bluuebunny/crossref_metadata_2025 huggingface dataset:
Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva
Authors: Lees-Shepard John B. , Yamamoto Masakazu , Biswas Arpita A. , Stoessel Sean J. , Nicholas Sarah-Anne E. , Cogswell Cathy A. , Devarakonda Parvathi M. , Schneider Michael J. , Cummins Samantha M. , Legendre Nicholas P. , Yamamoto Shoko , Kaartinen Vesa , Hunter Jeffrey W. , Goldhamer David J.
Published: January 2018

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (Acvr1
tnR206H
). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type Acvr1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted Acvr1
R206H/+
FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP.
Publisher Correction: Ticks parasitised feathered dinosaurs as revealed by Cretaceous amber assemblages
Authors: Peñalver Enrique , Arillo Antonio , Delclòs Xavier , Peris David , Grimaldi David A. , Anderson Scott R. , Nascimbene Paul C. , Fuente Ricardo Pérez-de la
Published: January 2018

The originally published version of this Article was updated shortly after publication to add the word ‘Ticks’ to the title, following its inadvertent removal during the production process. This has now been corrected in both the PDF and HTML versions of the Article.
Direct effects of transcranial electric stimulation on brain circuits in rats and humans
Authors: Vöröslakos Mihály , Takeuchi Yuichi , Brinyiczki Kitti , Zombori Tamás , Oliva Azahara , Fernández-Ruiz Antonio , Kozák Gábor , Kincses Zsigmond Tamás , Iványi Béla , Buzsáki György , Berényi Antal
Published: January 2018

Transcranial electric stimulation is a non-invasive tool that can influence brain activity; however, the parameters necessary to affect local circuits in vivo remain to be explored. Here, we report that in rodents and human cadaver brains, ~75% of scalp-applied currents are attenuated by soft tissue and skull. Using intracellular and extracellular recordings in rats, we find that at least 1 mV/mm voltage gradient is necessary to affect neuronal spiking and subthreshold currents. We designed an ‘intersectional short pulse’ stimulation method to inject sufficiently high current intensities into the brain, while keeping the charge density and sensation on the scalp surface relatively low. We verify the regional specificity of this novel method in rodents; in humans, we demonstrate how it affects the amplitude of simultaneously recorded EEG alpha waves. Our combined results establish that neuronal circuits are instantaneously affected by intensity currents that are higher than those used in conventional protocols.
Replication confers β cell immaturity
Authors: Puri Sapna , Roy Nilotpal , Russ Holger A. , Leonhardt Laura , French Esra K. , Roy Ritu , Bengtsson Henrik , Scott Donald K. , Stewart Andrew F. , Hebrok Matthias
Published: January 2018

Pancreatic β cells are highly specialized to regulate systemic glucose levels by secreting insulin. In adults, increase in β-cell mass is limited due to brakes on cell replication. In contrast, proliferation is robust in neonatal β cells that are functionally immature as defined by a lower set point for glucose-stimulated insulin secretion. Here we show that β-cell proliferation and immaturity are linked by tuning expression of physiologically relevant, non-oncogenic levels of c-Myc. Adult β cells induced to replicate adopt gene expression and metabolic profiles resembling those of immature neonatal β that proliferate readily. We directly demonstrate that priming insulin-producing cells to enter the cell cycle promotes a functionally immature phenotype. We suggest that there exists a balance between mature functionality and the ability to expand, as the phenotypic state of the β cell reverts to a less functional one in response to proliferative cues.
Author Correction: Induced unconventional superconductivity on the surface states of Bi2Te3 topological insulator
Authors: Charpentier Sophie , Galletti Luca , Kunakova Gunta , Arpaia Riccardo , Song Yuxin , Baghdadi Reza , Wang Shu Min , Kalaboukhov Alexei , Olsson Eva , Tafuri Francesco , Golubev Dmitry , Linder Jacob , Bauch Thilo , Lombardi Floriana
Published: January 2018

The original version of this Article contained an error in Fig. 6b. In the top scattering process, while the positioning of both arrows was correct, the colours were switched: the first arrow was red and the second arrow was blue, rather than the correct order of blue then red.
Author Correction: Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1
Authors: Pose-Utrilla Julia , García-Guerra Lucía , Del Puerto Ana , Martín Abraham , Jurado-Arjona Jerónimo , De León-Reyes Noelia S. , Gamir-Morralla Andrea , Sebastián-Serrano Álvaro , García-Gallo Mónica , Kremer Leonor , Fielitz Jens , Ireson Christofer , Pérez-Álvarez Mª José , Ferrer Isidro , Hernández Félix , Ávila Jesús , Lasa Marina , Campanero Miguel R. , Iglesias Teresa
Published: January 2018

The original version of this Article contained an error in the spelling of the author Álvaro Sebastián-Serrano, which was incorrectly given as Álvaro Sebastián Serrano. This has now been corrected in both the PDF and HTML versions of the Article.
Sustainable manufacture of insect repellents derived from Nepeta cataria
Authors: Patience Gregory S. , Karirekinyana Ginette , Galli Federico , Patience Nicolas A. , Kubwabo Cariton , Collin Guy , Bizimana Jean Claude , Boffito Daria C.
Published: January 2018

