bluuebunny/crossref_metadata_2025 huggingface dataset:
Light-driven liquid metal nanotransformers for biomedical theranostics
Authors: Chechetka Svetlana A. , Yu Yue , Zhen Xu , Pramanik Manojit , Pu Kanyi , Miyako Eijiro
Published: May 2017

Room temperature liquid metals (LMs) represent a class of emerging multifunctional materials with attractive novel properties. Here, we show that photopolymerized LMs present a unique nanoscale capsule structure characterized by high water dispersibility and low toxicity. We also demonstrate that the LM nanocapsule generates heat and reactive oxygen species under biologically neutral near-infrared (NIR) laser irradiation. Concomitantly, NIR laser exposure induces a transformation in LM shape, destruction of the nanocapsules, contactless controlled release of the loaded drugs, optical manipulations of a microfluidic blood vessel model and spatiotemporal targeted marking for X-ray-enhanced imaging in biological organs and a living mouse. By exploiting the physicochemical properties of LMs, we achieve effective cancer cell elimination and control of intercellular calcium ion flux. In addition, LMs display a photoacoustic effect in living animals during NIR laser treatment, making this system a powerful tool for bioimaging.
Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions
Authors: Sucker Antje , Zhao Fang , Pieper Natalia , Heeke Christina , Maltaner Raffaela , Stadtler Nadine , Real Birgit , Bielefeld Nicola , Howe Sebastian , Weide Benjamin , Gutzmer Ralf , Utikal Jochen , Loquai Carmen , Gogas Helen , Klein-Hitpass Ludger , Zeschnigk Michael , Westendorf Astrid M. , Trilling Mirko , Horn Susanne , Schilling Bastian , Schadendorf Dirk , Griewank Klaus G. , Paschen Annette
Published: May 2017

Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8+ T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ. Allelic JAK1/2 losses predisposing to IFNγ resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-tumour IFNγ activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNγ resistance should be considered in therapeutic decision-making.
Giant electron-hole transport asymmetry in ultra-short quantum transistors
Authors: McRae A. C. , Tayari V. , Porter J. M. , Champagne A. R.
Published: May 2017

Making use of bipolar transport in single-wall carbon nanotube quantum transistors would permit a single device to operate as both a quantum dot and a ballistic conductor or as two quantum dots with different charging energies. Here we report ultra-clean 10 to 100 nm scale suspended nanotube transistors with a large electron-hole transport asymmetry. The devices consist of naked nanotube channels contacted with sections of tube under annealed gold. The annealed gold acts as an n-doping top gate, allowing coherent quantum transport, and can create nanometre-sharp barriers. These tunnel barriers define a single quantum dot whose charging energies to add an electron or a hole are vastly different (e−h charging energy asymmetry). We parameterize the e−h transport asymmetry by the ratio of the hole and electron charging energies ηe−h. This asymmetry is maximized for short channels and small band gap tubes. In a small band gap device, we demonstrate the fabrication of a dual functionality quantum device acting as a quantum dot for holes and a much longer quantum bus for electrons. In a 14 nm-long channel, ηe−h reaches up to 2.6 for a device with a band gap of 270 meV. The charging energies in this device exceed 100 meV.
Smooth 2D manifold extraction from 3D image stack
Authors: Shihavuddin Asm , Basu Sreetama , Rexhepaj Elton , Delestro Felipe , Menezes Nikita , Sigoillot Séverine M , Del Nery Elaine , Selimi Fekrije , Spassky Nathalie , Genovesio Auguste
Published: May 2017

Three-dimensional fluorescence microscopy followed by image processing is routinely used to study biological objects at various scales such as cells and tissue. However, maximum intensity projection, the most broadly used rendering tool, extracts a discontinuous layer of voxels, obliviously creating important artifacts and possibly misleading interpretation. Here we propose smooth manifold extraction, an algorithm that produces a continuous focused 2D extraction from a 3D volume, hence preserving local spatial relationships. We demonstrate the usefulness of our approach by applying it to various biological applications using confocal and wide-field microscopy 3D image stacks. We provide a parameter-free ImageJ/Fiji plugin that allows 2D visualization and interpretation of 3D image stacks with maximum accuracy.
End-Triassic mass extinction started by intrusive CAMP activity
Authors: Davies J.H.F.L. , Marzoli A. , Bertrand H. , Youbi N. , Ernesto M. , Schaltegger U.
Published: May 2017

