bluuebunny/crossref_metadata_2025 huggingface dataset:
A Hidden Coordination-Bond Torsional Deformation as a Sign of Possible Spin Transition in Nickel(II)-Bis(nitroxide) Compounds
Authors: Kyoden Yukiya , Ishida Takayuki
Published: August 2020

Complex formation of nickel(II) tetrafluoroborate and tert-butyl 5-phenyl-2-pyridyl nitroxide (phpyNO) in the presence of sodium cyanate gave a discrete molecule [Ni(phpyNO)2(X)2] (X = NCO). The Ni-O-N-Csp2 torsion angles were reduced on heating; 33.5(5)° and 36.2(4)° at 100 K vs. 25.7(10)° and 32.3(11)° at 400 K. The magnetic behavior was almost diamagnetic below ca. 100 K, and the χmT value reached 1.04 cm3 K mol−1 at 400 K. An analysis using the van’t Hoff equation indicates a possible spin transition at T1/2 >> 400 K. Density functional theory calculation shows that the singlet-quintet energy gap decreases as the structural change from 100 to 400 K. The geometry optimization results suggest that the diamagnetic state has the Ni-O-N-Csp2 torsion angles of 32.7° while the Stotal = 2 state has those of 11.9°. The latter could not be experimentally observed even at 400 K. After overviewing the results on the known X = Br, Cl, and NCS derivatives, the magnetic behavior is described in a common phase diagram. The Br and Cl compounds undergo the energy level crossing of the high-/low-spin states, but the NCS and NCO compounds do not in a conventional experimental temperature range. The spin transition mechanism in this series involves the exchange coupling switch between ferro- and antiferromagnetic interactions, corresponding to the high- and low-spin phases, respectively.
Chromene- and Quinoline-3-Carbaldehydes: Useful Intermediates in the Synthesis of Heterocyclic Scaffolds
Authors: Rocha Djenisa H. A. , Batista Vasco F. , Balsa Emanuel J. F. , Pinto Diana C. G. A. , Silva Artur M. S.
Published: August 2020

Chromenes and quinolines are recognized as important scaffolds in medicinal chemistry. Herein, the efficient use of chromene- and quinoline-3-carbaldehydes to synthesize other valuable heterocycles is described. These carbaldehydes are obtained in excellent yields through the Vilsmeyer-Haack reaction of flavanones and azaflavanones. Protocols towards the synthesis of new heterocycles, such as 3H-chromeno[3–c]quinolines, (Z/E)-2-aryl-4-chloro-3-styryl-2H-chromenes, and (E)-2-aryl-4-chloro-3-styrylquinoline-1(2H)-carbaldehydes were established. Altogether, we demonstrate the value of chromene- and quinoline-3-carbaldehydes as building blocks.
Effects of N-Substituents on the Functional Activities of Naltrindole Derivatives for the δ Opioid Receptor: Synthesis and Evaluation of Sulfonamide Derivatives
Authors: Iwamatsu Chiharu , Hayakawa Daichi , Kono Tomomi , Honjo Ayaka , Ishizaki Saki , Hirayama Shigeto , Gouda Hiroaki , Fujii Hideaki
Published: August 2020

We have recently reported that N-alkyl and N-acyl naltrindole (NTI) derivatives showed activities for the δ opioid receptor (DOR) ranging widely from full inverse agonists to full agonists. We newly designed sulfonamide-type NTI derivatives in order to investigate the effects of the N-substituent on the functional activities because the side chain and S=O part in the sulfonamide moiety located in spatially different positions compared with those in the alkylamine and amide moieties. Among the tested compounds, cyclopropylsulfonamide 9f (SYK-839) was the most potent full inverse agonist for the DOR, whereas phenethylsulfonamide 9e (SYK-901) showed full DOR agonist activity with moderate potency. These NTI derivatives are expected to be useful compounds for investigation of the molecular mechanism inducing these functional activities.
Phytochemical Profile, Mineral Content, and Bioactive Compounds in Leaves of Seed-Propagated Artichoke Hybrid Cultivars
Authors: Rocchetti Gabriele , Lucini Luigi , Corrado Giandomenico , Colla Giuseppe , Cardarelli Mariateresa , Pascale Stefania De , Rouphael Youssef
Published: August 2020

The globe artichoke (Cynara cardunculus L. subsp. Scolymus (L.) Hegi) is a multi-year species rich in various classes of phytochemicals with known nutritional and pharmacological properties, such as polyphenols, sesquiterpene lactones, and terpenoids. Over the last decade, hybrids cultivars are transforming the artichoke market for their higher uniformity and stability over the traditional landraces, further increasing the potential of the artichoke as a source of commercial extracts and bioactive molecules. Our aim was to investigate the mineral and phytochemical profiles of leaves from seven seed-propagated hybrids by using an untargeted metabolomic approach based on ultra-high-pressure liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. Metabolomics identified several compounds in the tested varieties, namely 98 polyphenols, 123 sesquiterpene lactones, and 221 other metabolites. The phenolic content ranged from 3.01 mg Eq./g fw (for ‘Opera’) to 4.71 mg Eq./g fw (for ‘Opal’). Sesquiterpene lactones were, on average, 2.11 mg Eq./g fw. Multivariate statistics (HCA, PCA and OPLS-DA) highlighted the main metabolomics differences among cultivars, which weakly correlated with their agronomic classification. The seven cultivars showed distinctive metabolomics profiles, with ‘Opal’ and ‘Istar’ being the most valuable hybrids. The 3-hydroxyphenyl-valeric acid (a medium-chain fatty acid) and the 6-Gingesulfonic acid (a methoxyphenol) were the most discriminant markers. Our findings illustrated the quantitative and qualitative variation of several classes of phytochemicals in seed-propagated artichoke cultivars and allowed identifying distinctive metabolic signatures for both phenolic compounds and sesquiterpene lactones. This work supports the exploitation of the artichoke leaves from hybrid cultivars as a rich source of bioactive phytochemicals.
Interfacial and Foaming Properties of Tailor-Made Glycolipids—Influence of the Hydrophilic Head Group and Functional Groups in the Hydrophobic Tail
Authors: Hollenbach Rebecca , Völp Annika Ricarda , Höfert Ludwig , Rudat Jens , Ochsenreither Katrin , Willenbacher Norbert , Syldatk Christoph
Published: August 2020