Malaria devastates sub-Saharan Africa; the World Health Organization (WHO) estimates that 212 million people contract malaria annually and that the plasmodium virus will kill 419 000 in 2017. The disease affects rural populations who have the least economic means to fight it. Impregnated mosquito nets have reduced the mortality rate but the Anopheles mosquitoes are changing their feeding patterns and have become more active at dusk and early morning rather than after 22h00 as an adaptation to the nets. Everyone is susceptible to the Anopheles at these times but infants and pregnant women are the most vulnerable to the disease. Plant-based mosquito repellents are as effective as synthetic repellents that protect people from bites. They are sustainable preventative measures against malaria not only because of their efficacy but because the local population can produce and distribute them, which represents a source of economic growth for rural areas. Here, we extract and test the essential oil nepetalactone from Nepeta cataria via steam distillation. Families in endemic areas of Burundi found them effective against bites but commented that the odor was pungent. An epidemiological study is required to establish its clinical efficacy.
Structure-guided design of Serratia marcescens short-chain dehydrogenase/reductase for stereoselective synthesis of (R)-phenylephrine
Authors: Liu Jai-Shin , Kuan Yi-Chia , Tsou Yu , Lin Tung-Yueh , Hsu Wen-Hwei , Yang Ming-Te , Lin Jong-Yih , Wang Wen-Ching
Published: January 2018

Bioconversion is useful to produce optically pure enantiomers in the pharmaceutical industry, thereby avoiding problems with side reactions during organic synthesis processes. A short-chain dehydrogenase/reductase from Serratia marcescens BCRC 10948 (SmSDR) can stereoselectively convert 1-(3-hydroxyphenyl)-2-(methylamino) ethanone (HPMAE) into (R)-phenylephrine [(R)-PE], which is marketed medically as a nasal decongestant agent. The whole-cell conversion process for the synthesis of (R)-PE using SmSDR was reported to have an unexpectedly low conversion rate. We reported the crystal structure of the SmSDR and designed profitable variants to improve the enzymatic activity by structure-guided approach. Several important residues in the structure were observed to form hydrophobic clusters that stabilize the mobile loops surrounding the pocket. Of these, Phe98 and Phe202 face toward each other and connect the upper curvature from the two arms (i.e., the α7 helix and loopβ4–α4). The mutant structure of the double substitutions (F98YF202Y) exhibited a hydrogen bond between the curvatures that stabilizes the flexible arms. Site-directed mutagenesis characterization revealed that the mutations (F98Y, F98YF202Y, and F98YF202L) of the flexible loops that stabilize the region exhibited a higher transformation activity toward HPMAE. Together, our results suggest a robust structure-guided approach that can be used to generate a valuable engineered variant for pharmaceutical applications.
Implementation of a Talbot-Lau interferometer in a clinical-like c-arm setup: A feasibility study
Authors: Horn Florian , Leghissa Martino , Kaeppler Sebastian , Pelzer Georg , Rieger Jens , Seifert Maria , Wandner Johannes , Weber Thomas , Michel Thilo , Riess Christian , Anton Gisela
Published: January 2018

X-ray grating-based phase-contrast imaging has raised interest regarding a variety of potential clinical applications, whereas the method is feasible using a medical x-ray tube. Yet, the transition towards a clinical setup remains challenging due to the requirement of mechanical robustness of the interferometer and high demands applying to medical equipment in clinical use. We demonstrate the successful implementation of a Talbot-Lau interferometer in an interventional c-arm setup. The consequence of vibrations induced by the rotating anode of the tube is discussed and the prototype is shown to provide a visibility of 21.4% at a tube voltage of 60 kV despite the vibrations. Regarding clinical application, the prototype is mainly set back due to the limited size of the field of view covering an area of 17 mm × 46 mm. A c-arm offers the possibility to change the optical axis according to the requirements of the medical examination. We provide a method to correct for artifacts that result from the angulation of the c-arm. Finally, the images of a series of measurements with the c-arm in different angulated positions are shown. Thereby, it is sufficient to perform a single reference measurement in parking position that is valid for the complete series despite angulation.
High Density Lipoproteins Inhibit Oxidative Stress-Induced Prostate Cancer Cell Proliferation
Authors: Ruscica Massimiliano , Botta Margherita , Ferri Nicola , Giorgio Eleonora , Macchi Chiara , Franceschini Guido , Magni Paolo , Calabresi Laura , Gomaraschi Monica
Published: January 2018

Recent evidence suggests that oxidative stress can play a role in the pathogenesis and the progression of prostate cancer (PCa). Reactive oxygen species (ROS) generation is higher in PCa cells compared to normal prostate epithelial cells and this increase is proportional to the aggressiveness of the phenotype. Since high density lipoproteins (HDL) are known to exert antioxidant activities, their ability to reduce ROS levels and the consequent impact on cell proliferation was tested in normal and PCa cell lines. HDL significantly reduced basal and H2O2-induced oxidative stress in normal, androgen receptor (AR)-positive and AR-null PCa cell lines. AR, scavenger receptor BI and ATP binding cassette G1 transporter were not involved. In addition, HDL completely blunted H2O2-induced increase of cell proliferation, through their capacity to prevent the H2O2-induced shift of cell cycle distribution from G0/G1 towards G2/M phase. Synthetic HDL, made of the two main components of plasma-derived HDL (apoA-I and phosphatidylcholine) and which are under clinical development as anti-atherosclerotic agents, retained the ability of HDL to inhibit ROS production in PCa cells. Collectively, HDL antioxidant activity limits cell proliferation induced by ROS in AR-positive and AR-null PCa cell lines, thus supporting a possible role of HDL against PCa progression.
Third-order transport coefficients for localised and delocalised charged-particle transport
Authors: Stokes Peter W. , Simonović Ilija , Philippa Bronson , Cocks Daniel , Dujko Saša , White Ronald D.
Published: January 2018

