the activity depending on the substitution pattern. Derivatives Q5–Q8, bearing electron-donating moieties, were the most potent members of this series. Compounds were not genotoxic and considerably decreased the levels of DNA lesions induced by oxidants (H2O2, Fe2+ ions). Furthermore, compounds exhibited higher cytotoxicity in Caki-1 compared to that in TH-1 cells. Substantial antioxidant effect and DNA-protectivity along with the absence of genotoxicity suggested that the studied quinazolinones might represent potential model structures for the development of pharmacologically active agents.
Myosins, an Underestimated Player in the Infectious Cycle of Pathogenic Bacteria
Authors: Pillon Margaux , Doublet Patricia
Published: January 2021

Myosins play a key role in many cellular processes such as cell migration, adhesion, intracellular trafficking and internalization processes, making them ideal targets for bacteria. Through selected examples, such as enteropathogenic E. coli (EPEC), Neisseria, Salmonella, Shigella, Listeria or Chlamydia, this review aims to illustrate how bacteria target and hijack host cell myosins in order to adhere to the cell, to enter the cell by triggering their internalization, to evade from the cytosolic autonomous cell defense, to promote the biogenesis of intracellular replicative niche, to disseminate in tissues by cell-to-cell spreading, to exit out the host cell, and also to evade from macrophage phagocytosis. It highlights the diversity and sophistication of the strategy evolved by bacteria to manipulate one of their privileged targets, the actin cytoskeleton.
Genetic Insight into the Domain Structure and Functions of Dicer-Type Ribonucleases
Authors: Ciechanowska Kinga , Pokornowska Maria , Kurzyńska-Kokorniak Anna
Published: January 2021

Ribonuclease Dicer belongs to the family of RNase III endoribonucleases, the enzymes that specifically hydrolyze phosphodiester bonds found in double-stranded regions of RNAs. Dicer enzymes are mostly known for their essential role in the biogenesis of small regulatory RNAs. A typical Dicer-type RNase consists of a helicase domain, a domain of unknown function (DUF283), a PAZ (Piwi-Argonaute-Zwille) domain, two RNase III domains, and a double-stranded RNA binding domain; however, the domain composition of Dicers varies among species. Dicer and its homologues developed only in eukaryotes; nevertheless, the two enzymatic domains of Dicer, helicase and RNase III, display high sequence similarity to their prokaryotic orthologs. Evolutionary studies indicate that a combination of the helicase and RNase III domains in a single protein is a eukaryotic signature and is supposed to be one of the critical events that triggered the consolidation of the eukaryotic RNA interference. In this review, we provide the genetic insight into the domain organization and structure of Dicer proteins found in vertebrate and invertebrate animals, plants and fungi. We also discuss, in the context of the individual domains, domain deletion variants and partner proteins, a variety of Dicers’ functions not only related to small RNA biogenesis pathways.
The Odd Couple(s): An Overview of Beta-Lactam Antibiotics Bearing More Than One Pharmacophoric Group
Authors: De Rosa Margherita , Verdino Anna , Soriente Annunziata , Marabotti Anna
Published: January 2021

β-lactam antibiotics are among the most important and widely used antimicrobials worldwide and are comprised of a large family of compounds, obtained by chemical modifications of the common scaffolds. Usually these modifications include the addition of active groups, but less frequently, molecules were synthesized in which either two β-lactam rings were joined to create a single bifunctional compound, or the azetidinone ring was joined to another antibiotic scaffold or another molecule with a different activity, in order to create a molecule bearing two different pharmacophoric functions. In this review, we report some examples of these derivatives, highlighting their biological properties and discussing how this strategy can lead to the development of innovative antibiotics that can represent either novel weapons against the rampant increase of antimicrobial resistance, or molecules with a broader spectrum of action.
CXCR4 Regulates Temporal Differentiation via PRC1 Complex in Organogenesis of Epithelial Glands
Authors: Kim Junchul , Lee Sang-Woo , Park Kyungpyo
Published: January 2021

CXC-chemokine receptor type 4 (CXCR4), a 7-transmembrane receptor family member, displays multifaceted roles, participating in immune cell migration, angiogenesis, and even adipocyte metabolism. However, the activity of such a ubiquitously expressed receptor in epithelial gland organogenesis has not yet been fully explored. To investigate the relationship between CXCL12/CXCR4 signaling and embryonic glandular organogenesis, we used an ex vivo culture system with live imaging and RNA sequencing to elucidate the transcriptome and protein-level signatures of AMD3100, a potent abrogating reagent of the CXCR4-CXCL12 axis, imprinted on the developing organs. Immunostaining results showed that CXCR4 was highly expressed in embryonic submandibular gland, lung, and pancreas, especially at the periphery of end buds containing numerous embryonic stem/progenitor cells. Despite no significant increase in apoptosis, AMD3100-treated epithelial organs showed a retarded growth with significantly slower branching and expansion. Further analyses with submandibular glands revealed that such responses resulted from the AMD3100-induced precocious differentiation of embryonic epithelial cells, losing mitotic activity. RNA sequencing analysis revealed that inhibition of CXCR4 significantly down-regulated polycomb repressive complex (PRC) components, known as regulators of DNA methylation. Treatment with PRC inhibitor recapitulated the AMD3100-induced precocious differentiation. Our results indicate that the epigenetic modulation by the PRC-CXCR12/CXCR4 signaling axis is crucial for the spatiotemporal regulation of proliferation and differentiation of embryonic epithelial cells during embryonic glandular organogenesis.
GPR55 Receptor Activation by the N-Acyl Dopamine Family Lipids Induces Apoptosis in Cancer Cells via the Nitric Oxide Synthase (nNOS) Over-Stimulation
Authors: Akimov Mikhail G. , Gamisonia Alina M. , Dudina Polina V. , Gretskaya Natalia M. , Gaydaryova Anastasia A. , Kuznetsov Andrey S. , Zinchenko Galina N. , Bezuglov Vladimir V.
Published: January 2021

