bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term impact of maternal high-fat diet on offspring cardiac health: role of micro-RNA biogenesis
Authors: Siddeek Benazir , Mauduit Claire , Chehade Hassib , Blin Guillaume , Liand Marjorie , Chindamo Mariapia , Benahmed Mohamed , Simeoni Umberto
Published: March 2019

Heart failure is a worldwide leading cause of death. Diet and obesity are particularly of high concern in heart disease etiology. Gravely, altered nutrition during developmental windows of vulnerability can have long-term impact on heart health; however, the underlying mechanisms are poorly understood. In the understanding of the initiation of chronic diseases related to developmental exposure to environmental challenges, deregulations in epigenetic mechanisms including micro-RNAs have been proposed as key events. In this context, we aimed at delineating the role of micro-RNAs in the programming of cardiac alterations induced by early developmental exposure to nutritional imbalance. To reach our aim, we developed a human relevant model of developmental exposure to nutritional imbalance by maternally exposing rat to high-fat diet during gestation and lactation. In this model, offspring exposed to maternal high-fat diet developed cardiac hypertrophy and increased extracellular matrix depot compared to those exposed to chow diet. Microarray approach performed on cardiac tissue allowed the identification of a micro-RNA subset which was down-regulated in high-fat diet-exposed animals and which were predicted to regulate transforming growth factor-beta (TGFβ)-mediated remodeling. As indicated by in vitro approaches and gene expression measurement in the heart of our animals, decrease in DiGeorge critical region 8 (DGCR8) expression, involved in micro-RNA biogenesis, seems to be a critical point in the alterations of the micro-RNA profile and the TGFβ-mediated remodeling induced by maternal exposure to high-fat diet. Finally, increasing DGCR8 activity and/or expression through hemin treatment in vitro revealed its potential in the rescue of the pro-fibrotic phenotype in cardiomyocytes driven by DGCR8 decrease. These findings suggest that cardiac alterations induced by maternal exposure to high-fat diet is related to abnormalities in TGFβ pathway and associated with down-regulated micro-RNA processing. Our study highlighted DGCR8 as a potential therapeutic target for heart diseases related to early exposure to dietary challenge.
Degenerate conic anchoring and colloidal elastic dipole-hexadecapole transformations
Authors: Zhou Ye , Senyuk Bohdan , Zhang Rui , Smalyukh Ivan I. , de Pablo Juan J.
Published: March 2019

The defect structure associated with a colloid in a nematic liquid crystal is dictated by molecular orientation at the colloid surface. Perpendicular or parallel orientations to the surface lead to dipole-like or quadrupole-like defect structures. However, the so-called elastic hexadecapole discovered recently, has been assumed to result from a conic anchoring condition. In order to understand it at a fundamental level, a model for this anchoring is introduced here in the context of a Landau-de Gennes free energy functional. We investigate the evolution of defect configurations, as well as colloidal interactions, by tuning the preferred tilt angle (θe). The model predicts an elastic dipole whose stability decreases asθeincreases, along with a dipole-hexadecapole transformation, which are confirmed by our experimental observations. Taken together, our results suggest that previously unanticipated avenues may exist for design of self-assembled structures via control of tilt angle.
State-of-the-art global models underestimate impacts from climate extremes
Authors: Schewe Jacob , Gosling Simon N. , Reyer Christopher , Zhao Fang , Ciais Philippe , Elliott Joshua , Francois Louis , Huber Veronika , Lotze Heike K. , Seneviratne Sonia I. , van Vliet Michelle T. H. , Vautard Robert , Wada Yoshihide , Breuer Lutz , Büchner Matthias , Carozza David A. , Chang Jinfeng , Coll Marta , Deryng Delphine , de Wit Allard , Eddy Tyler D. , Folberth Christian , Frieler Katja , Friend Andrew D. , Gerten Dieter , Gudmundsson Lukas , Hanasaki Naota , Ito Akihiko , Khabarov Nikolay , Kim Hyungjun , Lawrence Peter , Morfopoulos Catherine , Müller Christoph , Müller Schmied Hannes , Orth René , Ostberg Sebastian , Pokhrel Yadu , Pugh Thomas A. M. , Sakurai Gen , Satoh Yusuke , Schmid Erwin , Stacke Tobias , Steenbeek Jeroen , Steinkamp Jörg , Tang Qiuhong , Tian Hanqin , Tittensor Derek P. , Volkholz Jan , Wang Xuhui , Warszawski Lila
Published: March 2019

Global impact models represent process-level understanding of how natural and human systems may be affected by climate change. Their projections are used in integrated assessments of climate change. Here we test, for the first time, systematically across many important systems, how well such impact models capture the impacts of extreme climate conditions. Using the 2003 European heat wave and drought as a historical analogue for comparable events in the future, we find that a majority of models underestimate the extremeness of impacts in important sectors such as agriculture, terrestrial ecosystems, and heat-related human mortality, while impacts on water resources and hydropower are overestimated in some river basins; and the spread across models is often large. This has important implications for economic assessments of climate change impacts that rely on these models. It also means that societal risks from future extreme events may be greater than previously thought.
Genesis of electron deficient Pt1(0) in PDMS-PEG aggregates
Authors: Liu Kairui , Hou Guangjin , Mao Jingbo , Xu Zhanwei , Yan Peifang , Li Huixiang , Guo Xinwen , Bai Shi , Zhang Z. Conrad
Published: March 2019