Glycolipids are a class of biodegradable surfactants less harmful to the environment than petrochemically derived surfactants. Here we discuss interfacial properties, foam stability, characterized in terms of transient foam height, gas volume fraction and bubble diameter as well as texture of seven enzymatically synthesized surfactants for the first time. Glycolipids consisting of different head groups, namely glucose, sorbitol, glucuronic acid and sorbose, combined with different C10 acyl chains, namely decanoate, dec-9-enoate and 4-methyl-nonanoate are compared. Equilibrium interfacial tension values vary between 24.3 and 29.6 mN/m, critical micelle concentration varies between 0.7 and 3.0 mM. In both cases highest values were found for the surfactants with unsaturated or branched tail groups. Interfacial elasticity and viscosity, however, were significantly reduced in these cases. Head and tail group both affect foam stability. Foams from glycolipids with sorbose and glucuronic acid derived head groups showed higher stability than those from surfactants with glucose head group, sorbitol provided lowest foam stability. We attribute this to different head group hydration also showing up in the time to reach equilibrium interfacial adsorption. Unsaturated tail groups reduced whereas branching enhanced foam stability compared to the systems with linear, saturated tail. Moreover, the tail group strongly influences foam texture. Glycolipids with unsaturated tail groups produced foams quickly collapsing even at smallest shear loads, whereas the branched tail group yielded a higher modulus than the linear tails. Normalized shear moduli for the systems with different head groups varied in a narrow range, with the highest value found for decylglucuronate.
The Curcumin Analogue, MS13 (1,5-Bis(4-hydroxy-3- methoxyphenyl)-1,4-pentadiene-3-one), Inhibits Cell Proliferation and Induces Apoptosis in Primary and Metastatic Human Colon Cancer Cells
Authors: Ismail Nor Isnida , Othman Iekhsan , Abas Faridah , H. Lajis Nordin , Naidu Rakesh
Published: August 2020

The cytotoxic and apoptotic effects of turmeric (Curcuma longa) on colon cancer have been well documented but specific structural modifications of curcumin have been shown to possess greater growth-suppressive potential on colon cancer than curcumin. Therefore, the aim of this study is to identify the anti-cancer properties of curcumin analogue-MS13, a diarylpentanoid on the cytotoxicity, anti-proliferative and apoptotic activity of primary (SW480) and metastatic (SW620) human colon cancer cells. A cell viability assay showed that MS13 has greater cytotoxicity effect on SW480 (EC50: 7.5 ± 2.8 µM) and SW620 (EC50: 5.7 ± 2.4 µM) compared to curcumin (SW480, EC50: 30.6 ± 1.4 µM) and SW620, EC50: 26.8 ± 2.1 µM). Treatment with MS13 at two different doses 1X EC50 and 2X EC50 suppressed the colon cancer cells growth with lower cytotoxicity against normal cells. A greater anti-proliferative effect was also observed in MS13 treated colon cancer cells compared to curcumin at 48 and 72 h. Subsequent analysis on the induction of apoptosis showed that MS13 treated cells exhibited morphological features associated with apoptosis. The findings are also consistent with cellular apoptotic activities shown by increased caspase-3 activity and decreased Bcl-2 protein level in both colon cancer cell lines. In conclusion, MS13 able to suppress colon cancer cell growth by inhibiting cell proliferation and induce apoptosis in primary and metastatic human colon cancer cells.
High-Pressure Behaviors of Ag2S Nanosheets: An in Situ High-Pressure X-Ray Diffraction Research
Authors: Liu Ran , Liu Bo , Li Quan-Jun , Liu Bing-Bing
Published: August 2020

An in situ high-pressure X-ray diffraction study was performed on Ag2S nanosheets, with an average lateral size of 29 nm and a relatively thin thickness. Based on the experimental data, we demonstrated that under high pressure, the samples experienced two different high-pressure structural phase transitions up to 29.4 GPa: from monoclinic P21/n structure (phase I, α-Ag2S) to orthorhombic P212121 structure (phase II) at 8.9 GPa and then to monoclinic P21/n structure (phase III) at 12.4 GPa. The critical phase transition pressures for phase II and phase III are approximately 2–3 GPa higher than that of 30 nm Ag2S nanoparticles and bulk materials. Additionally, phase III was stable up to the highest pressure of 29.4 GPa. Bulk moduli of Ag2S nanosheets were obtained as 73(6) GPa for phase I and 141(4) GPa for phase III, which indicate that the samples are more difficult to compress than their bulk counterparts and some other reported Ag2S nanoparticles. Further analysis suggested that the nanosize effect arising from the smaller thickness of Ag2S nanosheets restricts the relative position slip of the interlayer atoms during the compression, which leads to the enhancing of phase stabilities and the elevating of bulk moduli.
The Magnetic Proximity Effect Induced Large Valley Splitting in 2D InSe/FeI2 Heterostructures
Authors: Lin Yifeng , Zhang Changcheng , Guan Lixiu , Sun Zhipeng , Tao Junguang
Published: August 2020