GPR55 is a GPCR of the non-CB1/CB2 cannabinoid receptor family, which is activated by lysophosphatidylinositol (LPI) and stimulates the proliferation of cancer cells. Anandamide, a bioactive lipid endocannabinoid, acts as a biased agonist of GPR55 and induces cancer cell death, but is unstable and psychoactive. We hypothesized that other endocannabinoids and structurally similar compounds, which are more hydrolytically stable, could also induce cancer cell death via GPR55 activation. We chemically synthesized and tested a set of fatty acid amides and esters for cell death induction via GPR55 activation. The most active compounds appeared to be N-acyl dopamines, especially N-docosahexaenoyl dopamine (DHA-DA). Using a panel of cancer cell lines and a set of receptor and intracellular signal transduction machinery inhibitors together with cell viability, Ca2+, NO, ROS (reactive oxygen species) and gene expression measurement, we showed for the first time that for these compounds, the mechanism of cell death induction differed from that published for anandamide and included neuronal nitric oxide synthase (nNOS) overstimulation with concomitant oxidative stress induction. The combination of DHA-DA with LPI, which normally stimulates cancer proliferation and is increased in cancer setting, had an increased cytotoxicity for the cancer cells indicating a therapeutic potential.
The Functions and Unique Features of LncRNAs in Cancer Development and Tumorigenesis
Authors: Taniue Kenzui , Akimitsu Nobuyoshi
Published: January 2021

Over the past decades, research on cancer biology has focused on the involvement of protein-coding genes in cancer development. Long noncoding RNAs (lncRNAs), which are transcripts longer than 200 nucleotides that lack protein-coding potential, are an important class of RNA molecules that are involved in a variety of biological functions. Although the functions of a majority of lncRNAs have yet to be clarified, some lncRNAs have been shown to be associated with human diseases such as cancer. LncRNAs have been shown to contribute to many important cancer phenotypes through their interactions with other cellular macromolecules including DNA, protein and RNA. Here we describe the literature regarding the biogenesis and features of lncRNAs. We also present an overview of the current knowledge regarding the roles of lncRNAs in cancer from the view of various aspects of cellular homeostasis, including proliferation, survival, migration and genomic stability. Furthermore, we discuss the methodologies used to identify the function of lncRNAs in cancer development and tumorigenesis. Better understanding of the molecular mechanisms involving lncRNA functions in cancer is critical for the development of diagnostic and therapeutic strategies against tumorigenesis.
Medicinal Mushrooms: Bioactive Compounds, Use, and Clinical Trials
Authors: Venturella Giuseppe , Ferraro Valeria , Cirlincione Fortunato , Gargano Maria Letizia
Published: January 2021

Medicinal mushrooms have important health benefits and exhibit a broad spectrum of pharmacological activities, including antiallergic, antibacterial, antifungal, anti-inflammatory, antioxidative, antiviral, cytotoxic, immunomodulating, antidepressive, antihyperlipidemic, antidiabetic, digestive, hepatoprotective, neuroprotective, nephroprotective, osteoprotective, and hypotensive activities. The growing interest in mycotherapy requires a strong commitment from the scientific community to expand clinical trials and to propose supplements of safe origin and genetic purity. Bioactive compounds of selected medicinal mushrooms and their effects and mechanisms in in vitro and in vivo clinical studies are reported in this review. Besides, we analyzed the therapeutic use and pharmacological activities of mushrooms.
Human Embryo Models and Drug Discovery
Authors: Rosner Margit , Reithofer Manuel , Fink Dieter , Hengstschläger Markus
Published: January 2021