While numerous single atoms stabilized by support surfaces have been reported, the synthesis of in-situ reduced discrete metal atoms weakly coordinated and stabilized in liquid media is a more challenging goal. We report the genesis of mononuclear electron deficient Pt1(0) by reducing H2PtCl6 in liquid polydimethylsiloxane-polyethylene glycol (PDMS-PEG) (Pt1@PDMS-PEG). UV–Vis, far-IR, and X-ray photoelectron spectroscopies evidence the reduction of H2PtCl6. CO infrared, and 195Pt and 13C NMR spectroscopies provide strong evidence of Pt1(0), existing as a pseudo-octahedral structure of (R1OR2)2Pt(0)Cl2H2 (R1 and R2 are H, C, or Si groups accordingly). The weakly coordinated (R1OR2)2Pt(0)Cl2H2 structure and electron deficient Pt1(0) have been validated by comparing experimental and DFT calculated 195Pt NMR spectra. The H+ in protic state and the Cl− together resemble HCl as the weak coordination. Neutralization by a base causes the formation of Pt nanoparticles. The Pt1@PDMS-PEG shows ultrahigh activity in olefin hydrosilylation with excellent terminal adducts selectivity.
Thermochemiluminescent peroxide crystals
Authors: Schramm Stefan , Karothu Durga Prasad , Lui Nathan M. , Commins Patrick , Ahmed Ejaz , Catalano Luca , Li Liang , Weston James , Moriwaki Taro , Solntsev Kyril M. , Naumov Panče
Published: March 2019

Chemiluminescence, a process of transduction of energy stored within chemical bonds of ground-state reactants into light via high-energy excited intermediates, is known in solution, but has remained undetected in macroscopic crystalline solids. By detecting thermally induced chemiluminescence from centimeter-size crystals of an organic peroxide here we demonstrate direct transduction of heat into light by thermochemiluminescence of bulk crystals. Heating of crystals of lophine hydroperoxide to ~115 °C results in detectable emission of blue-green light with maximum at 530 nm with low chemiluminescent quantum yield [(2.1 ± 0.1) × 10‒7 E mol‒1]. Spectral comparison of the thermochemiluminescence in the solid state and in solution revealed that the solid-state thermochemiluminescence of lophine peroxide is due to emission from deprotonated lophine. With selected 1,2-dioxetane, endoperoxide and aroyl peroxide we also establish that the thermochemiluminescence is common for crystalline peroxides, with the color of the emitted light varying from blue to green to red.
SFPQ and NONO suppress RNA:DNA-hybrid-related telomere instability
Authors: Petti Eleonora , Buemi Valentina , Zappone Antonina , Schillaci Odessa , Broccia Pamela Veneziano , Dinami Roberto , Matteoni Silvia , Benetti Roberta , Schoeftner Stefan
Published: March 2019

In vertebrates, the telomere repeat containing long, non-coding RNA TERRA is prone to form RNA:DNA hybrids at telomeres. This results in the formation of R-loop structures, replication stress and telomere instability, but also contributes to alternative lengthening of telomeres (ALT). Here, we identify the TERRA binding proteins NONO and SFPQ as novel regulators of RNA:DNA hybrid related telomere instability. NONO and SFPQ locate at telomeres and have a common role in suppressing RNA:DNA hybrids and replication defects at telomeres. NONO and SFPQ act as heterodimers to suppress fragility and homologous recombination at telomeres, respectively. Combining increased telomere fragility with unleashing telomere recombination upon NONO/SFPQ loss of function causes massive recombination events, involving 35% of telomeres in ALT cells. Our data identify the RNA binding proteins SFPQ and NONO as novel regulators at telomeres that collaborate to ensure telomere integrity by suppressing telomere fragility and homologous recombination triggered by RNA:DNA hybrids.
Dynamic pigmentary and structural coloration within cephalopod chromatophore organs
Authors: Williams Thomas L. , Senft Stephen L. , Yeo Jingjie , Martín-Martínez Francisco J. , Kuzirian Alan M. , Martin Camille A. , DiBona Christopher W. , Chen Chun-Teh , Dinneen Sean R. , Nguyen Hieu T. , Gomes Conor M. , Rosenthal Joshua J. C. , MacManes Matthew D. , Chu Feixia , Buehler Markus J. , Hanlon Roger T. , Deravi Leila F.
Published: March 2019

Chromatophore organs in cephalopod skin are known to produce ultra-fast changes in appearance for camouflage and communication. Light-scattering pigment granules within chromatocytes have been presumed to be the sole source of coloration in these complex organs. We report the discovery of structural coloration emanating in precise register with expanded pigmented chromatocytes. Concurrently, using an annotated squid chromatophore proteome together with microscopy, we identify a likely biochemical component of this reflective coloration as reflectin proteins distributed in sheath cells that envelop each chromatocyte. Additionally, within the chromatocytes, where the pigment resides in nanostructured granules, we find the lens protein Ω- crystallin interfacing tightly with pigment molecules. These findings offer fresh perspectives on the intricate biophotonic interplay between pigmentary and structural coloration elements tightly co-located within the same dynamic flexible organ - a feature that may help inspire the development of new classes of engineered materials that change color and pattern.
Rapid one-step 18F-radiolabeling of biomolecules in aqueous media by organophosphine fluoride acceptors
Authors: Hong Huawei , Zhang Lei , Xie Fang , Zhuang Rongqiang , Jiang Donglang , Liu Huanhuan , Li Jindian , Yang Hongzhang , Zhang Xianzhong , Nie Liming , Li Zijing
Published: March 2019