The end-Triassic extinction is one of the Phanerozoic’s largest mass extinctions. This extinction is typically attributed to climate change associated with degassing of basalt flows from the central Atlantic magmatic province (CAMP). However, recent work suggests that the earliest known CAMP basalts occur above the extinction horizon and that climatic and biotic changes began before the earliest known CAMP eruptions. Here we present new high-precision U-Pb ages from CAMP mafic intrusive units, showing that magmatic activity was occurring ∼100 Kyr ago before the earliest known eruptions. We correlate the early magmatic activity with the onset of changes to the climatic and biotic records. We also report ages from sills in an organic rich sedimentary basin in Brazil that intrude synchronously with the extinction suggesting that degassing of these organics contributed to the climate change which drove the extinction. Our results indicate that the intrusive record from large igneous provinces may be more important for linking to mass extinctions than the eruptive record.
WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy
Authors: Bakula Daniela , Müller Amelie J. , Zuleger Theresia , Takacs Zsuzsanna , Franz-Wachtel Mirita , Thost Ann-Katrin , Brigger Daniel , Tschan Mario P. , Frickey Tancred , Robenek Horst , Macek Boris , Proikas-Cezanne Tassula
Published: May 2017

Autophagy is controlled by AMPK and mTOR, both of which associate with ULK1 and control the production of phosphatidylinositol 3-phosphate (PtdIns3P), a prerequisite for autophagosome formation. Here we report that WIPI3 and WIPI4 scaffold the signal control of autophagy upstream of PtdIns3P production and have a role in the PtdIns3P effector function of WIPI1-WIPI2 at nascent autophagosomes. In response to LKB1-mediated AMPK stimulation, WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes, controlling their size, to which WIPI3, in complex with FIP200, also contributes. Upstream, WIPI3 associates with AMPK-activated TSC complex at lysosomes, regulating mTOR. Our WIPI interactome analysis reveals the scaffold functions of WIPI proteins interconnecting autophagy signal control and autophagosome formation. Our functional kinase screen uncovers a novel regulatory link between LKB1-mediated AMPK stimulation that produces a direct signal via WIPI4, and we show that the AMPK-related kinases NUAK2 and BRSK2 regulate autophagy through WIPI4.
Real-time monitoring of hydrophobic aggregation reveals a critical role of cooperativity in hydrophobic effect
Authors: Jiang Liguo , Cao Siqin , Cheung Peter Pak-Hang , Zheng Xiaoyan , Leung Chris Wai Tung , Peng Qian , Shuai Zhigang , Tang Ben Zhong , Yao Shuhuai , Huang Xuhui
Published: May 2017

The hydrophobic interaction drives nonpolar solutes to aggregate in aqueous solution, and hence plays a critical role in many fundamental processes in nature. An important property intrinsic to hydrophobic interaction is its cooperative nature, which is originated from the collective motions of water hydrogen bond networks surrounding hydrophobic solutes. This property is widely believed to enhance the formation of hydrophobic core in proteins. However, cooperativity in hydrophobic interactions has not been successfully characterized by experiments. Here, we quantify cooperativity in hydrophobic interactions by real-time monitoring the aggregation of hydrophobic solute (hexaphenylsilole, HPS) in a microfluidic mixer. We show that association of a HPS molecule to its aggregate in water occurs at sub-microsecond, and the free energy change is −5.8 to −13.6 kcal mol−1. Most strikingly, we discover that cooperativity constitutes up to 40% of this free energy. Our results provide quantitative evidence for the critical role of cooperativity in hydrophobic interactions.
Inflammatory breast cancer: a model for investigating cluster-based dissemination
Authors: Jolly Mohit Kumar , Boareto Marcelo , Debeb Bisrat G. , Aceto Nicola , Farach-Carson Mary C. , Woodward Wendy A. , Levine Herbert
Published: May 2017

Metastases claim more than 90% of cancer-related patient deaths and are usually seeded by a subset of circulating tumor cells shed off from the primary tumor. In circulation, circulating tumor cells are found both as single cells and as clusters of cells. The clusters of circulating tumor cells, although many fewer in number, possess much higher metastatic potential as compared to that of individual circulating tumor cells. In this review, we highlight recent insights into molecular mechanisms that can enable the formation of these clusters—(a) hybrid epithelial/mesenchymal phenotype of cells that couples their ability to migrate and adhere, and (b) intercellular communication that can spatially coordinate the cluster formation and provide survival signals to cancer cells. Building upon these molecular mechanisms, we also offer a possible mechanistic understanding of why clusters are endowed with a higher metastatic potential. Finally, we discuss the highly aggressive Inflammatory Breast Cancer as an example of a carcinoma that can metastasize via clusters and corroborates the proposed molecular mechanisms.
Piezoelectric Microstructured Fibers via Drawing of Multimaterial Preforms
Authors: Lu Xin , Qu Hang , Skorobogatiy Maksim
Published: May 2017