For obvious reasons, such as, e.g., ethical concerns or sample accessibility, model systems are of highest importance to study the underlying molecular mechanisms of human maladies with the aim to develop innovative and effective therapeutic strategies. Since many years, animal models and highly proliferative transformed cell lines are successfully used for disease modelling, drug discovery, target validation, and preclinical testing. Still, species-specific differences regarding genetics and physiology and the limited suitability of immortalized cell lines to draw conclusions on normal human cells or specific cell types, are undeniable shortcomings. The progress in human pluripotent stem cell research now allows the growth of a virtually limitless supply of normal and DNA-edited human cells, which can be differentiated into various specific cell types. However, cells in the human body never fulfill their functions in mono-lineage isolation and diseases always develop in complex multicellular ecosystems. The recent advances in stem cell-based 3D organoid technologies allow a more accurate in vitro recapitulation of human pathologies. Embryoids are a specific type of such multicellular structures that do not only mimic a single organ or tissue, but the entire human conceptus or at least relevant components of it. Here we briefly describe the currently existing in vitro human embryo models and discuss their putative future relevance for disease modelling and drug discovery.
Cysteine-Rich Hydrophobin Gene Family: Genome Wide Analysis, Phylogeny and Transcript Profiling in Cordyceps militaris
Authors: Li Xiao , Wang Fen , Xu Yanyan , Liu Guijun , Dong Caihong
Published: January 2021

Hydrophobins are a family of small secreted proteins found exclusively in fungi, and they play various roles in the life cycle. In the present study, genome wide analysis and transcript profiling of the hydrophobin family in Cordyceps militaris, a well-known edible and medicinal mushroom, were studied. The distribution of hydrophobins in ascomycetes with different lifestyles showed that pathogenic fungi had significantly more hydrophobins than saprotrophic fungi, and class II members accounted for the majority. Phylogenetic analysis of hydrophobin proteins from the species of Cordyceps s.l. indicated that there was more variability among the class II members than class I. Only a few hydrophobin-encoding genes evolved by duplication in Cordyceps s.l., which was inconsistent with the important role of gene duplication in basidiomycetes. Different transcript patterns of four hydrophobin-encoding genes during the life cycle indicated the possible different functions for each. The transcripts of Cmhyd2, 3 and 4 can respond to light and were related with the photoreceptors. CmQHYD, with four hydrophobin II domains, was first found in C. militaris, and multi-domain hydrophobins were only distributed in the species of Cordycipitaceae and Clavicipitaceae. These results could be helpful for further function research of hydrophobins and could provide valuable information for the evolution of hydrophobins.
Increased Calbindin D28k Expression via Long-Term Alternate-Day Fasting Does Not Protect against Ischemia-Reperfusion Injury: A Focus on Delayed Neuronal Death, Gliosis and Immunoglobulin G Leakage
Authors: Sim Hyejin , Lee Tae-Kyeong , Yoo Yeon Ho , Ahn Ji Hyeon , Kim Dae Won , Kim Bora , Lee Jae-Chul , Park Joon Ha , Lim Soon-Sung , Park Jung-Seok , Kang Il Jun , Kim Young-Myeong , Shin Myoung Cheol , Cho Jun Hwi , Park Yoonsoo , Won Moo-Ho
Published: January 2021

Calbindin-D28k (CB), a calcium-binding protein, mediates diverse neuronal functions. In this study, adult gerbils were fed a normal diet (ND) or exposed to intermittent fasting (IF) for three months, and were randomly assigned to sham or ischemia operated groups. Ischemic injury was induced by transient forebrain ischemia for 5 min. Short-term memory was examined via passive avoidance test. CB expression was investigated in the Cornu Ammonis 1 (CA1) region of the hippocampus via western blot analysis and immunohistochemistry. Finally, histological analysis was used to assess neuroprotection and gliosis (microgliosis and astrogliosis) in the CA1 region. Short-term memory did not vary significantly between ischemic gerbils with IF and those exposed to ND. CB expression was increased significantly in the CA1 pyramidal neurons of ischemic gerbils with IF compared with that of gerbils fed ND. However, the CB expression was significantly decreased in ischemic gerbils with IF, similarly to that of ischemic gerbils exposed to ND. The CA1 pyramidal neurons were not protected from ischemic injury in both groups, and gliosis (astrogliosis and microgliosis) was gradually increased with time after ischemia. In addition, immunoglobulin G was leaked into the CA1 parenchyma from blood vessels and gradually increased with time after ischemic insult in both groups. Taken together, our study suggests that IF for three months increases CB expression in hippocampal CA1 pyramidal neurons; however, the CA1 pyramidal neurons are not protected from transient forebrain ischemia. This failure in neuroprotection may be attributed to disruption of the blood–brain barrier, which triggers gliosis after ischemic insults.
Elastic Electron Scattering from Methane Molecule in the Energy Range from 50–300 eV
Authors: Vukalović Jelena , Maljković Jelena B. , Tökési Karoly , Predojević Branko , Marinković Bratislav P.
Published: January 2021