Currently, only a few 18F-radiolabeling methods were conducted in aqueous media, with non-macroelement fluoride acceptors and stringent conditions required. Herein, we describe a one-step non-solvent-biased, room-temperature-driven 18F-radiolabeling methodology based on organophosphine fluoride acceptors. The high water tolerance for this isotope-exchange-based 18F-labeling method is attributed to the kinetic and thermodynamic preference of F/F over the OH/F substitution based on computational calculations and experimental validation. Compact [18/19F]di-tert-butyl-organofluorophosphine and its derivatives used as 18F-labeling synthons exhibit excellent stability in vivo. The synthons are further conjugated to several biomolecular ligands such as c(RGDyk) and human serum albumin. The one-step labeled biomolecular tracers demonstrate intrinsic target imaging ability and negligible defluorination in vivo. The current method thus offers a facile and efficient 18F-radiolabeling pathway, enabling further widespread application of 18F.
Author Correction: LOTUS domain protein MARF1 binds CCR4-NOT deadenylase complex to post-transcriptionally regulate gene expression in oocytes
Authors: Zhu Li , Kandasamy Suresh K. , Liao Susan E. , Fukunaga Ryuya
Published: March 2019

The originally published version of this Article contained an error in Figure 1a, in which the length of the protein fragment produced by the MARF1 null allele was incorrectly labelled as ‘34aa’ rather than the corrected ‘103aa’.Also, the second sentence of the third paragraph of the Results originally read ‘The MARF1null allele has a 241-nt-long deletion introduced at proximal to the N-terminal end of the protein, which produced a premature stop codon, resulting in production of the N-terminal 34 aa fragment of MARF1 (Fig. 1a).’ In the corrected version, ‘34aa’ is replaced by ‘103aa’.These errors have now been corrected in both the PDF and the HTML versions of the Article.
Adhesive behavior and detachment mechanisms of bacterial amyloid nanofibers
Authors: Wang Ao , Keten Sinan
Published: March 2019

Amyloid nanofibers, such as curli nanofibers, have proven capable of adhering strongly to abiotic surfaces. However, the adhesive performance of individual nanofibers and the dependence of this performance on physical properties remain to be characterized. We carried out coarse-grained molecular dynamics simulations to determine the detachment mechanisms of single amyloid fibers from surfaces. Taking a generic model inspired from the curli nanofiber subunit CsgA, we discover that the amyloid nanofibers can undergo three different peeling processes when pulled at a constant rate normal to the surface. Computational phase diagrams built from parametric studies indicate that strong nanofibers with high cohesive energy detach by peeling smoothly away from the substrate while weak fibers break prematurely. At intermediate ratios, hinge formation occurs and the work of peeling the nanofiber is twice the adhesive energy due to the additional energy required to bend the nanofiber during desorption. Varying the geometry of amyloid subunits revealed that the work of peeling decreases for thicker nanofibers, suggesting that the tape-like monomeric structure of amyloids may facilitate better adhesive performance. Our results demonstrate how the dimensions and adhesive and cohesive properties of the amyloid nanofibers can be optimized to resist mechanical peeling.
Comparative effect of alkaline elements and calcium on alteration of International Simple Glass
Authors: Aréna Hélène , Rébiscoul Diane , Garcès Emmanuelle , Godon Nicole
Published: March 2019

In the concept of deep geological repository for High Level Wastes, the chemical elements present in the media are expected to impact the long-term behavior of the glass. The effects of Ca, K, and Cs on International Simple Glass glass alteration are compared through long-term experiments (180–500 days). These elements limit glass alteration by their incorporation into the gel layer. The limiting mechanisms driving glass alteration appear to be mainly diffusive, at least during the first six months. The three cations are not equally efficient in limiting glass alteration: the effects of Ca are stronger than those of Cs and K. Multi-element experiments show that the effects of these elements are additive and proportional to the quantity of each element incorporated. When they play the role of charge compensator in the gel network, their incorporation is competitive and follows the order Ca ≫ Cs > K. In addition, when Ca is added to the solution in excess, the quantity of elements incorporated into the gel layer is higher than the amount required for charge compensation. The incorporation of Ca in the gel nanopores as calcium carbonate could explain this phenomenon. These processes could slow the transport phenomena through the gel and enhance its protective properties.
The role of quantum coherence in non-equilibrium entropy production
Authors: Santos Jader P. , Céleri Lucas C. , Landi Gabriel T. , Paternostro Mauro
Published: March 2019

Thermodynamic irreversibility is well characterized by the entropy production arising from non-equilibrium quantum processes. We show that the entropy production of a quantum system undergoing open-system dynamics can be formally split into a term that only depends on population unbalances, and one that is underpinned by quantum coherences. This allows us to identify a genuine quantum contribution to the entropy production in non-equilibrium quantum processes. We discuss how these features emerge both in Lindblad-Davies differential maps and finite maps subject to the constraints of thermal operations. We also show how this separation naturally leads to two independent entropic conservation laws for the global system-environment dynamics, one referring to the redistribution of populations between system and environment and the other describing how the coherence initially present in the system is distributed into local coherences in the environment and non-local coherences in the system-environment state. Finally, we discuss how the processing of quantum coherences and the incompatibility of non-commuting measurements leads to fundamental limitations in the description of quantum trajectories and fluctuation theorems.
Addressing how multiple household water sources and uses build water resilience and support sustainable development
Authors: Elliott Mark , Foster Tim , MacDonald Morgan C. , Harris Angela R. , Schwab Kellogg J. , Hadwen Wade L.
Published: March 2019