We derive third-order transport coefficients of skewness for a phase-space kinetic model that considers the processes of scattering collisions, trapping, detrapping and recombination losses. The resulting expression for the skewness tensor provides an extension to Fick’s law which is in turn applied to yield a corresponding generalised advection-diffusion-skewness equation. A physical interpretation of trap-induced skewness is presented and used to describe an observed negative skewness due to traps. A relationship between skewness, diffusion, mobility and temperature is formed by analogy with Einstein’s relation. Fractional transport is explored and its effects on the flux transport coefficients are also outlined.
Diffraction based Hanbury Brown and Twiss interferometry at a hard x-ray free-electron laser
Authors: Gorobtsov O. Yu. , Mukharamova N. , Lazarev S. , Chollet M. , Zhu D. , Feng Y. , Kurta R. P. , Meijer J.-M. , Williams G. , Sikorski M. , Song S. , Dzhigaev D. , Serkez S. , Singer A. , Petukhov A. V. , Vartanyants I. A.
Published: January 2018

X-ray free-electron lasers (XFELs) provide extremely bright and highly spatially coherent x-ray radiation with femtosecond pulse duration. Currently, they are widely used in biology and material science. Knowledge of the XFEL statistical properties during an experiment may be vitally important for the accurate interpretation of the results. Here, for the first time, we demonstrate Hanbury Brown and Twiss (HBT) interferometry performed in diffraction mode at an XFEL source. It allowed us to determine the XFEL statistical properties directly from the Bragg peaks originating from colloidal crystals. This approach is different from the traditional one when HBT interferometry is performed in the direct beam without a sample. Our analysis has demonstrated nearly full (80%) global spatial coherence of the XFEL pulses and an average pulse duration on the order of ten femtoseconds for the monochromatized beam, which is significantly shorter than expected from the electron bunch measurements.
3D auxetic single material periodic structure with ultra-wide tunable bandgap
Authors: D’Alessandro Luca , Zega Valentina , Ardito Raffaele , Corigliano Alberto
Published: January 2018

The design and the combination of innovative metamaterials are attracting increasing interest in the scientific community because of their unique properties that go beyond the ones of natural materials. In particular, auxetic materials and phononic crystals are widely studied for their negative Poisson’s ratio and their bandgap opening properties, respectively. In this work, auxeticity and phononic crystals bandgap properties are properly combined to obtain a single phase periodic structure with a tridimensional wide tunable bandgap. When an external tensile load is applied to the structure, the auxetic unit cells change their configurations by exploiting the negative Poisson’s ratio and this results in the tuning, either hardening or softening, of the frequencies of the modes limiting the 3D bandgap. Moreover, the expansion of the unit cell in all the directions, due to the auxeticity property, guarantees a fully 3D bandgap tunability of the proposed structure. Numerical simulations and analytical models are proposed to prove the claimed properties. The first experimental evidence of the tunability of a wide 3D bandgap is then shown thanks to the fabrication of a prototype by means of additive manufacturing.
Haloperidol–induced catalepsy is ameliorated by deep brain stimulation of the inferior colliculus
Authors: Engelhardt K.-Alexander , Marchetta Philine , Schwarting Rainer K. W. , Melo-Thomas Liana
Published: January 2018

Deep brain stimulation (DBS) has evolved as a promising alternative treatment for Parkinson’s disease (PD), but the underlying mechanisms remain poorly understood. Moreover, conventional DBS protocols targeted at basal ganglia sites can turn out completely ineffective for some PD patients, warranting the search for alternative targets. The inferior colliculus (IC) is a midbrain auditory relay station involved in sensorimotor processes. High-frequency 2500 Hz electrical stimulation of the IC elicits escape behaviour and interferes with haloperidol-induced catalepsy in rats, a state reminiscent of Parkinsonian akinesia, but clinical implication is limited since the protocol is aversive. However, typical DBS stimulation frequencies range between 20–180 Hz. We therefore tested the effects of a low-frequency 30 Hz-DBS protocol on haloperidol-induced catalepsy and aversive behaviour in rats. We show that low-frequency 30 Hz-DBS targeted at the IC strongly ameliorates haloperidol-induced catalepsy without any evidence of stimulation-induced escape behaviour. Furthermore, 30 Hz-DBS of the IC produced no place avoidance in a place conditioning paradigm and induced no anxiety-related behaviour on the elevated plus maze, indicating that the protocol has no aversive or anxiogenic side effects. Our findings provide first evidence that the IC can serve as an alternative, non-conventional DBS target.
Ants improve the reproduction of inferior morphs to maintain a polymorphism in symbiont aphids
Authors: Watanabe Saori , Yoshimura Jin , Hasegawa Eisuke
Published: January 2018