Electron interaction with methane molecule and accurate determination of its elastic cross-section is a demanding task for both experimental and theoretical standpoints and relevant for our better understanding of the processes in Earth’s and Solar outer planet atmospheres, the greenhouse effect or in plasma physics applications like vapor deposition, complex plasma-wall interactions and edge plasma regions of Tokamak. Methane can serve as a test molecule for advancing novel electron-molecule collision theories. We present a combined experimental and theoretical study of the elastic electron differential cross-section from methane molecule, as well as integral and momentum transfer cross-sections in the intermediate energy range (50–300 eV). The experimental setup, based on a crossed beam technique, comprising of an electron gun, a single capillary gas needle and detection system with a channeltron is used in the measurements. The absolute values for cross-sections are obtained by relative-flow method, using argon as a reference. Theoretical results are acquired using two approximations: simple sum of individual atomic cross-sections and the other with molecular effect taken into the account.
The Acquisition of Colistin Resistance Is Associated to the Amplification of a Large Chromosomal Region in Klebsiella pneumoniae kp52145
Authors: Sánchez María Blanca , Sánchez-Gorostiaga Alicia , Cuesta Trinidad , Martínez José Luis
Published: January 2021

The appearance of carbapenem-resistant Klebsiella pneumoniae has increased the use of colistin as a last-resort antibiotic for treating infections by this pathogen. A consequence of its use has been the spread of colistin-resistant strains, in several cases carrying colistin resistance genes. In addition, when susceptible strains are confronted with colistin during treatment, mutation is a major cause of the acquisition of resistance. To analyze the mechanisms of resistance that might be selected during colistin treatment, an experimental evolution assay for 30 days using as a model the clinical K. pneumoniae kp52145 isolate in the presence of increasing amounts of colistin was performed. All evolved populations presented a decreased susceptibility to colistin, without showing cross-resistance to antibiotics belonging to other structural families. We did not find any common mutation in the evolved mutants, neither in already known genes, previously known to be associated with the resistance phenotype, nor in new ones. The only common genetic change observed in the strains that evolved in the presence of colistin was the amplification of a 34 Kb sequence, homologous to a prophage (Enterobacteria phage Fels-2). Our data support that gene amplification can be a driving force in the acquisition of colistin resistance by K. pneumoniae.
Comparative Analysis of Transcriptome and sRNAs Expression Patterns in the Brachypodium distachyon—Magnaporthe oryzae Pathosystems
Authors: Zanini Silvia , Šečić Ena , Busche Tobias , Galli Matteo , Zheng Ying , Kalinowski Jörn , Kogel Karl-Heinz
Published: January 2021

The hemibiotrophic fungus Magnaporthe oryzae (Mo) is the causative agent of rice blast and can infect aerial and root tissues of a variety of Poaceae, including the model Brachypodium distachyon (Bd). To gain insight in gene regulation processes occurring at early disease stages, we comparatively analyzed fungal and plant mRNA and sRNA expression in leaves and roots. A total of 310 Mo genes were detected consistently and differentially expressed in both leaves and roots. Contrary to Mo, only minor overlaps were observed in plant differentially expressed genes (DEGs), with 233 Bd-DEGs in infected leaves at 2 days post inoculation (DPI), compared to 4978 at 4 DPI, and 138 in infected roots. sRNA sequencing revealed a broad spectrum of Mo-sRNAs that accumulated in infected tissues, including candidates predicted to target Bd mRNAs. Conversely, we identified a subset of potential Bd-sRNAs directed against fungal cell wall components, virulence genes and transcription factors. We also show a requirement of operable RNAi genes from the DICER-like (DCL) and ARGONAUTE (AGO) families for fungal virulence. Overall, our work elucidates the extensive reprogramming of transcriptomes and sRNAs in both plant host (Bd) and fungal pathogen (Mo), further corroborating the critical role played by sRNA species in the establishment of the interaction and its outcome.
QTL Mapping and Candidate Gene Identification of Swollen Root Formation in Turnip
Authors: Wu Yudi , Zhang Shifan , Zhang Hui , Li Fei , Li Guoliang , Fan Chuchuan , Sun Rifei , Zhang Shujiang
Published: January 2021

The swollen root is an important agronomic trait and is a determinant of yield for turnips, which are cultivated as both vegetables and fodder. However, the genetic mechanism of swollen root formation is poorly understood. In this study, we analyzed the F2 and BC1P2 populations derived from a cross between “10601” (European turnip with swollen root, Brassica rapa ssp. rapifera, AA, 2n = 2× = 20) and “10603” (Chinese cabbage with normal root, Brassica rapa ssp. pekinensis, AA, 2n = 2× = 20), and suggested that the swollen root is a quantitative trait. Two major quantitative trait loci (QTLs), FR1.1 (Fleshy root 1.1) and FR7.1 (Fleshy root 7.1), were identified by QTL-seq analysis and further confirmed by QTL mapping in F2 and BC1P2 populations. The QTL FR1.1 with a likelihood of odd (LOD) of 7.01 explained 17.2% of the total phenotypic variations for root diameter and the QTL FR7.1 explained 23.0% (LOD = 9.38) and 31.0% (LOD = 13.27) of the total phenotypic variations in root diameter and root weight, respectively. After a recombinant screening, the major QTL FR7.1 was further narrowed down to a 220 kb region containing 47 putative genes. A candidate gene, Bra003652, which is a homolog of AT1G78240 that plays an essential role in cell adhesion and disorganized tumor-like formation in Arabidopsis thaliana, was identified in this region. In addition, expression and parental allele analysis supported that Bra003652 was a possible candidate gene of QTL FR7.1 for swollen root formation in turnip. Our research may provide new insight into the molecular mechanism of swollen root formation in root crops.
α-Pinene Enhances the Anticancer Activity of Natural Killer Cells via ERK/AKT Pathway
Authors: Jo Hantae , Cha Byungsun , Kim Haneul , Brito Sofia , Kwak Byeong Mun , Kim Sung Tae , Bin Bum-Ho , Lee Mi-Gi
Published: January 2021