We demonstrate planar laminated piezoelectric generators and piezoelectric microstructured fibers based on BaTiO3-polyvinylidene and carbon-loaded-polyethylene materials combinations. The laminated piezoelectric generators were assembled by sandwiching the electrospun BaTiO3-polyvinylidene mat between two carbon-loaded-polyethylene films. The piezoelectric microstructured fiber was fabricated via drawing of the multilayer fiber preform, and features a swissroll geometry that have ~10 alternating piezoelectric and conductive layers. Both piezoelectric generators have excellent mechanical durability, and could retain their piezoelectric performance after 3 day’s cyclic bend-release tests. Compared to the laminated generators, the piezoelectric fibers are advantageous as they could be directly woven into large-area commercial fabrics. Potential applications of the proposed piezoelectric fibers include micro-power-generation and remote sensing in wearable, automotive and aerospace industries.
Myricetin protects Galleria mellonella against Staphylococcus aureus infection and inhibits multiple virulence factors
Authors: Silva L. N. , Da Hora G. C. A. , Soares T. A. , Bojer M. S. , Ingmer H. , Macedo A. J. , Trentin D. S.
Published: May 2017

Staphylococcus aureus is an opportunistic pathogen related to a variety of life-threatening infections but for which antimicrobial resistance is liming the treatment options. We report here that myricetin, but not its glycosylated form, can remarkably decrease the production of several S. aureus virulence factors, including adhesion, biofilm formation, hemolysis and staphyloxanthin production, without interfering with growth. Myricetin affects both surface proteins and secreted proteins which indicate that its action is unrelated to inhibition of the agr quorum sensing system. Analysis of virulence related gene expression and computational simulations of pivotal proteins involved in pathogenesis demonstrate that myricetin downregulates the saeR global regulator and interacts with sortase A and α-hemolysin. Furthermore, Myr confers a significant degree of protection against staphylococcal infection in the Galleria mellonella model. The present findings reveal the potential of Myr as an alternative multi-target antivirulence candidate to control S. aureus pathogenicity.
Temporal evolution of a seismic sequence induced by a gas injection in the Eastern coast of Spain
Authors: Ruiz-Barajas S. , Sharma N. , Convertito V. , Zollo A. , Benito B.
Published: May 2017

Induced seismicity associated with energy production is becoming an increasingly important issue worldwide for the hazard it poses to the exposed population and structures. We analyze one of the rare cases of induced seismicity associated with the underwater gas storage operations observed in the Castor platform, located in the Valencia gulf, east Spain, near a complex and important geological structure. In September 2013, some gas injection operations started at Castor, producing a series of seismic events around the reservoir area. The larger magnitude events (up to 4.2) took place some days after the end of the injection, with EMS intensities in coastal towns up to degree III. In this work, the seismic sequence is analyzed with the aim of detecting changes in statistical parameters describing the earthquake occurrence before and after the injection and identifying possible proxies to be used for monitoring the sequence evolution. Moreover, we explore the potential predictability of these statistical parameters which can be used to control the field operations in injection/storage fluid reservoirs. We firstly perform a retrospective approach and next a perspective analysis. We use different techniques for estimating the value of the expected maximum magnitude that can occur due to antropogenic activities in Castor.
Electron Ptychographic Diffractive Imaging of Boron Atoms in LaB6 Crystals
Authors: Wang Peng , Zhang Fucai , Gao Si , Zhang Mian , Kirkland Angus I.
Published: May 2017

Ptychographic diffractive imaging has the potential for structural determination of materials without the constraints of relatively small, isolated samples required for conventional coherent diffractive imaging. The increased illumination diversity introduced using multiple measurements (overlapped probe positions) also provides higher sensitivity to phase changes in weakly scattering samples. The resolution of a ptychographic reconstruction is ultimately determined by the diffraction limit for the wavelength of the radiation used. However, in practical experiments using electrons either the maximum collection angle of the detector used to record the data or the partial coherence of the source impose lower resolution limits. Nonetheless for medium energy electrons this suggests a potential sub 0.1 nm spatial resolution limit, comparable to that obtained using aberration corrected instruments. However, simultaneous visualization of light and heavier atoms in specimens using ptychography at sub 0.1 nm resolution presents a significant challenge. Here, we demonstrate a ptychographic reconstruction of a LaB6 crystal in which light B atoms were clearly resolved together with the heavy La atoms in the reconstructed phase. The technique used is general and can also be applied to non-crystalline and extended crystalline samples. As such it offers an alternative future basis for imaging the atomic structure of materials, particularly those containing low atomic number elements.
Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers
Authors: Lemieux Hélène , Blier Pierre U. , Gnaiger Erich
Published: May 2017