Identifying stable polymorphisms is essential for understanding biodiversity. Distinctive polymorphisms are rare in nature because a superior morph should dominate a population. In addition to the three known mechanisms for polymorphism persistence, we recently reported a fourth mechanism: protection of the polymorphism by symbionts. Attending ants preferentially protect polymorphic aphid colonies consisting of green and red morphs. Here, we show that attending ants manipulate the reproductive rate of their preferred green morphs to equal that of the red morphs, leading to the persistence of the polymorphism within the colonies. We could not, however, explain how the ants maintained the polymorphism in aphid colonies regardless of inter-morph competition. Manipulation by symbionts may be important for the maintenance of polymorphisms and the resulting biodiversity in certain symbiotic systems.
Comparative phosphoproteomic analysis reveals signaling networks regulating monopolar and bipolar cytokinesis
Authors: Karayel Özge , Şanal Erdem , Giese Sven H. , Üretmen Kagıalı Zeynep Cansu , Polat Ayşe Nur , Hu Chi-Kuo , Renard Bernhard Y. , Tuncbag Nurcan , Özlü Nurhan
Published: January 2018

The successful completion of cytokinesis requires the coordinated activities of diverse cellular components including membranes, cytoskeletal elements and chromosomes that together form partly redundant pathways, depending on the cell type. The biochemical analysis of this process is challenging due to its dynamic and rapid nature. Here, we systematically compared monopolar and bipolar cytokinesis and demonstrated that monopolar cytokinesis is a good surrogate for cytokinesis and it is a well-suited system for global biochemical analysis in mammalian cells. Based on this, we established a phosphoproteomic signature of cytokinesis. More than 10,000 phosphorylation sites were systematically monitored; around 800 of those were up-regulated during cytokinesis. Reconstructing the kinase-substrate interaction network revealed 31 potentially active kinases during cytokinesis. The kinase-substrate network connects proteins between cytoskeleton, membrane and cell cycle machinery. We also found consensus motifs of phosphorylation sites that can serve as biochemical markers specific to cytokinesis. Beyond the kinase-substrate network, our reconstructed signaling network suggests that combination of sumoylation and phosphorylation may regulate monopolar cytokinesis specific signaling pathways. Our analysis provides a systematic approach to the comparison of different cytokinesis types to reveal alternative ways and a global overview, in which conserved genes work together and organize chromatin and cytoplasm during cytokinesis.
Climate Based Predictability of Oil Palm Tree Yield in Malaysia
Authors: Oettli Pascal , Behera Swadhin K. , Yamagata Toshio
Published: January 2018

The influence of local conditions and remote climate modes on the interannual variability of oil palm fresh fruit bunches (FFB) total yields in Malaysia and two major regions (Peninsular Malaysia and Sabah/Sarawak) is explored. On a country scale, the state of sea-surface temperatures (SST) in the tropical Pacific Ocean during the previous boreal winter is found to influence the regional climate. When El Niño occurs in the Pacific Ocean, rainfall in Malaysia reduces but air temperature increases, generating a high level of water stress for palm trees. As a result, the yearly production of FFB becomes lower than that of a normal year since the water stress during the boreal spring has an important impact on the total annual yields of FFB. Conversely, La Niña sets favorable conditions for palm trees to produce more FFB by reducing chances of water stress risk. The region of the Leeuwin current also seems to play a secondary role through the Ningaloo Niño/ Niña in the interannual variability of FFB yields. Based on these findings, a linear model is constructed and its ability to reproduce the interannual signal is assessed. This model has shown some skills in predicting the total FFB yield.
Theory of frequency response of mechanically driven cardiomyocytes
Authors: Cohen Ohad , Safran Samuel A.
Published: January 2018

We theoretically predict and compare with experiments, transitions from spontaneous beating to dynamical entrainment of cardiomyocytes induced by an oscillating, external mechanical probe. In accord with recent experiments, we predict the dynamical behavior as a function of the probe amplitude and frequency. The theory is based on a phenomenological model for a non-linear oscillator, motivated by acto-myosin contractility. The generic behavior is independent of the detailed, molecular origins of the dynamics and, consistent with experiment, we find three regimes: spontaneous beating with the natural frequency of the cell, entrained beating with the frequency of the probe, and a “bursting” regime where the two frequencies alternate in time. We quantitatively predict the properties of the “bursting” regime as a function of the amplitude and frequency of the probe. Furthermore, we examine the pacing process in the presence of weak noise and explain how this might relate to cardiomyocyte physiology.
Movement Strategies for Countermovement Jumping are Potentially Influenced by Elastic Energy Stored and Released from Tendons
Authors: Wade Logan , Lichtwark Glen , Farris Dominic James
Published: January 2018

The preferred movement strategies that humans choose to produce work for movement are not fully understood. Previous studies have demonstrated an important contribution of elastic energy stored within the Achilles tendon (AT) during jumping. This study aimed to alter energy available for storage in the AT to examine changes in how jumpers distribute work among lower limb joints. Participants (n = 16) performed maximal and sub-maximal jumps under two paradigms, matched for increasing total work output by manipulating jump height or adding body mass. Motion capture and ground reaction force data were combined in an inverse dynamics analysis to compute ankle, knee and hip joint kinetics. Results demonstrated higher peak moments about the ankle joint with added body mass (+26 Nm), likely resulting in additional energy storage in the AT. Work at the ankle joint increased proportionally with added mass, maintaining a constant contribution (~64%) to total work that was not matched with increasing jump height (−14%). This implies greater energy storage and return by the AT with added mass but not with increased height. When total work during jumping is constant but energy stored in tendons is not, humans prioritise the use of stored elastic energy over muscle work.
Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function
Authors: Lundgaard Iben , Wang Wei , Eberhardt Allison , Vinitsky Hanna Sophia , Reeves Benjamin Cameron , Peng Sisi , Lou Nanhong , Hussain Rashad , Nedergaard Maiken
Published: January 2018