Natural killer (NK) cells are lymphocytes that can directly destroy cancer cells. When NK cells are activated, CD56 and CD107a markers are able to recognize cancer cells and release perforin and granzyme B proteins that induce apoptosis in the targeted cells. In this study, we focused on the role of phytoncides in activating NK cells and promoting anticancer effects. We tested the effects of several phytoncide compounds on NK-92mi cells and demonstrated that α-pinene treatment exhibited higher anticancer effects, as observed by the increased levels of perforin, granzyme B, CD56 and CD107a. Furthermore, α-pinene treatment in NK-92mi cells increased NK cell cytotoxicity in two different cell lines, and immunoblot assays revealed that the ERK/AKT pathway is involved in NK cell cytotoxicity in response to phytoncides. Furthermore, CT-26 colon cancer cells were allografted subcutaneously into BALB/c mice, and α-pinene treatment then inhibited allografted tumor growth. Our findings demonstrate that α-pinene activates NK cells and increases NK cell cytotoxicity, suggesting it is a potential compound for cancer immunotherapy.
Ex Vivo Live Full-Thickness Porcine Skin Model as a Versatile In Vitro Testing Method for Skin Barrier Research
Authors: Hwang Jee-hyun , Jeong Haengdueng , Lee Nahyun , Hur Sumin , Lee Nakyum , Han Jeong Jun , Jang Hye Won , Choi Wang Keun , Nam Ki Taek , Lim Kyung-Min
Published: January 2021

Since the European Union (EU) announced their animal testing ban in 2013, all animal experiments related to cosmetics have been prohibited, creating a demand for alternatives to animal experiments for skin studies. Here, we investigated whether an ex vivo live porcine skin model can be employed to study the safety and skin barrier-improving effects of hydroxyacids widely used in cosmetics for keratolytic peels. Glycolic acid (1–10%), salicylic acid (0.2–2%), and lactobionic acid (1.2–12%) were used as representative substances for α-hydroxyacid (AHA), β-hydroxyacid (BHA), and polyhydroxyacid (PHA), respectively. When hydroxyacids were applied at high concentrations on the porcine skin every other day for 6 days, tissue viability was reduced to 50–80%, suggesting that the toxicity of cosmetic ingredients can be evaluated with this model. Based on tissue viability, the treatment scheme was changed to a single exposure for 20 min. The protective effects of a single exposure of hydroxyacids on skin barrier function were evaluated by examining rhodamine permeability and epidermal structural components of barrier function using immunohistochemistry (IHC) and immunofluorescence (IF) staining. Lactobionic acid (PHAs) improved skin barrier function most compared to other AHAs and BHAs. Most importantly, trans-epidermal water loss (TEWL), an important functional marker of skin barrier function, could be measured with this model, which confirmed the significant skin barrier-protective effects of PHAs. Collectively, we demonstrated that the ex vivo live full-thickness porcine skin model can be an excellent alternative to animal experiments for skin studies on the safety and efficacy of cosmetic ingredients.
Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms
Authors: Yung Yammy , Lee Emily , Chu Hiu-Tung , Yip Pui-Kwan , Gill Harinder
Published: January 2021

Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is rarely achieved. In this review article, we discuss the novel agents and combination therapy that can potentially abnormal hematopoietic stem cells in CML and MPNs and the CML/MPN stem cell-sustaining bone marrow microenvironment.
Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia
Authors: Aguilar-Ballester María , Hurtado-Genovés Gema , Taberner-Cortés Alida , Herrero-Cervera Andrea , Martínez-Hervás Sergio , González-Navarro Herminia
Published: January 2021

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.
Oxygen Is an Ambivalent Factor for the Differentiation of Human Pluripotent Stem Cells in Cardiac 2D Monolayer and 3D Cardiac Spheroids
Authors: Souidi Monia , Sleiman Yvonne , Acimovic Ivana , Pribyl Jan , Charrabi Azzouz , Baecker Volker , Scheuermann Valerie , Pesl Martin , Jelinkova Sarka , Skladal Petr , Dvorak Petr , Lacampagne Alain , Rotrekl Vladimir , Meli Albano C.
Published: January 2021