The routine use of multiple water sources to meet household water needs is widely practiced and has been reported in many developing countries. However, it is typically neglected by implementers, development organizations, and researchers who tend to focus exclusively on the “main source of drinking water.” In this Perspective, we explain the nature and scope of multiple water source use (MWSU) at the household level in developing countries. We also describe the implications of MWSU for human health and water resilience, and identify key knowledge gaps, risks, and opportunities associated with MWSU. Finally, we argue that understanding MWSU is feasible for researchers and implementers and is essential for properly designing research studies and water supply projects.
Spin-charge-lattice coupling in YBaCuFeO5: Optical properties and first-principles calculations
Authors: Chen H. W. , Chen Y.-W. , Kuo J.-L. , Lai Y. C. , Chou F. C. , Du C. H. , Liu H. L.
Published: March 2019

We combined spectroscopic ellipsometry, Raman scattering spectroscopy, and first-principles calculations to explore the optical properties of YBaCuFeO5 single crystals. Measuring the optical absorption spectrum of YBaCuFeO5 at room temperature revealed a direct optical band gap at approximately 1.41 eV and five bands near 1.69, 2.47, 3.16, 4.26, and 5.54 eV. Based on first-principles calculations, the observed optical excitations were appropriately assigned. Analysis of the temperature dependence of the band gap indicated anomalies in antiferromagnetic phase transition at 455 and 175 K. Additionally, a hardening in the frequency of the Eg phonon mode was observed at 175 K. The value of the spin–phonon coupling constant was 15.7 mRy/Å2. These results suggest a complex nature of spin–charge–lattice interactions in YBaCuFeO5.
Complex magnetic structure and magnetocapacitance response in a non-oxide NiF2 system
Authors: Arumugam S. , Sivaprakash P. , Dixit Ambesh , Chaurasiya Rajneesh , Govindaraj L. , Sathiskumar M. , Chatterjee Souvik , Suryanarayanan R.
Published: March 2019

We report here on the complex magnetic structure and magnetocapacitance in NiF2, a non-oxide multifunctional system. It undergoes an anti-ferromagnetic transition near 68.5 K, superimposed with canted Ni spin driven weak ferromagnetic ordering, followed by a metastable ferromagnetic phase at or below 10 K. Our density functional calculations account for the complex magnetic structure of NiF2deduced from the temperature and the field dependent measurements. Near room temperature, NiF2exhibits a relatively large dielectric response reaching >103with a low dielectric loss of <0.5 at frequencies >20 Hz. This is attributed to the intrinsic grain contribution in contrast to the grain boundary contribution in most of the known dielectric materials. The response time is 10 μs or more at 280 K. The activation energy for such temperature dependent relaxation is ~500 meV and is the main source for grain contribution. Further, a large negative magneto capacitance >90% is noticed in 1 T magnetic field. We propose that our findings provide a new non-oxide multifunctional NiF2, useful for dielectric applications.
Genetic and Phytochemical Characterization of Lettuce Flavonoid Biosynthesis Mutants
Authors: Gurdon Csanad , Poulev Alexander , Armas Isabel , Satorov Shukhratdzhon , Tsai Meg , Raskin Ilya
Published: March 2019

We previously developed red lettuce (Lactuca sativa L.) cultivars with high flavonoid and phenolic acid content and demonstrated their anti-diabetic effect. Here we report on developing three fertile and true-breeding lettuce lines enriched with flavonoids with reported beneficial health effects. These lines were identified in a segregating population of EMS-mutagenized red lettuce and characterized biochemically and genetically. Change in red coloration was used as a visual indicator of a mutation in a flavonoid pathway gene, leading to accumulation of flavonoid precursors of red anthocyanins. Pink-green kaempferol overproducing kfoA and kfoB mutants accumulated kaempferol to 0.6–1% of their dry weight, higher than in any vegetable reported. The yellow-green naringenin chalcone overproducing mutant (nco) accumulated naringenin chalcone, not previously reported in lettuce, to 1% dry weight, a level only observed in tomato peel. Kfo plants carried a mutation in the FLAVONOID-3′ HYDROXYLASE (F3′H) gene, nco in CHALCONE ISOMERASE (CHI). This work demonstrates how non-GMO approaches can transform a common crop plant into a functional food with possible health benefits.
Late effect of larval co-exposure to the insecticide clothianidin and fungicide pyraclostrobin in Africanized Apis mellifera
Authors: Tadei Rafaela , Domingues Caio E. C. , Malaquias José Bruno , Camilo Erasnilson Vieira , Malaspina Osmar , Silva-Zacarin Elaine C. M.
Published: March 2019

Among the factors that contribute to the reduction of honeybee populations are the pesticides. These chemical compounds reach the hive through forager bees, and once there, they can be ingested by the larvae. We evaluated the effects of repeated larval exposure to neonicotinoid insecticide, both in isolation and in combination with strobilurin fungicide, at environmentally relevant doses. The total consumption of the contaminated diet was 23.63 ng fungicide/larvae (pyraclostrobin) and 0.2364 ng insecticide/larvae (clothianidin). The effects on post-embryonic development were evaluated over time. Additionally, we assessed the survival pattern of worker bees after emergence, and the pesticides’ effects on the behavior of newly emerged workers and young workers. Young bees that were exposed to the fungicide and those subjected to co-exposure to both pesticides during larval phase showed behavioral changes. The insecticide, both in isolation and in combination with fungicide reduced the bees’ longevity; this effect of larval exposure to pesticides was stronger in bees that were exposed only to the insecticide. Although the larvae did not have sensitivity to exposure to pesticides, they showed later effects after emergence, which may compromise the dynamics of the colony, contributing to the reduction of the populations of bees in agroecosystems.
Rapid measurement of hydrogen sulphide in human blood plasma using a microfluidic method
Authors: Karunya R. , Jayaprakash K. S. , Gaikwad R. , Sajeesh P. , Ramshad K. , Muraleedharan K. M. , Dixit M. , Thangaraj P. R. , Sen A. K.
Published: March 2019