Prolonged intake of excessive amounts of ethanol is known to have adverse effects on the central nervous system (CNS). Here we investigated the effects of acute and chronic ethanol exposure and withdrawal from chronic ethanol exposure on glymphatic function, which is a brain-wide metabolite clearance system connected to the peripheral lymphatic system. Acute and chronic exposure to 1.5 g/kg (binge level) ethanol dramatically suppressed glymphatic function in awake mice. Chronic exposure to 1.5 g/kg ethanol increased GFAP expression and induced mislocation of the astrocyte-specific water channel aquaporin 4 (AQP4), but decreased the levels of several cytokines. Surprisingly, glymphatic function increased in mice treated with 0.5 g/kg (low dose) ethanol following acute exposure, as well as after one month of chronic exposure. Low doses of chronic ethanol intake were associated with a significant decrease in GFAP expression, with little change in the cytokine profile compared with the saline group. These observations suggest that ethanol has a J-shaped effect on the glymphatic system whereby low doses of ethanol increase glymphatic function. Conversely, chronic 1.5 g/kg ethanol intake induced reactive gliosis and perturbed glymphatic function, which possibly may contribute to the higher risk of dementia observed in heavy drinkers.
PCSK9 induces a pro-inflammatory response in macrophages
Authors: Ricci Chiara , Ruscica Massimiliano , Camera Marina , Rossetti Laura , Macchi Chiara , Colciago Alessandra , Zanotti Ilaria , Lupo Maria Giovanna , Adorni Maria Pia , Cicero Arrigo F. G. , Fogacci Federica , Corsini Alberto , Ferri Nicola
Published: January 2018

Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250 ÷ 2.5 µg/ml) of human recombinant PCSK9 (hPCSK9). After 24 h incubation with 2.5 µg/ml PCSK9, a significant induction of IL-1β, IL-6, TNF-α, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP-1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF-α (2.4 ± 0.5 fold) and IL-1β (8.6 ± 1.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-α mRNA in murine LDLR−/− bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3 ± 1.6 fold vs 31.1 ± 6.1 fold for LDLR−/− and LDLR+/+, respectively). Finally, a positive correlation between PCSK9 and TNF-α plasma levels of healthy adult subjects (males 533, females 537) was observed (B = 8.73, 95%CI 7.54 ÷ 9.93, p < 0.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR.
Conserved DNA Methylation Signatures in Early Maternal Separation and in Twins Discordant for CO2 Sensitivity
Authors: Giannese Francesca , Luchetti Alessandra , Barbiera Giulia , Lampis Valentina , Zanettini Claudio , Knudsen Gun Peggy , Scaini Simona , Lazarevic Dejan , Cittaro Davide , D’Amato Francesca R. , Battaglia Marco
Published: January 2018

Respiratory and emotional responses to blood-acidifying inhalation of CO2 are markers of some human anxiety disorders, and can be enhanced by repeatedly cross-fostering (RCF) mouse pups from their biological mother to unrelated lactating females. Yet, these dynamics remain poorly understood. We show RCF-associated intergenerational transmission of CO2 sensitivity in normally-reared mice descending from RCF-exposed females, and describe the accompanying alterations in brain DNA methylation patterns. These epigenetic signatures were compared to DNA methylation profiles of monozygotic twins discordant for emotional reactivity to a CO2 challenge. Altered methylation was consistently associated with repeated elements and transcriptional regulatory regions among RCF-exposed animals, their normally-reared offspring, and humans with CO2 hypersensitivity. In both species, regions bearing differential methylation were associated with neurodevelopment, circulation, and response to pH acidification processes, and notably included the ASIC2 gene. Our data show that CO2 hypersensitivity is associated with specific methylation clusters and genes that subserve chemoreception and anxiety. The methylation status of genes implicated in acid-sensing functions can inform etiological and therapeutic research in this field.
Three Dimensional Polarimetric Neutron Tomography of Magnetic Fields
Authors: Sales Morten , Strobl Markus , Shinohara Takenao , Tremsin Anton , Kuhn Luise Theil , Lionheart William R. B. , Desai Naeem M. , Dahl Anders Bjorholm , Schmidt Søren
Published: January 2018

Through the use of Time-of-Flight Three Dimensional Polarimetric Neutron Tomography (ToF 3DPNT) we have for the first time successfully demonstrated a technique capable of measuring and reconstructing three dimensional magnetic field strengths and directions unobtrusively and non-destructively with the potential to probe the interior of bulk samples which is not amenable otherwise. Using a pioneering polarimetric set-up for ToF neutron instrumentation in combination with a newly developed tailored reconstruction algorithm, the magnetic field generated by a current carrying solenoid has been measured and reconstructed, thereby providing the proof-of-principle of a technique able to reveal hitherto unobtainable information on the magnetic fields in the bulk of materials and devices, due to a high degree of penetration into many materials, including metals, and the sensitivity of neutron polarisation to magnetic fields. The technique puts the potential of the ToF time structure of pulsed neutron sources to full use in order to optimise the recorded information quality and reduce measurement time.
Broad impact of extracellular DNA on biofilm formation by clinically isolated Methicillin-resistant and -sensitive strains of Staphylococcus aureus
Authors: Sugimoto Shinya , Sato Fumiya , Miyakawa Reina , Chiba Akio , Onodera Shoichi , Hori Seiji , Mizunoe Yoshimitsu
Published: January 2018