Numerous protocols of cardiac differentiation have been established by essentially focusing on specific growth factors on human pluripotent stem cell (hPSC) differentiation efficiency. However, the optimal environmental factors to obtain cardiac myocytes in network are still unclear. The mesoderm germ layer differentiation is known to be enhanced by low oxygen exposure. Here, we hypothesized that low oxygen exposure enhances the molecular and functional maturity of the cardiomyocytes. We aimed at comparing the molecular and functional consequences of low (5% O2 or LOE) and high oxygen exposure (21% O2 or HOE) on cardiac differentiation of hPSCs in 2D- and 3D-based protocols. hPSC-CMs were differentiated through both the 2D (monolayer) and 3D (embryoid body) protocols using several lines. Cardiac marker expression and cell morphology were assessed. The mitochondrial localization and metabolic properties were evaluated. The intracellular Ca2+ handling and contractile properties were also monitored. The 2D cardiac monolayer can only be differentiated in HOE. The 3D cardiac spheroids containing hPSC-CMs in LOE further exhibited cardiac markers, hypertrophy, steadier SR Ca2+ release properties revealing a better SR Ca2+ handling, and enhanced contractile force. Preserved distribution of mitochondria and similar oxygen consumption by the mitochondrial respiratory chain complexes were also observed. Our results brought evidences that LOE is moderately beneficial for the 3D cardiac spheroids with hPSC-CMs exhibiting further maturity. In contrast, the 2D cardiac monolayers strictly require HOE.
TGF-β Activity of a Demineralized Bone Matrix
Authors: Panahipour Layla , Omerbasic Anes , Nasirzade Jila , Gruber Reinhard
Published: January 2021

Allografts consisting of demineralized bone matrix (DBM) are supposed to retain the growth factors of native bone. However, it is not clear if transforming growth factor β1 (TGF-β1) is maintained in the acid-extracted human bone. To this aim, the aqueous solutions of supernatants and acid lysates of OraGRAFT® Demineralized Cortical Particulate and OraGRAFT® Prime were prepared. Exposing fibroblasts to the aqueous solution caused a TGF-β receptor type I kinase-inhibitor SB431542-dependent increase in interleukin 11 (IL11), NADPH oxidase 4 (NOX4), and proteoglycan 4 (PRG4) expression. Interleukin 11 expression and the presence of TGF-β1 in the aqueous solutions were confirmed by immunoassay. Immunofluorescence further confirmed the nuclear translocation of Smad2/3 when fibroblasts were exposed to the aqueous solutions of both allografts. Moreover, allografts released matrix metalloprotease-2 activity and blocking proteases diminished the cellular TGF-β response to the supernatant. These results suggest that TGF-β is preserved upon the processing of OraGRAFT® and released by proteolytic activity into the aqueous solution.
The Two-Layer Hierarchical Distribution Model of Zeros of Riemann’s Zeta Function along the Critical Line
Authors: Riguidel Michel
Published: January 2021

This article numerically analyzes the distribution of the zeros of Riemann’s zeta function along the critical line (CL). The zeros are distributed according to a hierarchical two-layered model, one deterministic, the other stochastic. Following a complex plane anamorphosis involving the Lambert function, the distribution of zeros along the transformed CL follows the realization of a stochastic process of regularly spaced independent Gaussian random variables, each linked to a zero. The value of the standard deviation allows the possible overlapping of adjacent realizations of the random variables, over a narrow confidence interval. The hierarchical model splits the ζ function into sequential equivalence classes, with the range of probability densities of realizations coinciding with the spectrum of behavioral styles of the classes. The model aims to express, on the CL, the coordinates of the alternating cancellations of the real and imaginary parts of the ζ function, to dissect the formula for the number of zeros below a threshold, to estimate the statistical laws of two consecutive zeros, of function maxima and moments. This also helps explain the absence of multiple roots.
Land-Use Effect on Olive Groves Pest Prays oleae and on Its Potential Biocontrol Agent Chrysoperla carnea
Authors: Alves João Frederico , Mendes Sara , Alves da Silva António , Sousa José Paulo , Paredes Daniel
Published: January 2021

Olive growing has been intensified through the simplification of agricultural landscapes. In order to rethink the environmental drawbacks of these practices, conservation biological control techniques have been examined. In this work, Prays oleae and its natural enemy Chrysoperla carnea were monitored to account for the effects of the amount and diversity of different land-uses. We found that C. carnea showed an attraction to areas with high abundances of P. oleae but this predator did not display any affection by the different land-uses. Inversely, P. oleae abundance was lower in diverse landscapes and higher in simplified ones. Importantly, higher abundances of C. carnea were related to lower infestation levels of P. oleae in the late part of the season. These results corroborate the attraction of C. carnea to the olive moth, highlighting the potential of C. carnea as a biological control agent of this pest, assert that the promotion of land-use diversity can reduce P. oleae and confirm that landscapes dominated by olive groves can promote this pest. The present study aims at contributing to the discussion about the management of agricultural ecosystems by providing farmers with sustainable alternatives that do not have harmful effects on the environment and public health.
Bioactivity of Different Chemotypes of Oregano Essential Oil against the Blowfly Calliphora vomitoria Vector of Foodborne Pathogens
Authors: Bedini Stefano , Farina Priscilla , Napoli Edoardo , Flamini Guido , Ascrizzi Roberta , Verzera Antonella , Conti Barbara , Zappalà Lucia
Published: January 2021