The manipulation of valley splitting has potential applications in valleytronics, which lacks in pristine two-dimensional (2D) InSe. Here, we demonstrate that valley physics in InSe can be activated via the magnetic proximity effect exerted by ferromagnetic FeI2 substrate with spin-orbit coupling. The valley splitting energy can reach 48 meV, corresponding to a magnetic exchange field of ~800 T. The system also presents magnetic anisotropy behavior with its easy magnetization axis tunable from in-plane to out-of-plane by the stacking configurations and biaxial tensile strain. The d-orbital-resolved magnetic anisotropic energy contributions indicate that the tensile strain effect arises from the increase of hybridization between minority Fe dxy and dx2−y2 states. Our results reveal that the magnetic proximity effect is an effective approach to stimulate the valley properties in InSe to extend its spintronic applications, which is expected to be feasible in other group-III monochalcogenides.
Dehydrogenation of Ethylene on Supported Palladium Nanoparticles: A Double View from Metal and Hydrocarbon Sides
Authors: Usoltsev Oleg A. , Pnevskaya Anna Yu. , Kamyshova Elizaveta G. , Tereshchenko Andrei A. , Skorynina Alina A. , Zhang Wei , Yao Tao , Bugaev Aram L. , Soldatov Alexander V.
Published: August 2020

Adsorption of ethylene on palladium, a key step in various catalytic reactions, may result in a variety of surface-adsorbed species and formation of palladium carbides, especially under industrially relevant pressures and temperatures. Therefore, the application of both surface and bulk sensitive techniques under reaction conditions is important for a comprehensive understanding of ethylene interaction with Pd-catalyst. In this work, we apply in situ X-ray absorption spectroscopy, X-ray diffraction and infrared spectroscopy to follow the evolution of the bulk and surface structure of an industrial catalysts consisting of 2.6 nm supported palladium nanoparticles upon exposure to ethylene under atmospheric pressure at 50 °C. Experimental results were complemented by ab initio simulations of atomic structure, X-ray absorption spectra and vibrational spectra. The adsorbed ethylene was shown to dehydrogenate to C2H3, C2H2 and C2H species, and to finally decompose to palladium carbide. Thus, this study reveals the evolution pathway of ethylene on industrial Pd-catalyst under atmospheric pressure at moderate temperatures, and provides a conceptual framework for the experimental and theoretical investigation of palladium-based systems, in which both surface and bulk structures exhibit a dynamic nature under reaction conditions.
Covalently Conjugated Gold–Porphyrin Nanostructures
Authors: Spitaleri Luca , Gangemi Chiara M. A. , Purrello Roberto , Nicotra Giuseppe , Trusso Sfrazzetto Giuseppe , Casella Girolamo , Casarin Maurizio , Gulino Antonino
Published: August 2020

Gold nanoparticles show important electronic and optical properties, owing to their size, shape, and electronic structures. Indeed, gold nanoparticles containing no more than 30–40 atoms are only luminescent, while nanometer-sized gold nanoparticles only show surface plasmon resonance. Therefore, it appears that gold nanoparticles can alternatively be luminescent or plasmonic and this represents a severe restriction for their use as optical material. The aim of our study was the fabrication of nanoscale assembly of Au nanoparticles with bi-functional porphyrin molecules that work as bridges between different gold nanoparticles. This functional architecture not only exhibits a strong surface plasmon, due to the Au nanoparticles, but also a strong luminescence signal due to porphyrin molecules, thus, behaving as an artificial organized plasmonic and fluorescent network. Mutual Au nanoparticles–porphyrin interactions tune the Au network size whose dimension can easily be read out, being the position of the surface plasmon resonance strongly indicative of this size. The present system can be used for all the applications requiring plasmonic and luminescent emitters.
Antiviral Potential of Nanoparticles—Can Nanoparticles Fight Against Coronaviruses?
Authors: Gurunathan Sangiliyandi , Qasim Muhammad , Choi Youngsok , Do Jeong Tae , Park Chankyu , Hong Kwonho , Kim Jin-Hoi , Song Hyuk
Published: August 2020