Fuel substrate supply and oxidative phosphorylation are key determinants of muscle performance. Numerous studies of mammalian mitochondria are carried out (i) with substrate supply that limits electron flow, and (ii) far below physiological temperature. To analyze potentially implicated biases, we studied mitochondrial respiratory control in permeabilized mouse myocardial fibers using high-resolution respirometry. The capacity of oxidative phosphorylation at 37 °C was nearly two-fold higher when fueled by physiological substrate combinations reconstituting tricarboxylic acid cycle function, compared with electron flow measured separately through NADH to Complex I or succinate to Complex II. The relative contribution of the NADH pathway to physiological respiratory capacity increased with a decrease in temperature from 37 to 25 °C. The apparent excess capacity of cytochrome c oxidase above physiological pathway capacity increased sharply under hypothermia due to limitation by NADH-linked dehydrogenases. This mechanism of mitochondrial respiratory control in the hypothermic mammalian heart is comparable to the pattern in ectotherm species, pointing towards NADH-linked mt-matrix dehydrogenases and the phosphorylation system rather than electron transfer complexes as the primary drivers of thermal sensitivity at low temperature. Delineating the link between stress and remodeling of oxidative phosphorylation is important for understanding metabolic perturbations in disease evolution and cardiac protection.
De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity
Authors: Nishi Akira , Numata Shusuke , Tajima Atsushi , Zhu Xiaolei , Ito Koki , Saito Atsushi , Kato Yusuke , Kinoshita Makoto , Shimodera Shinji , Ono Shinji , Ochi Shinichiro , Imamura Akira , Kurotaki Naohiro , Ueno Shu-ichi , Iwata Nakao , Fukui Kiyoshi , Imoto Issei , Kamiya Atsushi , Ohmori Tetsuro
Published: May 2017

Here we report de novo non-synonymous single-nucleotide variants (SNVs) by conducting whole exome sequencing of 18 trios consisting of Japanese patients with sporadic schizophrenia and their parents. Among nine SNVs, we explored the functional impact of the de novo mutation in TBL1XR1 [c.30 C > G (p.Phe10Leu)], a gene previously found to be associated with autism spectrum disorder and epilepsy. Protein structural analysis revealed that Phe10Leu mutation may decrease the structural stability of the TBL1XR1 protein. We demonstrate that Phe10Leu mutation alters the interaction of TBL1XR1 with N-CoR and β-catenin, which play critical roles in regulation of Wnt-mediated transcriptional activity. Consistently, TBL1XR1-mediated activation of Wnt signaling was up-regulated by Phe10Leu mutation. These results suggest that a de novo TBL1XR1 point mutation could alter Wnt/β-catenin signaling activity. Further studies are required to clarify the involvement of TBL1XR1 mutations in neuropsychiatric conditions.
High-resolution promoter map of human limbal epithelial cells cultured with keratinocyte growth factor and rho kinase inhibitor
Authors: Yoshihara Masahito , Sasamoto Yuzuru , Hayashi Ryuhei , Ishikawa Yuki , Tsujikawa Motokazu , Hayashizaki Yoshihide , Itoh Masayoshi , Kawaji Hideya , Nishida Kohji
Published: May 2017

An in vitro model of corneal epithelial cells (CECs) has been developed to study and treat corneal disorders. Nevertheless, conventional CEC culture supplemented with epidermal growth factor (EGF) results in a loss of CEC characteristics. It has recently been reported that limbal epithelial cells (LECs) cultured with keratinocyte growth factor (KGF) and the rho kinase inhibitor Y-27632 could maintain the expression of several CEC-specific markers. However, the molecular mechanism underlying the effect of culture media on LECs remains to be elucidated. To elucidate this mechanism, we performed comprehensive gene expression analysis of human LECs cultured with EGF or KGF/Y-27632, by cap analysis of gene expression (CAGE). Here, we found that LECs cultured with KGF and Y-27632 presented a gene expression profile highly similar to that of CECs in vivo. In contrast, LECs cultured with EGF lost the characteristic CEC gene expression profile. We further discovered that CEC-specific PAX6 promoters are highly activated in LECs cultured with KGF and Y-27632. Our results provide strong evidence that LECs cultured with KGF and Y-27632 would be an improved in vitro model in the context of gene expression. These findings will accelerate basic studies of CECs and clinical applications in regenerative medicine.
Comparison and immunobiological characterization of retinoic acid inducible gene-I-like receptor expression in mesenchymal stromal cells
Authors: Raicevic Gordana , Najar Mehdi , Busser Hélène , Crompot Emerence , Bron Dominique , Toungouz Michel , Lagneaux Laurence
Published: May 2017