Blowflies play a substantial role as vectors of microorganisms, including human pathogens. The control of these insect pests is an important aspect of the prevention of foodborne diseases, which represent a significant public health threat worldwide. Among aromatic plants, spices essential oils (EOs) are the most suitable to protect food from insect pests. In this study, we determined the chemical composition of three oregano EOs and assessed their toxicity and deterrence to oviposition against the blowfly Calliphora vomitoria L. The chemical analyses showed that the EOs belonged to three chemotypes: one with a prevalence of carvacrol, the carvacrol chemotype (CC; carvacrol, 81.5%), and two with a prevalence of thymol, the thymol/p-cymene and thymol/γ-terpinene chemotypes (TCC and TTC; thymol, 43.8, and 36.7%, respectively). The bioassays showed that although all the three EOs chemotypes are able to exert a toxic activity against C. vomitoria adults (LD50 from 0.14 to 0.31 μL insect−1) and eggs (LC50 from 0.008 to 0.038 μL cm−2) as well as deter the oviposition (Oviposition Activity Index, OAI, from 0.40 ± 0.04 to 0.87 ± 0.02), the bioactivity of oregano EOs significantly varies among the chemotypes, with the thymol-rich EOs (TCC and TTC) overall demonstrating more effectiveness than the carvacrol-rich (CC) EO.
Comparison of Short- and Long-Term Prognosis between ST-Elevation and Non-ST-Elevation Myocardial Infarction
Authors: Bouisset Frédéric , Ruidavets Jean-Bernard , Dallongeville Jean , Moitry Marie , Montaye Michele , Biasch Katia , Ferrières Jean
Published: January 2021

Background: Available data comparing long-term prognosis according to the type of acute coronary syndrome (ACS) are scarce, contradictory, and outdated. Our aim was to compare short- and long-term mortality in ST-elevated (STEMI) and non-ST-elevated myocardial infarction (non-STEMI) ACS patients. Methods: Patients presenting with an inaugural ACS during the year 2006 and living in one of the three areas in France covered by the Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) registry were included. Results: A total of 1822 patients with a first ACS—1121 (61.5%) STEMI and 701 (38.5%) non-STEMI—were included in the study. At the 28-day follow-up, the mortality rates were 6.7% and 4.7% (p = 0.09) for STEMI and non-STEMI patients, respectively, and after adjustment of potential confounding factors, the 28-day probability of death was significantly lower for non-STEMI ACS patients (Odds Ratio = 0.58 (0.36–0.94), p = 0.03). At the 10-year follow-up, the death rates were 19.6% and 22.8% (p = 0.11) for STEMI and non-STEMI patients, respectively, and after adjustment of potential confounding factors, the 10-year probability of death did not significantly differ between non-STEMI and STEMI events (OR = 1.07 (0.83–1.38), p = 0.59). Over the first year, the mortality rate was 7.2%; it then decreased and stabilized at 1.7% per year between the 2nd and 10th year following ACS. Conclusion: STEMI patients have a worse vital prognosis than non-STEMI patients within 28 days following ACS. However, at the 10-year follow-up, STEMI and non-STEMI patients have a similar vital prognosis. From the 2nd year onwards following the occurrence of a first ACS, the patients become stable coronary artery disease patients with an annual mortality rate in the 2% range, regardless of the type of ACS they initially present with.
Integrating Academic and Community Cancer Care and Research through Multidisciplinary Oncology Pathways for Value-Based Care: A Review and the City of Hope Experience
Authors: Bosserman Linda D. , Cianfrocca Mary , Yuh Bertram , Yeon Christina , Chen Helen , Sentovich Stephen , Polverini Amy , Zachariah Finly , Deaville Debbie , Lee Ashley B. , Sedrak Mina S. , King Elisabeth , Gray Stacy , Morse Denise , Glaser Scott , Bhatt Geetika , Adeimy Camille , Tan TingTing , Chao Joseph , Nam Arin , Paz Isaac B. , Kruper Laura , Rao Poornima , Sokolov Karen , Kulkarni Prakash , Salgia Ravi , Yamzon Jonathan , Johnson Deron
Published: January 2021

As the US transitions from volume- to value-based cancer care, many cancer centers and community groups have joined to share resources to deliver measurable, high-quality cancer care and clinical research with the associated high patient satisfaction, provider satisfaction, and practice health at optimal costs that are the hallmarks of value-based care. Multidisciplinary oncology care pathways are essential components of value-based care and their payment metrics. Oncology pathways are evidence-based, standardized but personalizable care plans to guide cancer care. Pathways have been developed and studied for the major medical, surgical, radiation, and supportive oncology disciplines to support decision-making, streamline care, and optimize outcomes. Implementing multidisciplinary oncology pathways can facilitate comprehensive care plans for each cancer patient throughout their cancer journey and across large multisite delivery systems. Outcomes from the delivered pathway-based care can then be evaluated against individual and population benchmarks. The complexity of adoption, implementation, and assessment of multidisciplinary oncology pathways, however, presents many challenges. We review the development and components of value-based cancer care and detail City of Hope’s (COH) academic and community-team-based approaches for implementing multidisciplinary pathways. We also describe supportive components with available results towards enterprise-wide value-based care delivery.
Acute Pancreatitis: Genetic Risk and Clinical Implications
Authors: Weiss Frank U. , Laemmerhirt Felix , Lerch Markus M.
Published: January 2021