Hydrogen sulfide (H2S) is emerging as an important gasotransmitter in both physiological and pathological states. Rapid measurement of H2S remains a challenge. We report a microfluidic method for rapid measurement of sulphide in blood plasma using Dansyl-Azide, a fluorescence (FL) based probe. We have measured known quantities of externally added (exogenous) H2S to both buffer and human blood plasma. Surprisingly, a decrease in FL intensity with increase in exogenous sulphide concentration in plasma was observed which is attributed to the interaction between the proteins and sulphide present in plasma underpinning our observation. The effects of mixing and incubation time, pH, and dilution of plasma on the FL intensity is studied which revealed that the FL assay required a mixing time of 2 min, incubation time of 5 min, a pH of 7.1 and performing the test within 10 min of sampling; these together constitute the optimal parameters at room temperature. A linear correlation (with R2 ≥ 0.95) and an excellent match was obtained when a comparison was done between the proposed microfluidic and conventional spectrofluorometric methods for known concentrations of H2S (range 0–100 µM). We have measured the baseline level of endogenous H2S in healthy volunteers which was found to lie in the range of 70 μM – 125 μM. The proposed microfluidic device with DNS-Az probe enables rapid and accurate estimation of a key gasotransmitter H2S in plasma in conditions closely mimicking real time clinical setting. The availability of this device as at the point of care, will help in understanding the role of H2S in health and disease.
A proteomic time course through the differentiation of human induced pluripotent stem cells into hepatocyte-like cells
Authors: Hurrell Tracey , Segeritz Charis-Patricia , Vallier Ludovic , Lilley Kathryn S. , Cromarty Allan D.
Published: March 2019

Numerous in vitro models endeavour to mimic the characteristics of primary human hepatocytes for applications in regenerative medicine and pharmaceutical science. Mature hepatocyte-like cells (HLCs) derived from human induced pluripotent stem cells (hiPSCs) are one such in vitro model. Due to insufficiencies in transcriptome to proteome correlation, characterising the proteome of HLCs is essential to provide a suitable framework for their continual optimization. Here we interrogated the proteome during stepwise differentiation of hiPSCs into HLCs over 40 days. Whole cell protein lysates were collected and analysed using stabled isotope labelled mass spectrometry based proteomics. Quantitative proteomics identified over 6,000 proteins in duplicate multiplexed labelling experiments across two different time course series. Inductive cues in differentiation promoted sequential acquisition of hepatocyte specific markers. Analysis of proteins classically assigned as hepatic markers demonstrated trends towards maximum relative abundance between differentiation day 30 and 32. Characterisation of abundant proteins in whole cells provided evidence of the time dependent transition towards proteins corresponding with the functional repertoire of the liver. This data highlights how far the proteome of undifferentiated precursors have progressed to acquire a hepatic phenotype and constructs a platform for optimisation and improved maturation of HLC differentiation.
A Naturally Occurring Polymorphism in the HIV-1 Tat Basic Domain Inhibits Uptake by Bystander Cells and Leads to Reduced Neuroinflammation
Authors: Ruiz Arthur P. , Ajasin David O. , Ramasamy Santhamani , DesMarais Vera , Eugenin Eliseo A. , Prasad Vinayaka R.
Published: March 2019

HIV-1 Tat protein contributes to HIV-neuropathogenesis in several ways including its ability to be taken up by uninfected bystander CNS cells and to activate inflammatory host genes causing synaptic injury. Here, we report that in the globally dominant HIV-1 clade C, Tat displays a naturally occurring polymorphism, R57S, in its basic domain, which mediates cellular uptake. We examined the effect of this polymorphism on Tat uptake and its consequences for cellular gene transactivation. In decapeptides corresponding to the basic domain, a R57S substitution caused up to a 70% reduction in uptake. We also used a transcellular Tat transactivation assay, where we expressed Tat proteins of HIV-1 clade B (Tat-B) or C (Tat-C) or their position 57 variants in HeLa cells. We quantified the secreted Tat proteins and measured their uptake by TZM-bl cells, which provide readout via an HIV-1 Tat-responsive luciferase gene. Transactivation by Tat-B was significantly reduced by R57S substitution, while that of Tat-C was enhanced by the reciprocal S57R substitution. Finally, we exposed microglia to Tat variants and found that R57 is required for maximal neuroinflammation. The R57S substitution dampened this response. Thus, genetic variations can modulate the ability of HIV-1 Tat to systemically disseminate neuroinflammation.
miR-193b regulates tumorigenesis in liposarcoma cells via PDGFR, TGFβ, and Wnt signaling
Authors: Mazzu Ying Z. , Hu Yulan , Shen Yawei , Tuschl Thomas , Singer Samuel
Published: March 2019