Staphylococcus aureus is a major causative agent for biofilm-associated infections. Inside biofilms, S. aureus cells are embedded in an extracellular matrix (ECM) composed of polysaccharide-intercellular adhesins (PIA), proteins, and/or extracellular DNA (eDNA). However, the importance of each component and the relationship among them in biofilms of diverse strains are largely unclear. Here, we characterised biofilms formed by 47 S. aureus clinical isolates. In most (42/47) of the strains, biofilm formation was augmented by glucose supplementation. Sodium chloride (NaCl)-triggered biofilm formation was more prevalent in methicillin-sensitive S. aureus (15/24) than in methicillin-resistant strain (1/23). DNase I most effectively inhibited and disrupted massive biofilms, and Proteinase K was also effective. Anti-biofilm effects of Dispersin B, which cleaves PIA, were restricted to PIA-dependent biofilms formed by specific strains and showed significant negative correlations with those of Proteinase K, suggesting independent roles of PIA and proteins in each biofilm. ECM profiling demonstrated that eDNA was present in all strains, although its level differed among strains and culture conditions. These results indicate that eDNA is the most common component in S. aureus biofilms, whereas PIA is important for a small number of isolates. Therefore, eDNA can be a primary target for developing eradication strategies against S. aureus biofilms.
Dynamic changes of phenotypically different circulating tumor cells sub-populations in patients with recurrent/refractory small cell lung cancer treated with pazopanib
Authors: Messaritakis Ippokratis , Politaki Eleni , Koinis Fillipos , Stoltidis Dimitris , Apostolaki Stella , Plataki Maria , Dermitzaki Eleftheria-Kleio , Georgoulias Vassilis , Kotsakis Athanasios
Published: January 2018

The aim of the study was to investigate the effect of 2nd-line pazopanib on the different CTCs subpopulations in SCLC patients and evaluate the clinical relevance of their changes. Different CTCs subpopulations were evaluated before pazopanib initiation (n = 56 patients), after one-cycle (n = 35) and on disease progression (n = 45) by CellSearch and double immunofluorescence using anti-CKs and anti-Ki67, anti-M30 or anti-Vimentin antibodies. Before treatment, CTCs were detected in 50% of patients by CellSearch whereas 53.4%, 15.5% and 74.1% patients had CK+/Ki67+, CK+/M30+ and CK+/Vim+ CTCs, respectively. One pazopanib cycle significantly decreased the number of CTCs as detected by CellSearch (p = 0.043) as well as the number of CK+/Ki67+ (p < 0.001), CK+/M30+ (p = 0.015) and CK+/Vim+ (p < 0.001) cells. On disease progression, both the incidence and CTC numbers were significantly increased (CellSearch, p = 0.027; CK+/Ki67+, p < 0.001; CK+/M30+, p = 0.001 and CK+/Vim+, p < 0.001). In multivariate analysis, the detection of CK+/Vim+ CTCs after one treatment cycle (HR: 7.9, 95% CI: 2.9–21.8; p < 0.001) and CTCs number on disease progression, as assessed by CellSearch, (HR: 2.0, 95% CI: 1.0–6.0; p = 0.005) were emerged as independent factors associated with decreased OS. In conclusion, pazopanib can eliminate different CTC subpopulations in patients with relapsed SCLC. The analysis of CTCs could be used as a dynamic biomarker of treatment efficacy.
VO2-dispersed glass: A new class of phase change material
Authors: Muramoto Kei , Takahashi Yoshihiro , Terakado Nobuaki , Yamazaki Yoshiki , Suzuki Shigeru , Fujiwara Takumi
Published: January 2018

Energy storage technology is crucial for a sustainable society, and its realisation strongly depends on the development of materials. Oxide glass exhibits high durability. Moreover, the amorphous structure of the glass without periodic ordering demonstrates excellent formability and controllability, thus enabling a large-scale production. These factors provide impetus for the development of new materials for thermal management applications. As vanadium dioxide (VO2) with a strongly correlated electron system exhibits a structural phase transition, leading to a large heat of transition. Therefore, VO2 demonstrates immense potential as a phase change material (PCM). This study reports the fabrication of VO2-dispersed glass and examines its potential as a new latent heat storage material, which can be applied for massive PCM heat storage applications.
Blocking extracellular activation of myostatin as a strategy for treating muscle wasting
Authors: Pirruccello-Straub M. , Jackson J. , Wawersik S. , Webster M. T. , Salta L. , Long K. , McConaughy W. , Capili A. , Boston C. , Carven G. J. , Mahanthappa N. K. , Turner K. J. , Donovan A.
Published: January 2018