Infectious diseases account for more than 20% of global mortality and viruses are responsible for about one-third of these deaths. Highly infectious viral diseases such as severe acute respiratory (SARS), Middle East respiratory syndrome (MERS) and coronavirus disease (COVID-19) are emerging more frequently and their worldwide spread poses a serious threat to human health and the global economy. The current COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of 27 July 2020, SARS-CoV-2 has infected over 16 million people and led to the death of more than 652,434 individuals as on 27 July 2020 while also causing significant economic losses. To date, there are no vaccines or specific antiviral drugs to prevent or treat COVID-19. Hence, it is necessary to accelerate the development of antiviral drugs and vaccines to help mitigate this pandemic. Non-Conventional antiviral agents must also be considered and exploited. In this regard, nanoparticles can be used as antiviral agents for the treatment of various viral infections. The use of nanoparticles provides an interesting opportunity for the development of novel antiviral therapies with a low probability of developing drug resistance compared to conventional chemical-based antiviral therapies. In this review, we first discuss viral mechanisms of entry into host cells and then we detail the major and important types of nanomaterials that could be used as antiviral agents. These nanomaterials include silver, gold, quantum dots, organic nanoparticles, liposomes, dendrimers and polymers. Further, we consider antiviral mechanisms, the effects of nanoparticles on coronaviruses and therapeutic approaches of nanoparticles. Finally, we provide our perspective on the future of nanoparticles in the fight against viral infections.
Multifunctional Fe3O4-Au Nanoparticles for the MRI Diagnosis and Potential Treatment of Liver Cancer
Authors: Kozenkova Elena , Levada Kateryna , Efremova Maria V. , Omelyanchik Alexander , Nalench Yulia A. , Garanina Anastasiia S. , Pshenichnikov Stanislav , Zhukov Dmitry G. , Lunov Oleg , Lunova Mariia , Kozenkov Ivan , Innocenti Claudia , Albino Martin , Abakumov Maxim A. , Sangregorio Claudio , Rodionova Valeria
Published: August 2020

Heterodimeric nanoparticles comprising materials with different functionalities are of great interest for fundamental research and biomedical/industrial applications. In this work, Fe3O4-Au nano-heterostructures were synthesized by a one-step thermal decomposition method. The hybrid nanoparticles comprise a highly crystalline 12 nm magnetite octahedron decorated with a single noble metal sphere of 6 nm diameter. Detailed analysis of the nanoparticles was performed by UV-visible spectroscopy, magnetometry, calorimetry and relaxometry studies. The cytotoxic effect of the nanoparticles in the human hepatic cell line Huh7 and PLC/PRF/5-Alexander was also assessed. These Fe3O4-Au bifunctional nanoparticles showed no significant cytotoxicity in these two cell lines. The nanoparticles showed a good theranostic potential for liver cancer treatment, since the r2 relaxivity (166.5 mM−1·s−1 and 99.5 mM−1·s−1 in water and HepG2 cells, respectively) is higher than the corresponding values for commercial T2 contrast agents and the Specific Absorption Rate (SAR) value obtained (227 W/gFe) is enough to make them suitable as heat mediators for Magnetic Fluid Hyperthermia. The gold counterpart can further allow the conjugation with different biomolecules and the optical sensing.
Comparison of Poly-A+ Selection and rRNA Depletion in Detection of lncRNA in Two Equine Tissues Using RNA-seq
Authors: Dahlgren Anna R. , Scott Erica Y. , Mansour Tamer , Hales Erin N. , Ross Pablo J. , Kalbfleisch Theodore S. , MacLeod James N. , Petersen Jessica L. , Bellone Rebecca R. , Finno Carrie J.
Published: August 2020

Long non-coding RNAs (lncRNAs) are untranslated regulatory transcripts longer than 200 nucleotides that can play a role in transcriptional, post-translational, and epigenetic regulation. Traditionally, RNA-sequencing (RNA-seq) libraries have been created by isolating transcriptomic RNA via poly-A+ selection. In the past 10 years, methods to perform ribosomal RNA (rRNA) depletion of total RNA have been developed as an alternative, aiming for better coverage of whole transcriptomic RNA, both polyadenylated and non-polyadenylated transcripts. The purpose of this study was to determine which library preparation method is optimal for lncRNA investigations in the horse. Using liver and cerebral parietal lobe tissues from two healthy Thoroughbred mares, RNA-seq libraries were prepared using standard poly-A+ selection and rRNA-depletion methods. Averaging the two biologic replicates, poly-A+ selection yielded 327 and 773 more unique lncRNA transcripts for liver and parietal lobe, respectively. More lncRNA were found to be unique to poly-A+ selected libraries, and rRNA-depletion identified small nucleolar RNA (snoRNA) to have a higher relative expression than in the poly-A+ selected libraries. Overall, poly-A+ selection provides a more thorough identification of total lncRNA in equine tissues while rRNA-depletion may allow for easier detection of snoRNAs.
Antiviral Properties of Flavonoids and Delivery Strategies
Authors: Ninfali Paolino , Antonelli Antonella , Magnani Mauro , Scarpa Emanuele Salvatore
Published: August 2020

This review summarizes the latest advancements in phytochemicals as functional antiviral agents. We focused on flavonoids, like apigenin, vitexin, quercetin, rutin and naringenin, which have shown a wide range of biological effects including antiviral activities. The molecular mechanisms of their antiviral effects mainly consist in the inhibition of viral neuraminidase, proteases and DNA/RNA polymerases, as well as in the modification of various viral proteins. Mixtures of different flavonoids or combination of flavonoids with antiviral synthetic drugs provide an enhancement of their antiviral effects. Recent strategies in drug delivery significantly contribute to overcoming the low bioavailability of flavonoids. Frequent viral infections worldwide have led to the need for new effective antiviral agents, which can be identified among the various phytochemicals. In this light, screening the antiviral activities of a cocktail of flavonoids would be advantageous in order to prevent viral infections and improve current antiviral therapies.
Effect of Maternal Diet and Milk Lipid Composition on the Infant Gut and Maternal Milk Microbiomes
Authors: Babakobi Michal Dayagi , Reshef Leah , Gihaz Shalev , Belgorodsky Bogdan , Fishman Ayelet , Bujanover Yoram , Gophna Uri
Published: August 2020