Liposarcoma is the most common soft tissue sarcoma. Molecularly targeted therapeutics have had limited efficacy in liposarcomas, in part because of inadequate knowledge of the complex molecular alterations in these tumors. Our recent study revealed the tumor suppressive function of miR-193b in liposarcoma. Considering the biological and clinical heterogeneity of liposarcoma, here, we confirmed the under-expression of miR-193b in additional patient liposarcoma samples and cell lines. Based on STRING analysis of protein-protein interactions among the reported putative miR-193b targets, we validated three: PDGFRβ, SMAD4, and YAP1, belonging to strongly interacting pathways (focal adhesion, TGFβ, and Hippo, respectively). We show that all three are directly targeted by miR-193b in liposarcoma. Inhibition of PDGFRβ reduces liposarcoma cell viability and increases adipogenesis. Knockdown of SMAD4 promotes adipogenic differentiation. miR-193b targeting of the Hippo signaling effector YAP1 indirectly inhibits Wnt/β-catenin signaling. Both a PDGFR inhibitor (CP-673451) and a Wnt/ β-catenin inhibitor (ICG-001) had potent inhibitory effects on liposarcoma cells, suggesting their potential application in liposarcoma treatment. In summary, we demonstrate that miR-193b controls cell growth and differentiation in liposarcoma by targeting multiple key components (PDGFRβ, SMAD4, and YAP1) in several oncogenic signaling pathways.
Development of colorectal cancer predicts increased risk of subsequent hepatocellular carcinoma in patients with alcoholic liver disease: case-control and cohort study
Authors: Kim Won , Jeong Dongjae , Chung Jungwha , Lee Donghyeon , Joo Saekyoung , Jang Eun Sun , Choi Yoon Jin , Yoon Hyuk , Shin Cheol Min , Park Young Soo , Jeong Sook-Hyang , Kim Nayoung , Lee Dong Ho , Kim Jin-Wook
Published: March 2019

Alcohol increases the risk of both hepatocellular carcinoma (HCC) and colorectal neoplasia. In this hospital-based case-control and retrospective cohort study, we sought to determine whether development of colorectal neoplasia increases the risk of HCC in patients with alcoholic liver disease (ALD). In the phase I case-control analysis, the association between history of colorectal cancer (CRC) and HCC development was assessed in patients with ALD by logistic regression modeling (n = 1,659). In the phase II retrospective cohort analysis, the relative risk of HCC development was compared in ALD patients with respect to the history of CRC by a Cox model (n = 1,184). The history of CRC was significantly associated with HCC in the case-control analysis (adjusted odds ratio, 1.82; 95% CI, 1.06–3.15; P < 0.05). ALD patients with CRC had higher risk of developing HCC compared to those without CRC (adjusted hazards ratio [HR], 5.48; 95% CI, 1.63–18.36; P = 0.006) in the cohort analysis. Presence of CRC, liver cirrhosis, elevated baseline alpha-fetoprotein level, and low platelet counts were independent predictors of HCC development in ALD patients. Patients with history of CRC had an increased risk of HCC in both cirrhotic (HR, 3.76; 95% CI, 1.05–13.34, P = 0.041) and non-cirrhotic (HR, 23.46; 95% CI, 2.81–195.83, P = 0.004) ALD patients. In conclusion, ALD patients with CRC are at increased risk of developing HCC.
Toll-Like Receptor 4 Activation Promotes Multiple Myeloma Cell Growth and Survival Via Suppression of The Endoplasmic Reticulum Stress Factor Chop
Authors: Bagratuni Tina , Sklirou Aimilia D. , Kastritis Efstathios , Liacos Christine Ivy , Spilioti Christina , Eleutherakis-Papaiakovou Evangelos , Kanellias Nikolaos , Gavriatopoulou Maria , Terpos Evangelos , Trougakos Ioannis P. , Dimopoulos Meletios A.
Published: March 2019

Despite recent biomedical improvements in treating Multiple Myeloma (MM), the disease still remains incurable. Toll like receptors (TLRs) provide a link between innate and adaptive immune responses and hence potentially correlate inflammation to cancer. Although the regulatory role of TLRs in MM has been under investigation the underlying mechanisms remain unclear. In this study we assayed the function of TLR4 in MM cell lines and in MM patients’ samples. We found that lipopolysaccharide-mediated TLR4 activation increased MM cells proliferation and decreased endoplasmic reticulum (ER) stress-induced apoptosis. Furthermore, we observed that either the endogenous CHOP expression or the ER stress-mediated CHOP induction, were suppressed by TLR4 activation or its overexpression in MM cell lines; TLR4 induction also suppressed ER stress-induced apoptotic signals. In support, TLR4 gene expression silencing in MM cell lines significantly decreased cell proliferation and promoted CHOP and ATF4 upregulation. TLR4 activation was also able to partially abrogate the effect of bortezomib in MM cell lines by suppressing PERK, ATF4 and phospho-eIF2A. We suggest that TLR4-mediated disruption of ER stress responses contributes to MM cells proliferation and suppresses ER-dependent death signals.
New ecosystems in the deep subsurface follow the flow of water driven by geological activity
Authors: Borgonie G. , Magnabosco C. , García-Moyano A. , Linage-Alvarez B. , Ojo A. O. , Freese L. B. , Van Jaarsveld C. , Van Rooyen C. , Kuloyo O. , Cason E. D. , Vermeulen J. , Pienaar C. , Van Heerden E. , Sherwood Lollar B. , Onstott T. C. , Mundle S. O. C.
Published: March 2019

Eukarya have been discovered in the deep subsurface at several locations in South Africa, but how organisms reach the subsurface remains unknown. We studied river-subsurface fissure water systems and identified Eukarya from a river that are genetically identical for 18S rDNA. To further confirm that these are identical species one metazoan species recovered from the overlying river interbred successfully with specimen recovered from an underlying mine at −1.4 km. In situ seismic simulation experiments were carried out and show seismic activity to be a major force increasing the hydraulic conductivity in faults allowing organisms to create ecosystems in the deep subsurface. As seismic activity is a non-selective force we recovered specimen of algae and Insecta that defy any obvious other explanation at a depth of −3.4 km. Our results show there is a steady flow of surface organisms to the deep subsurface where some survive and adapt and others perish. As seismic activity is also present on other planets and moons in our solar system the mechanism elucidated here may be relevant for future search and selection of landing sites in planetary exploration.
Automated tracking of label-free cells with enhanced recognition of whole tracks
Authors: Al-Zaben Naim , Medyukhina Anna , Dietrich Stefanie , Marolda Alessandra , Hünniger Kerstin , Kurzai Oliver , Figge Marc Thilo
Published: March 2019