Many growth factors are intimately bound to the extracellular matrix, with regulated processing and release leading to cellular stimulation. Myostatin and GDF11 are closely related members of the TGFβ family whose activation requires two proteolytic cleavages to release the growth factor from the prodomain. Specific modulation of myostatin and GDF11 activity by targeting growth factor-receptor interactions has traditionally been challenging. Here we demonstrate that a novel strategy for blocking myostatin and GDF11, inhibition of growth factor release, specifically and potently inhibits signaling both in vitro and in vivo. We developed human monoclonal antibodies that selectively bind the myostatin and GDF11 precursor forms, including a subset that inhibit myostatin proteolytic activation and prevent muscle atrophy in vivo. The most potent myostatin activation-blocking antibodies promoted robust muscle growth and resulted in significant gains in muscle performance in healthy mice. Altogether, we show that blocking the extracellular activation of growth factors is a potent method for preventing signaling, serving as proof of concept for a novel therapeutic strategy that can be applied to other members of the TGFβ family of growth factors.
Decreased TESK1-mediated cofilin 1 phosphorylation in the jejunum of IBS-D patients may explain increased female predisposition to epithelial dysfunction
Authors: Rodiño-Janeiro Bruno K. , Martínez Cristina , Fortea Marina , Lobo Beatriz , Pigrau Marc , Nieto Adoración , González-Castro Ana María , Salvo-Romero Eloísa , Guagnozzi Danila , Pardo-Camacho Cristina , Iribarren Cristina , Azpiroz Fernando , Alonso-Cotoner Carmen , Santos Javier , Vicario Maria
Published: January 2018

Disturbed intestinal epithelial barrier and mucosal micro-inflammation characterize irritable bowel syndrome (IBS). Despite intensive research demonstrating ovarian hormones modulation of IBS severity, there is still limited knowledge on the mechanisms underlying female predominance in this disorder. Our aim was to identify molecular pathways involved in epithelial barrier dysfunction and female predominance in diarrhea-predominant IBS (IBS-D) patients. Total RNA and protein were obtained from jejunal mucosal biopsies from healthy controls and IBS-D patients meeting the Rome III criteria. IBS severity was recorded based on validated questionnaires. Gene and protein expression profiles were obtained and data integrated to explore biological and molecular functions. Results were validated by western blot. Tight junction signaling, mitochondrial dysfunction, regulation of actin-based motility by Rho, and cytoskeleton signaling were differentially expressed in IBS-D. Decreased TESK1-dependent cofilin 1 phosphorylation (pCFL1) was confirmed in IBS-D, which negatively correlated with bowel movements only in female participants. In conclusion, deregulation of cytoskeleton dynamics through TESK1/CFL1 pathway underlies epithelial intestinal dysfunction in the small bowel mucosa of IBS-D, particularly in female patients. Further understanding of the mechanisms involving sex-mediated regulation of mucosal epithelial integrity may have significant preventive, diagnostic, and therapeutic implications for IBS.
A multidrug ABC transporter with a taste for GTP
Authors: Orelle Cédric , Durmort Claire , Mathieu Khadija , Duchêne Benjamin , Aros Sandrine , Fenaille François , André François , Junot Christophe , Vernet Thierry , Jault Jean-Michel
Published: January 2018

During the evolution of cellular bioenergetics, many protein families have been fashioned to match the availability and replenishment in energy supply. Molecular motors and primary transporters essentially need ATP to function while proteins involved in cell signaling or translation consume GTP. ATP-Binding Cassette (ABC) transporters are one of the largest families of membrane proteins gathering several medically relevant members that are typically powered by ATP hydrolysis. Here, a Streptococcus pneumoniae ABC transporter responsible for fluoroquinolones resistance in clinical settings, PatA/PatB, is shown to challenge this concept. It clearly favors GTP as the energy supply to expel drugs. This preference is correlated to its ability to hydrolyze GTP more efficiently than ATP, as found with PatA/PatB reconstituted in proteoliposomes or nanodiscs. Importantly, the ATP and GTP concentrations are similar in S. pneumoniae supporting the physiological relevance of GTP as the energy source of this bacterial transporter.
Three-dimensional imaging of KNDy neurons in the mammalian brain using optical tissue clearing and multiple-label immunocytochemistry
Authors: Moore Aleisha M. , Lucas Kathryn A. , Goodman Robert L. , Coolen Lique M. , Lehman Michael N.
Published: January 2018

Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons of the arcuate nucleus (ARC) play a key role in the regulation of fertility. The ability to detect features of KNDy neurons that are essential for fertility may require three-dimensional (3D) imaging of the complete population. Recently developed protocols for optical tissue clearing permits 3D imaging of neuronal populations in un-sectioned brains. However, these techniques have largely been described in the mouse brain. We report 3D imaging of the KNDy cell population in the whole rat brain and sheep hypothalamus using immunolabelling and modification of a solvent-based clearing protocol, iDISCO. This study expands the use of optical tissue clearing for multiple mammalian models and provides versatile analysis of KNDy neurons across species. Additionally, we detected a small population of previously unreported kisspeptin neurons in the lateral region of the ovine mediobasal hypothalamus, demonstrating the ability of this technique to detect novel features of the kisspeptin system.
TDP-43 self-interaction is modulated by redox-active compounds Auranofin, Chelerythrine and Riluzole
Authors: Oberstadt Moritz , Stieler Jens , Simpong David Larbi , Römuß Ute , Urban Nicole , Schaefer Michael , Arendt Thomas , Holzer Max
Published: January 2018