Inter-subject variability in human milk microbiome is well known; however, its origins and possible relationship to the mother’s diet are still debated. We investigated associations between maternal nutrition, milk fatty acids composition and microbiomes in mother–infant dyads. Breast milk and infant fecal samples were collected across three time points (one week, one month and three months postpartum) from 22 mother–infant pairs. Food frequency questionnaires for the months of pregnancy and three months postpartum were collected. Milk fatty acids were analyzed by GC–MS and the microbiome in breast milk and infant feces was determined by 16S rRNA sequencing. Statistical interactions were computed using Spearman’s method and corrected for multiple comparisons. We found significant negative correlation between Streptococcus relative abundance in maternal milk and intake of unsaturated fatty acids and folic acid at one month postpartum. At three months postpartum, vitamin B-12 consumption was significantly associated with a single operational taxonomic unit belonging to Streptococcus. Comparison between milk microbiome and lipid composition showed, one-month postpartum, significant negative correlation between Streptococcus relative abundance and the abundance of oleic acid. Additional correlations were detected between Staphylococcus hominis and two medium-chain saturated fatty acids. Our results reinforce the hypothesis that maternal nutrition may affect milk microbiome.
A Clinical Tool to Predict Low Serum Selenium in Patients with Worsening Heart Failure
Authors: Al-Mubarak Ali A. , Grote Beverborg Niels , Anker Stefan D. , Samani Nilesh J. , Dickstein Kenneth , Filippatos Gerasimos , van Veldhuisen Dirk Jan , Voors Adriaan A. , Bomer Nils , van der Meer Peter
Published: August 2020

Selenium is an essential micronutrient, and a low selenium concentration (<100 µg/L) is associated with a poorer quality of life and exercise capacity, and an impaired prognosis in patients with worsening heart failure. Measuring selenium concentrations routinely is laborious and costly, and although its clinical utility is yet to be proven, an easy implemented model to predict selenium status is desirable. A stepwise multivariable logistic regression analysis was performed using routinely measured clinical factors. Low selenium was independently predicted by: older age, lower serum albumin, higher N-terminal pro-B-type natriuretic peptide levels, worse kidney function, and the presence of orthopnea and iron deficiency. A 10-points risk-model was developed, and a score of ≥6 points identified >80% of patients with low selenium (sensitivity of 44%, specificity of 80%). Given that selenium and iron overlap in their physiological roles, we evaluated the shared determinants and prognostic associates. Both deficiencies shared similar clinical characteristics, including the model risk factors and, in addition, a low protein intake and high levels of C-reactive protein. Low selenium was associated with a similar or worse prognosis compared to iron deficiency. In conclusion, although it is difficult to exclude low selenium based on clinical characteristics alone, we provide a prediction tool which identifies heart failure patients at higher risk of having a low selenium status.
Leptin Distribution in Rat Foetal and Extraembryonic Tissues in Late Gestation: A Physiological View of Amniotic Fluid Leptin
Authors: Yau-Qiu Zhi Xin , Picó Catalina , Rodríguez Ana María , Palou Andreu
Published: August 2020

Prenatal leptin is key to regulating foetal growth and early metabolic programming. The presence of intact leptin in rat foetal (at late gestation) and neonatal (immediately after birth) stomach content and mucosa has been previously described, suggesting that it may act as a regulatory nutrient for the neonate rats, be internalised by the stomach, and play a physiological role early in life, which requires to be further investigated, including its origin. We aimed to study the ontogeny of the presence of leptin in the foetal stomach and key extraembryonic tissues in rats at late gestation (days 18–21). Leptin concentration was determined by enzyme-linked immunosorbent assay, and placental leptin immunolocalisation was analysed by immunohistochemistry. Leptin showed a sudden appearance in the amniotic fluid (AF) at day 20 of gestation, gastric content (swallowed AF), stomach, and umbilical cord, significantly increasing at day 21. Leptin levels in these fluids and tissues were positively correlated. In the placenta, leptin was detectable at all the studied days, but its localisation changed from widespread throughout the placenta at day 18 to well-defined in the labyrinth zone from day 19 onwards. The results support a possible internalisation of AF leptin by the immature stomach of near-term foetuses and suggest that changes in placental leptin localisation might help to explain the sudden appearance of leptin in AF at gestational day 20, with potential physiological significance regarding short-term feeding control and metabolic programming in the developing offspring.
Survival of Lassa Virus in Blood and Tissue Culture Media and in a Small Particle Aerosol
Authors: Smither Sophie J , Eastaugh Lin S , Findlay James S , O’Brien Lyn M , Lever Mark S
Published: August 2020

Knowledge of the survival and stability of a pathogen is important for understanding its risk, reducing its transmission, and establishing control measures. Lassa virus is endemic in West Africa, causes severe disease, and is an emerging pathogen of concern. Our study examined the survival of Lassa virus in blood and tissue culture media at two different temperatures. The stability of Lassa virus held within a small particle aerosol was also measured. In liquids, Lassa virus was found to decay more quickly at 30 °C compared to room temperature. Sealed samples protected from environmental desiccation were more stable than samples open to the environment. In a small particle aerosol, the decay rate of Lassa virus was determined at 2.69% per minute. This information can contribute to risk assessments and inform mitigation strategies in the event of an outbreak of Lassa virus.
In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii
Authors: Hahn Hye Jee , Escrig Jose Ignacio , Shing Brian , Debnath Anjan
Published: August 2020