Migration and interactions of immune cells are routinely studied by time-lapse microscopy of in vitro migration and confrontation assays. To objectively quantify the dynamic behavior of cells, software tools for automated cell tracking can be applied. However, many existing tracking algorithms recognize only rather short fragments of a whole cell track and rely on cell staining to enhance cell segmentation. While our previously developed segmentation approach enables tracking of label-free cells, it still suffers from frequently recognizing only short track fragments. In this study, we identify sources of track fragmentation and provide solutions to obtain longer cell tracks. This is achieved by improving the detection of low-contrast cells and by optimizing the value of the gap size parameter, which defines the number of missing cell positions between track fragments that is accepted for still connecting them into one track. We find that the enhanced track recognition increases the average length of cell tracks up to 2.2-fold. Recognizing cell tracks as a whole will enable studying and quantifying more complex patterns of cell behavior, e.g. switches in migration mode or dependence of the phagocytosis efficiency on the number and type of preceding interactions. Such quantitative analyses will improve our understanding of how immune cells interact and function in health and disease.
A systematic review of the caries prevalence among children living in Chernobyl fallout countries
Authors: Wolgin Michael , Filina Nicole , Shakavets Natalia , Dvornyk Valentyn , Lynch Edward , Kielbassa Andrej M.
Published: March 2019

The present study analyzed the data concerning the caries prevalence in children born and permanently residing in Chernobyl fallout areas. Setting forth to evaluate if differences regarding the caries prevalence can be observed compared to non-contaminated sites of affected East European countries. Methods used to assess the caries prevalence were limited to DMFT/dmft (decayed, missing and filled teeth) for the primary and the permanent dentitions. The databases PubMed, EMBASE/Ovid, Cochrane Library, Scopus, and eLIBRARY were consulted for the electronic literature search. Screening of titles and abstracts followed the MOOSE guidelines, while data extraction and the assessment of the full texts were performed in accordance to the Newcastle Ottawa Scale. The statistical analysis revealed considerable heterogeneity of DMFT/dmft values (from I2 = 94% up to I2 = 99.9%; p < 0.05) in children of different ages (5–7; 12–15; and average of 12 years). Scattering of the weighted mean differences (95% CI) ranged from −1.03 (−1.36; −0.7) to 6.51 (6.11; 6.91). Although individual studies demonstrated a greater prevalence of dental caries in children residing in radiation-contaminated areas, no conclusive statement is possible regarding the effect of small dose radiation on the dentition. Hence, further high-quality epidemiologic investigations are needed.
Food Transport of Red Imported Fire Ants (Hymenoptera: Formicidae) on Vertical Surfaces
Authors: Qin Wenquan , Lin Shucong , Chen Xuan , Chen Jian , Wang Lei , Xiong Hongpeng , Xie Qinxi , Sun Zhaohui , Wen Xiujun , Wang Cai
Published: March 2019

Many ants can cooperatively transport large food items (either coordinated or uncoordinated during transportation), which can be rarely observed in other animals besides humans. Although these behaviors have been extensively investigated on horizontal surfaces, few studies dealt with food transport on vertical surfaces. The red imported fire ant, Solenopsis invicta Buren, is an invasive ant species that commonly forages on trees. Our studies showed that S. invicta used multiple strategies to transport food items on vertical surfaces (tree trunks). Small food items (1 × 1 × 1 mm sausage) were carried and transported by individual ants, and larger food items were either collectively and directly transported or cut collaboratively first and small particles were then transported individually or collectively. Competition and deadlocks were frequently observed during individual and collective transport respectively. During cutting, groups of ants tightly fixed the food on the tree trunks by holding the edges of the food item, while other ants cut the food into smaller particles. All food items and particles were moved downward. We investigated the effects of food placement (placed on a platform or fixed on tree trunk), food shape (cuboid or flattened), particle sizes (0.45–1, 1–2, 2–3, or 3–4 mm), and placement height (20, 80, or 150 cm) on the food transport on tree trunks. Our studies are the first to show how fire ants transport food on a vertical surface, and may provide insights into the development of novel fire ant baiting systems that can be placed on tree trunks.
Mobilization of Stem and Progenitor Cells in Septic Shock Patients
Authors: Skirecki Tomasz , Mikaszewska-Sokolewicz Małgorzata , Godlewska Marlena , Dołęgowska Barbara , Czubak Jarosław , Hoser Grażyna , Kawiak Jerzy , Zielińska-Borkowska Urszula
Published: March 2019