Amyotrophic lateral sclerosis (ALS) represents a fatal neurodegenerative disease, which is characterized by a rapid loss of lower and upper motor neurons. As a major neuropathological hallmark, protein aggregates containing the Transactivating Response Region (TAR) DNA Binding Protein (TDP-43) are detectable in about 95% of sporadic ALS patients. TDP-43 interacts with itself physiologically to form liquid droplets, which may progress to pathological aggregates. In this study, we established the NanoBit luciferase complementation assay to measure TDP-43 self-interaction and found the fusion of the split luciferase subunits to the N-terminus of the protein as the strongest interacting partners. A screen of pharmacologically active compounds from the LOPAC®1280 library identified auranofin, chelerythrine and riluzole as dose-dependent inhibitors of TDP-43 self-interaction. Further analysis of drug action of the gold-containing thioredoxin reductase inhibitor auranofin revealed a redistribution from insoluble TDP-43 protein pool to PBS-soluble protein pool in N2a cells. In addition, auranofin treatment diminished reduced glutathione as a sign for oxidative modulation.
Tunable phonon blockade in quadratically coupled optomechanical systems
Authors: Shi Hai-Quan , Zhou Xiao-Tong , Xu Xun-Wei , Liu Nian-Hua
Published: January 2018

We theoretically investigate the phonon statistics of a quadratically coupled optomechanical system, in which an effective second-order nonlinear interaction between an optical mode and a mechanical mode is induced by a strong optical driving field on two-phonon red-sideband resonance. We show that strong phonon antibunching can be observed even if the strength of the effective second-order nonlinear interaction is much weaker than the decay rates of the system, by driving the optical and mechanical modes with weak driving fields respectively. Moreover, the phonon statistics can be dynamically controlled by tuning the strengths and the phase difference of the weak driving fields. The scheme proposed here can be used to realize tunable single-phonon sources with quadratically optomechanical coupling.
Water Resistant Cellulose – Titanium Dioxide Composites for Photocatalysis
Authors: Garusinghe Uthpala M. , Raghuwanshi Vikram S. , Batchelor Warren , Garnier Gil
Published: January 2018

Novel water resistant photocatalytic composites of microfibrillated cellulose (MFC)—polyamide-amine-epichlorohydrin (PAE)—TiO2 nanoparticles (NPs) were prepared by a simple two-step mixing process. The composites produced are flexible, uniform, reproducible and reusable; they can readily be removed from the pollutant once used. Small amount of TiO2 NPs are required for the loaded composites to exhibit a remarkable photocatalytic activity which is quantified here as achieving at least 95% of methyl orange degradation under 150 min of UV light irradiation for the composite with best combination. The cellulose network combined with PAE strongly retains NPs and hinders their release in the environment. PAE dosage (10 and 50 mg/g MFC) controls the NP retention in the cellulose fibrous matrix. As TiO2 content increases, the photocatalytic activity of the composites levels off to a constant; this is reached at 2wt% TiO2 NPs for 10 mg/g PAE and 20wt% for 50 mg/g PAE. SEM and SAXS analysis confirms the uniform distribution of NPs and their formation of aggregates in the cellulose fibre network. These economical and water resistant photocatalytic paper composites made by a simple, robust and easily scalable process are ideal for applications such as waste water treatment where efficiency, reusability and recyclability are important.
Functional loss of p53 cooperates with the in vivo microenvironment to promote malignant progression of gastric cancers
Authors: Ohtsuka Junko , Oshima Hiroko , Ezawa Issei , Abe Ryo , Oshima Masanobu , Ohki Rieko
Published: January 2018

p53 mutations are frequently detected in malignant gastric cancers. However, the molecular mechanisms by which loss of p53 function promotes gastric cancer are not clear. We utilized Gan mice (K19-Wnt1/C2mE), which have functional p53 and develop intestinal-type gastric tumors, to investigate the role of p53 in gastric cancer progression by knocking out p53. We found that gastric epithelial cells acquire tumorigenicity in the subcutis of C57BL/6 mice as a result of Wnt activation, COX-2 activation and p53 deficiency. With repeated allograft transfers, these gastric epithelial cells gradually acquired the properties of malignant gastric cancer. Loss of p53 conferred cell stemness and induced epithelial to mesenchymal transition (EMT) in gastric epithelial cells, and these properties were further enhanced by the in vivo microenvironment, ultimately leading to gastric cancer formation and metastasis. We also found that the in vivo microenvironment enhanced activation of the COX-2 pathway, which further contributed to cancer progression. With this system, we have succeeded in recapitulating the development of malignant gastric cancer from gastric epithelial cells in a normal immune environment.
Most species are not limited by an Amazonian river postulated to be a border between endemism areas
Authors: Santorelli Sergio , Magnusson William E. , Deus Claudia P.
Published: January 2018

At broad scales in the Amazon, it is often hypothesized that species distributions are limited by geographical barriers, such as large rivers (river-barrier hypothesis). This hypothesis has been used to explain the spatial-distribution limits of species and to indicate endemism areas for several phylogenetic lineages. We tested the ability of the river-barrier hypothesis to explain patterns of species diversity and spatial-distribution limits for 1952 easily-detected species in 14 taxonomic groups that occur around the Madeira River, and our results indicate that the hypothesis that the Madeira River is the border between endemism areas and explains much of the diversity found in the region is inappropriate for >99% of species. This indicates that alternative hypotheses should be proposed to explain the limits of distributions of species around the Madeira River, as well as a revision of the criteria that are used to determine species-endemism areas.