Acanthamoeba keratitis (AK) can occur in healthy individuals wearing contact lenses and it is a painful, blinding infection of the cornea caused by a free-living ameba Acanthamoeba. Current treatment for AK relies on a combination of chlorhexidine, propamidine isethionate, and polyhexamethylene biguanide. However, the current regimen includes an aggressive disinfectant and in 10% of cases recurrent infection ensues. Therefore, development of efficient and safe drugs is a critical unmet need to avert blindness. Acanthamoeba sterol biosynthesis includes two essential enzymes HMG-CoA reductase (HMGR) and sterol 14-demethylase (CYP51), and we earlier identified a CYP51 inhibitor isavuconazole that demonstrated nanomolar potency against A. castellanii trophozoites. In this study, we investigated the effect of well-tolerated HMGR inhibitors and identified pitavastatin that is active against trophozoites of three different clinical strains of A.castellanii. Pitavastatin demonstrated an EC50 of 0.5 to 1.9 µM, depending on strains. Combination of pitavastatin and isavuconazole is synergistic and led to 2- to 9-fold dose reduction for pitavastatin and 11- to 4000-fold dose reduction for isavuconazole to achieve 97% of growth inhibition. Pitavastatin, either alone or in combination with isavuconazole, may lead to repurposing for the treatment of Acanthamoeba keratitis.
Lack of Evidence on the Susceptibility of Ticks and Wild Rodent Species to PCV3 Infection
Authors: Grassi Laura , Tagliapietra Valentina , Rizzoli Annapaola , Martini Marco , Drigo Michele , Franzo Giovanni , Menandro Maria Luisa
Published: August 2020

Porcine circovirus 3 (PCV3) is an emerging virus, first detected in 2016 and widespread in the swine industry. Although not considered a primary pathogen, PCV3 is potentially linked to several clinical conditions that threaten swine farming. Wild boars are considered the main reservoir species for PCV3 infection in the wild, but recent detection in roe deer, chamois and associated ticks has complicated our understanding of its epidemiology. Much emphasis has been placed on ticks, as competent vectors, and wild rodents, which typically feed immature tick stages. The aim of this study was to clarify whether wild rodent species and associated ticks are susceptible to PCV3 infection and involved in its spread. Wild small mammals’ serum samples and hosted ticks were, therefore, collected from areas where no wild boars were present and tested by PCR, targeting the PCV3 rep gene. A total of 90 yellow-necked mice (Apodemus flavicollis), two wood mice (A. sylvaticus), 26 bank voles (Myodes glareolus) and 262 Ixodes spp. ticks were investigated. PCV3 DNA was not detected in serum or in tick samples. These findings support the hypothesis that the investigated species do not have an actual role as PCV3 reservoirs. Further studies would be necessary to state whether these species, or others that we did not test, are involved in PCV3 infection spread—in particular when susceptible species share the same habitat.
Relevant Features of Polypharmacologic Human-Target Antimicrobials Discovered by Machine-Learning Techniques
Authors: Nava Lara Rodrigo A. , Beltrán Jesús A. , Brizuela Carlos A. , Del Rio Gabriel
Published: August 2020

Polypharmacologic human-targeted antimicrobials (polyHAM) are potentially useful in the treatment of complex human diseases where the microbiome is important (e.g., diabetes, hypertension). We previously reported a machine-learning approach to identify polyHAM from FDA-approved human targeted drugs using a heterologous approach (training with peptides and non-peptide compounds). Here we discover that polyHAM are more likely to be found among antimicrobials displaying a broad-spectrum antibiotic activity and that topological, but not chemical features, are most informative to classify this activity. A heterologous machine-learning approach was trained with broad-spectrum antimicrobials and tested with human metabolites; these metabolites were labeled as antimicrobials or non-antimicrobials based on a naïve text-mining approach. Human metabolites are not commonly recognized as antimicrobials yet circulate in the human body where microbes are found and our heterologous model was able to classify those with antimicrobial activity. These results provide the basis to develop applications aimed to design human diets that purposely alter metabolic compounds proportions as a way to control human microbiome.
A Comprehensive Spectroscopic Analysis of the Ibuprofen Binding with Human Serum Albumin, Part I
Authors: Ploch-Jankowska Anna , Pentak Danuta
Published: August 2020

Human serum albumin (HSA) plays a fundamental role in the human body. It takes part in the transport of exogenic and endogenic substances, especially drugs. Ibuprofen (IBU) is one of the most commonly used non-steroidal anti-inflammatory drugs, used for pain relief, fever relief, and for anti-inflammatory purposes. The binding of ligands with HSA is a significant factor which determines the toxicity and the therapeutic dosages of these substances. The aim of this study was to compare the degree of ibuprofen binding with human serum albumin at various temperatures and protein solution pH values. In order to evaluate conformational changes in HSA caused by interaction with ibuprofen, spectrophotometric (first and second derivatives of the UV-VIS spectrum), and spectrofluorometric analyses were performed concerning the mutual interactions of IBU-HSA. The use of fluorescent spectroscopy allowed for recording fluorescent emissive spectra of HSA (5 × 10−6 mol/dm3) without and with the presence of ibuprofen (1 × 10−5–1 × 10−4 mol/dm3) at temperatures of 308, 310, 312, and 314 K at pH values of 6.5, 6.8, 7.4, 7.8, and 8.1. System fluorescence was excited by radiation of wavelengths of λex = 275 nm and λex = 295 nm. Based on this, original and modified Stern-Volmer, Scatchard, Klotz and Hill curves were determined. The data that were obtained showed a significant effect of temperature and pH of the human serum albumin solution on the strength and type of interaction of ibuprofen with HSA.
Metformin Restores the Drug Sensitivity of MCF-7 Cells Resistant Derivates via the Cooperative Modulation of Growth and Apoptotic-Related Pathways
Authors: Sorokin Danila , Shchegolev Yuri , Scherbakov Alexander , Ryabaya Oxana , Gudkova Margarita , Berstein Lev , Krasil’nikov Mikhail
Published: August 2020