Acute pancreatitis (AP) is one of the most common gastroenterological indications for emergency admittance and hospitalization. Gallstones, alcohol consumption or the presence of additional initiating factors give rise to a disease with a diverse clinical appearance and a hard-to predict course of progression. One major challenge in the treatment of AP patients is the early identification of patients at risk for the development of systemic complications and organ failure. In addition, 20%–30% of patients with a first episode of AP later experience progress to recurrent or chronic disease. Complex gene–environment interactions have been identified to play a role in the pathogenesis of pancreatitis, but so far no predictive genetic biomarkers could be implemented into the routine clinical care of AP patients. The current review explains common and rare etiologies of acute pancreatitis with emphasis on underlying genetic aberrations and ensuing clinical management.
Evaluation of Regional Pulmonary Ventilation in Spontaneously Breathing Patients with Idiopathic Pulmonary Fibrosis (IPF) Employing Electrical Impedance Tomography (EIT): A Pilot Study from the European IPF Registry (eurIPFreg)
Authors: Krauss Ekaterina , van der Beck Daniel , Schmalz Isabel , Wilhelm Jochen , Tello Silke , Dartsch Ruth C. , Mahavadi Poornima , Korfei Martina , Teschner Eckhard , Seeger Werner , Guenther Andreas
Published: January 2021

Objectives: In idiopathic pulmonary fibrosis (IPF), alterations in the pulmonary surfactant system result in an increased alveolar surface tension and favor repetitive alveolar collapse. This study aimed to assess the usefulness of electrical impedance tomography (EIT) in characterization of regional ventilation in IPF. Materials and methods: We investigated 17 patients with IPF and 15 healthy controls from the University of Giessen and Marburg Lung Center (UGMLC), Germany, for differences in the following EIT parameters: distribution of ventilation (TID), global inhomogeneity index (GI), regional impedance differences through the delta of end-expiratory lung impedance (dEELI), differences in surface of ventilated area (SURF), as well as center of ventilation (CG) and intratidal gas distribution (ITV). These parameters were assessed under spontaneous breathing and following a predefined escalation protocol of the positive end-expiratory pressure (PEEP), applied through a face mask by an intensive care respirator (EVITA, Draeger, Germany). Results: Individual slopes of dEELI over the PEEP increment protocol were found to be highly significantly increased in both groups (p < 0.001) but were not found to be significantly different between groups. Similarly, dTID slopes were increasing in response to PEEP, but this did not reach statistical significance within or between groups. Individual breathing patterns were very heterogeneous. There were no relevant differences of SURF, GI or CGVD over the PEEP escalation range. A correlation of dEELI to FVC, BMI, age, or weight did not forward significant results. Conclusions: In this study, we did see a significant increase in dEELI and a non-significant increase in dTID in IPF patients as well as in healthy controls in response to an increase of PEEP under spontaneous breathing. We propose the combined measurements of EIT and lung function to assess regional lung ventilation in spontaneously breathing subjects.
Different Background: Natural Killer Cell Profiles in Secondary versus Primary Recurrent Pregnancy Loss
Authors: Strobel Laura , Vomstein Kilian , Kyvelidou Christiana , Hofer-Tollinger Susanne , Feil Katharina , Kuon Ruben-Jeremias , Ebner Susanne , Troppmair Jakob , Toth Bettina
Published: January 2021

(1) Background: Prior studies suggested a significant impact of previous live births on peripheral natural killer cells (pNK) in patients with recurrent pregnancy loss (RPL). Patients with primary RPL (pRPL, no live birth) showed higher numbers of pNK than secondary RPL patients (sRPL, ≥ 1 live birth). (2) Methods: To further determine immunological differences between RPL patients and controls, we analysed pNK subpopulations and activation markers in pRPL (n = 47), sRPL (n = 24) and controls with previous live birth (sCtrl, n = 25) and nullipara (pCtrl, n = 60) within a prospective study. Percentages and numbers of CD56dimCD16bright cells, subpopulations and activation markers (CD57+, CD62L+, NKG2D+, NKp46+) were measured in non-pregnant RPL patients and n = 85 controls (n = 60 pCtrl, n = 25 sCtrl) in the mid-luteal phase by flow cytometry. (3) Results: Compared to sRPL patients, sCtrls showed higher CD56+ and CD56dimCD16bright numbers. Further, sRPL patients showed lower numbers of CD56dimCD16brightNKG2D+ and CD56dimCD16brightNKp46+ than sCtrls. (4) Conclusion: We suggest a chronic immune stimulation leading to a lower NK-cell count in sRPL patients with a lower NK cytotoxicity. This underlines the necessity to investigate pNK subpopulations as well as pRPL and sRPL separately to delineate the immune alterations in RPL.