Septic shock is associated with multiple injuries to organs and tissues. These events may induce the regenerative response of adult stem cells. However, little is known about how endogenous stem cells are modulated by sepsis. This study analyzed the circulation of hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs) and very small embryonic-like stem cells (VSELs) in the peripheral blood of patients with septic shock. Thirty-three patients with septic shock and twenty-two healthy control subjects were enrolled in this prospective observational study. Blood samples were collected on the first, third and seventh days of septic shock. Populations of stem cells were analyzed by flow cytometry. Chemotactic mediators were analyzed by HPLC and ELISA. Populations of early HSCs (Lin-CD133+CD45+ and CD34+CD38−) were mobilized to the peripheral blood after an initial decrease. Mobilized HSCs showed significantly increased expression of Ki-67, a marker of cell proliferation. Circulating EPCs and VSELs were mobilized to the blood circulation upon the first day of sepsis. Patients with a greater number of Lin-CD133+CD45+ HSCs and Lin-CD34+CD45− VSELs had a significantly lower probability of 60-day survival. The concentration of CXCL12 was elevated in the blood of septic patients, while the concentration of sphingosine-1-phosphate was significantly decreased. As an emergency early response to sepsis, VSELs and EPCs were mobilized to the peripheral blood, while the HSCs showed delayed mobilization. Differential mobilization of stem cell subsets reflected changes in the concentration of chemoattractants in the blood. The relationship between the probability of death and a large number of HSCs and VSELs in septic shock patients can be used as a novel prognostic marker and may provide new therapeutic approaches.
Fenofibrate induces human hepatoma Hep3B cells apoptosis and necroptosis through inhibition of thioesterase domain of fatty acid synthase
Authors: You Bang-Jau , Hour Mann-Jen , Chen Li-Yun , Luo Shu-Ching , Hsu Po-Hsiang , Lee Hong-Zin
Published: March 2019

This study demonstrated that fenofibrate, a lipid-lowering drug, induced a significant time-dependent cytotoxicity of hepatoma Hep3B cells. Hep3B cells are significantly more sensitive to cell killing by fenofibrate than hepatoma HepG2, lung cancer CH27 and oral cancer HSC-3 cells. From the result of docking simulation, fenofibrate can bind excellently to the thioesterase domain of fatty acid synthase (FASN) binding site as orlistat, a FASN inhibitor, acts. The fenofibrate-induced cell cytotoxicity was protected by addition of palmitate, indicating that the cytotoxic effect of fenofibrate is due to starvation of Hep3B cells by inhibiting the formation of end product in the FASN reaction. Inhibition of lipid metabolism-related proteins expression, such as proteins containing thioesterase domain and fatty acid transport proteins, was involved in the fenofibrate-induced Hep3B cell death. Fenofibrate caused S and G2/M cell cycle arrest by inducing cyclin A/Cdk2 and reducing cyclin D1 and E protein levels in Hep3B cells. The anti-tumor roles of fenofibrate on Hep3B cells by inducing apoptosis and necroptosis were dependent on the expression of Bcl-2/caspase family members and RIP1/RIP3 proteins, respectively. These results suggest that fenofibrate has an anti-cancer effect in Hep3B cells and inhibition of lipid metabolism may be involved in fenofibrate-induced Hep3B cells apoptosis and necroptosis.
Identification of Streptococcus pneumoniae by a real-time PCR assay targeting SP2020
Authors: Tavares Débora A. , Handem Sara , Carvalho Ricardo J. , Paulo A. Cristina , de Lencastre Hermínia , Hinds Jason , Sá-Leão Raquel
Published: March 2019

Real-time PCR targeting lytA (the major autolysin gene) and piaB (permease gene of the pia ABC transporter) are currently used as the gold-standard culture-independent assays for Streptococcus pneumoniae identification. We evaluated the performance of a new real-time PCR assay – targeting SP2020 (putative transcriptional regulator gene) – and compared its performance with the assays previously described. A collection of 150 pneumococci, 433 non-pneumococci and 240 polymicrobial samples (obtained from nasopharynx, oropharynx, and saliva; 80 from each site) was tested. SP2020 and lytA-CDC assays had the best performance (sensitivity of 100% for each compared to 95.3% for piaB). The specificity for lytA and piaB was 99.5% and for SP2020 was 99.8%. Misidentifications occurred for the three genes: lytA, piaB and SP2020 were found in non-pneumococcal strains; piaB was absent in some pneumococci including a serotype 6B strain. Combining lytA and SP2020 assays resulted in no misidentifications. Most polymicrobial samples (88.8%) yielded concordant results for the three molecular targets. The remaining samples seemed to contain non-typeable pneumococci (0.8%), and non-pneumococci positive for lytA (1.7%) or SP2020 (8.7%). We propose that combined detection of both lytA-CDC and SP2020 is a powerful strategy for the identification of pneumococcus either in pure cultures or in polymicrobial samples.
Selecting variants of unknown significance through network-based gene-association significantly improves risk prediction for disease-control cohorts
Authors: Oulas Anastasis , Minadakis George , Zachariou Margarita , Spyrou George M.
Published: March 2019

Variants of unknown/uncertain significance (VUS) pose a huge dilemma in current genetic variation screening methods and genetic counselling. Driven by methods of next generation sequencing (NGS) such as whole exome sequencing (WES), a plethora of VUS are being detected in research laboratories as well as in the health sector. Motivated by this overabundance of VUS, we propose a novel computational methodology, termed VariantClassifier (VarClass), which utilizes gene-association networks and polygenic risk prediction models to shed light into this grey area of genetic variation in association with disease. VarClass has been evaluated using numerous validation steps and proves to be very successful in assigning significance to VUS in association with specific diseases of interest. Notably, using VUS that are deemed significant by VarClass, we improved risk prediction accuracy in four large case-studies involving disease-control cohorts from GWAS as well as WES, when compared to traditional odds ratio analysis. Biological interpretation of selected high scoring VUS revealed interesting biological themes relevant to the diseases under investigation. VarClass is available as a standalone tool for large-scale data analyses, as well as a web-server with additional functionalities through a user-friendly graphical interface.