The phenomenon of the primary or acquired resistance of cancer cells to antitumor drugs is among the key problems of oncology. For breast cancer, the phenomenon of the resistance to hormonal or target therapy may be based on the numerous mechanisms including the loss or mutation of estrogen receptor, alterations of antiapoptotic pathways, overexpression of growth-related signaling proteins, etc. The perspective approaches for overcoming the resistance may be based on the usage of compounds such as inhibitors of the cell energetic metabolism. Among the latter, the antidiabetic drug metformin exerts antitumor activity via the activation of AMPK and the subsequent inhibition of mTOR signaling. The experiments were performed on the ERα-positive MCF-7 breast cancer cells, the MCF-7 sublines resistant to tamoxifen (MCF-7/T) and rapamycin (MCF-7/Rap), and on triple-negative MDA-MB-231 breast cancer cells. We have demonstrated metformin’s ability to enhance the cytostatic activity of the tamoxifen and rapamycin on both parent MCF-7 cells and MCF-7-resistant derivates mediated via the suppression of mTOR signaling and growth-related transcriptional factors. The cooperative effect of metformin and tested drugs was realized in an estrogen-independent manner, and, in the case of tamoxifen, was associated with the activation of apoptotic cell death. Similarly, the stimulation of apoptosis under metformin/tamoxifen co-treatment was shown to occur in the MCF-7 cells after steroid depletion as well as in the ERα-negative MDA-MB-231 cells. We conclude that metformin co-treatment may be used for the increase and partial restoration of the cancer cell sensitivity to hormonal and target drugs. Moreover, the combination of metformin with tamoxifen induces the apoptotic death in the ERα-negative breast cancer cells opening the additional perspectives in the treatment of estrogen-independent breast tumors.
Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib
Authors: Hussaarts Koen G. A. M. , van Doorn Leni , Eechoute Karel , Damman Jeffrey , Fu Qiang , van Doorn Nadia , Eisenmann Eric D. , Gibson Alice A. , Oomen-de Hoop Esther , de Bruijn Peter , Baker Sharyn D. , Koolen Stijn L. W. , van Gelder Teun , van Leeuwen Roelof W. F. , Mathijssen Ron H. J. , Sparreboom Alex , Bins Sander
Published: August 2020

Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200–800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2–15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC0–12 h) as primary endpoint. During concomitant probenecid, sorafenib plasma AUC0–12 h decreased by 27% (90% CI: −38% to −14%; P < 0.01). Furthermore, peak and trough levels of sorafenib, as well as sorafenib concentrations in skin, decreased to a similar extent in the presence of probenecid. The metabolic ratio of sorafenib-glucuronide to parent drug increased (+29%) in the presence of probenecid. A decrease in systemic sorafenib concentrations during probenecid administration seems to have influenced cutaneous concentrations. Since sorafenib-glucuronide concentrations increased compared with sorafenib and sorafenib-N-oxide, probenecid may have interrupted enterohepatic circulation of sorafenib by inhibition of the organic anion transporting polypeptides 1B1 (OATP1B1). Sorafenib treatment with probenecid is, therefore, not bioequivalent to sorafenib monotherapy. A clear effect of probenecid on sorafenib toxicity could not be identified in this study.
Advanced Characterization of Imiquimod-Induced Psoriasis-Like Mouse Model
Authors: Jabeen Mehwish , Boisgard Anne-Sophie , Danoy Alix , El Kholti Naima , Salvi Jean-Paul , Boulieu Roselyne , Fromy Bérengère , Verrier Bernard , Lamrayah Myriam
Published: August 2020

Many autoimmune disorders such as psoriasis lead to the alteration of skin components which generally manifests as unwanted topical symptoms. One of the most widely approved psoriasis-like animal models is the imiquimod (IMQ)-induced mouse model. This representation mimics various aspects of the complex cutaneous pathology and could be appropriate for testing topical treatment options. We perform a thorough characterization of this model by assessing some parameters that are not fully described in the literature, namely a precise description of skin disruption. It was evaluated by transepidermal water loss measurements and analyses of epidermis swelling as a consequence of keratinocyte hyperproliferation. The extent of neo-angiogenesis and hypervascularity in dermis were highlighted by immunostaining. Moreover, we investigated systemic inflammation through cytokines levels, spleen swelling and germinal centers appearance in draining lymph nodes. The severity of all parameters was correlated to IMQ concentration in skin samples. This study outlines new parameters of interest useful to assess this model. We highlight the skin barrier disruption and report a systemic inflammatory reaction occurring at distance both in spleen and lymph nodes. These newly identified biological endpoints could be exploited to investigate the efficacy of therapeutic candidates for psoriasis and more extensively for several other skin inflammatory diseases.
In Vivo Electroporation-Mediated, Intrahepatic Alpha1 Antitrypsin Gene Transfer Reduces Pulmonary Emphysema in Pallid Mice
Authors: Sutter Marco , Cremona Tiziana , Nita Izabela , Cavarra Eleonora , Lungarella Giuseppe , Lewis Eli , Schittny Johannes , Geiser Thomas , Gazdhar Amiq
Published: August 2020

Rationale: Mutation in the alpha1 antitrypsin (AAT) gene leads to low circulating levels of AAT, which is associated with several disease processes including pulmonary emphysema. The standard of care relies on substitution with plasma-purified AAT. We studied a novel approach to obtain sustained therapeutic levels of circulating AAT using nonviral in vivo electroporation-mediated gene transfer to the liver. Methods: In vivo intrahepatic electroporation-mediated human AAT gene transfer was performed in C57 Bl/6J mice carrying a genetic deficiency of murine AAT (pallid mice) and suffering from pulmonary emphysema. The animals were evaluated for lung function using flexiVent and detailed stereological assessments. Lung neutrophilic burden was assessed. Results: Pallid mice showed morphologically detectable pulmonary emphysema. Thirty days after in vivo electroporation-mediated gene transfer directly aimed at the liver, circulating human AAT was elevated and lung function was significantly improved compared to non-treated pallid mice. Stereological analysis revealed a reduction in pulmonary emphysema. Conclusion: Our data indicate that in vivo intrahepatic electroporation-mediated gene transfer of AAT is a safe and efficient procedure resulting in reduction of pulmonary emphysema in pallid mice.
Subcellular Roles of Glutathione in Mediating Plant Defense during Biotic Stress
Authors: Zechmann Bernd
Published: August 2020

Glutathione and reactive oxygen species (ROS) play important roles, within different cell compartments, in activating plant defense and the development of resistance. In mitochondria, the accumulation of ROS and the change of glutathione towards its oxidized state leads to mitochondrial dysfunction, activates cell death, and triggers resistance. The accumulation of glutathione in chloroplasts and peroxisomes at the early stages of plant pathogen interactions is related to increased tolerance and resistance. The collapse of the antioxidative system in these two cell compartments at the later stages leads to cell death through retrograde signaling. The cytosol can be considered to be the switchboard during biotic stress where glutathione is synthesized, equally distributed to, and collected from different cell compartments. Changes in the redox state of glutathione and the accumulation of ROS in the cytosol during biotic stress can initiate the activation of defense genes in nuclei through pathways that involve salicylic acid, jasmonic acid, auxins, and abscisic acid. This review dissects the roles of glutathione in individual organelles during compatible and incompatible bacterial, fungal, and viral diseases in plants and explores the subcelluar roles of ROS, glutathione, ascorbate, and related enzymes in the development of resistance.
An Abiotic Stress Responsive U-Box E3 Ubiquitin Ligase Is Involved in OsGI-Mediating Diurnal Rhythm Regulating Mechanism
Authors: Yoo Yo-Han , Jiang Xu , Jung Ki-Hong
Published: August 2020

The plant U-box (PUB) protein is the E3 ligase that plays roles in the degradation or post-translational modification of target proteins. In rice, 77 U-box proteins were identified and divided into eight classes according to the domain configuration. We performed a phylogenomic analysis by integrating microarray expression data under abiotic stress to the phylogenetic tree context. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) expression analyses identified that eight, twelve, and eight PUB family genes are associated with responses to drought, salinity, and cold stress, respectively. In total, 16 genes showed increased expression in response to three abiotic stresses. Among them, the expression of OsPUB2 in class II and OsPUB33, OsPUB39, and OsPUB41 in class III increased in all three abiotic stresses, indicating their involvement in multiple abiotic stress regulation. In addition, we identified the circadian rhythmic expression for three out of 16 genes responding to abiotic stress through meta-microarray expression data analysis. Among them, OsPUB4 is predicted to be involved in the rice GIGANTEA (OsGI)-mediating diurnal rhythm regulating mechanism. In the last, we constructed predicted protein-protein interaction networks associated with OsPUB4 and OsGI. Our analysis provides essential information to improve environmental stress tolerance mediated by the PUB family members in rice.
A Genome-Wide Survey of MATE Transporters in Brassicaceae and Unveiling Their Expression Profiles under Abiotic Stress in Rapeseed
Authors: Qiao Cailin , Yang Jing , Wan Yuanyuan , Xiang Sirou , Guan Mingwei , Du Hai , Tang Zhanglin , Lu Kun , Li Jiana , Qu Cunmin
Published: August 2020

The multidrug and toxic compound extrusion (MATE) protein family is important in the export of toxins and other substrates, but detailed information on this family in the Brassicaceae has not yet been reported compared to Arabidopsis thaliana. In this study, we identified 57, 124, 81, 85, 130, and 79 MATE genes in A. thaliana, Brassica napus, Brassica oleracea, Brassica rapa, Brassica juncea, and Brassica nigra, respectively, which were unevenly distributed on chromosomes owing to both tandem and segmental duplication events. Phylogenetic analysis showed that these genes could be classified into four subgroups, shared high similarity and conservation within each group, and have evolved mainly through purifying selection. Furthermore, numerous B. napusMATE genes showed differential expression between tissues and developmental stages and between plants treated with heavy metals or hormones and untreated control plants. This differential expression was especially pronounced for the Group 2 and 3 BnaMATE genes, indicating that they may play important roles in stress tolerance and hormone induction. Our results provide a valuable foundation for the functional dissection of the different BnaMATE homologs in B. napus and its parental lines, as well as for the breeding of more stress-tolerant B. napus genotypes.