Due to their immunomodulatory and regenerative properties, Mesenchymal stromal cells (MSC) have generated major interests in several clinical settings including transplantation and inflammatory diseases. MSC functions can be influenced by their tissue origin. Their microenvironment strongly affects their biology notably through TLR sensing. In this study, we show that MSC isolated from four different sources express another type of cytosolic pathogen recognition receptors known as retinoic acid inducible gene-I (RIG-I)-like receptors (RLR). RLR activation in MSC induces the production of Type I IFN (IFN-β) and Type III IFN (IFN-λ1). The highest producers are adipose tissue(AT)-MSC. We further show that Interferon production is induced through TBK1/IKK-ε signaling and IRF7 phosphorylation. Depending on MSC source, the knockdown of TLR3 and/or RIG-I decreases the MSC response to RLR ligand poly(I:C)/Lyovec. Among the different MSC types, AT-MSCs display the highest sensitivity to viral stimuli as shown by the alteration of their viability after prolonged stimulation. Our work indicates that this could be linked to an increase of pro-apoptotic Noxa expression. Finally, the expression of IDO1 and LIF upon RLR activation indicate the increase of MSC immunomodulatory potential, especially in AT-MSCs. Altogether, these data should be considered when designing MSC-based therapy in clinical settings where inflammation or infection are present.
Disentangling Auger decays in O2 by photoelectron-ion coincidences
Authors: Liu Xiao-Jing , Nicolas Christophe , Patanen Minna , Miron Catalin
Published: May 2017

In non-resonant Auger electron spectroscopies, multi core-ionized states lead to numerous energetically close-lying electronic transitions in Auger spectra, this hampering the assignment and interpretation of the experimental results. Here we reveal a new method to overcome this intrinsic limitation of non-resonant inner-shell spectroscopies. In a proof-of-principle experiment performed for the O2 molecule, most of the Auger final states are dissociative, and we measure in coincidence the kinetic energy of the photoelectron and the kinetic energy release of the (O+, O+) ion pairs produced after the Auger decay of the O 1s−1 core-ionized states. The Auger final states are assigned using energy conservation. We fully separate the contributions from the 4Σ− and 2Σ− intermediate ionic states and conclusively demonstrate that the Auger decay probability can dramatically depend on the different O2 1s−1 intermediate multiplet states. In addition, a metastable Auger final state also exists, with lifetime longer than 3.8 μs, and clear changes are observed in both branching ratio and spectral profile of the O 1s photoelectron spectrum when they are recorded in coincidence with either $${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{+}}{\boldsymbol{+}}}$$

O

2

+
+

or with other ionic species. These changes are attributed to the population of the metastable $${{\boldsymbol{B}}}^{{\boldsymbol{^{\prime} }}3}{{\boldsymbol{\Sigma }}}_{{\boldsymbol{u}}}^{-}({\boldsymbol{\nu }}{\boldsymbol{^{\prime\prime} }}{\boldsymbol{=}}0)$$

B

′
3

Σ

u

−

(
ν
″
=
0
)
Auger final state via different intermediate states.
Gut Dysbiosis and Neurobehavioral Alterations in Rats Exposed to Silver Nanoparticles
Authors: Javurek Angela B. , Suresh Dhananjay , Spollen William G. , Hart Marcia L. , Hansen Sarah A. , Ellersieck Mark R. , Bivens Nathan J. , Givan Scott A. , Upendran Anandhi , Kannan Raghuraman , Rosenfeld Cheryl S.
Published: May 2017

Due to their antimicrobial properties, silver nanoparticles (AgNPs) are being used in non-edible and edible consumer products. It is not clear though if exposure to these chemicals can exert toxic effects on the host and gut microbiome. Conflicting studies have been reported on whether AgNPs result in gut dysbiosis and other changes within the host. We sought to examine whether exposure of Sprague-Dawley male rats for two weeks to different shapes of AgNPs, cube (AgNC) and sphere (AgNS) affects gut microbiota, select behaviors, and induces histopathological changes in the gastrointestinal system and brain. In the elevated plus maze (EPM), AgNS-exposed rats showed greater number of entries into closed arms and center compared to controls and those exposed to AgNC. AgNS and AgNC treated groups had select reductions in gut microbiota relative to controls. Clostridium spp., Bacteroides uniformis, Christensenellaceae, and Coprococcus eutactus were decreased in AgNC exposed group, whereas, Oscillospira spp., Dehalobacterium spp., Peptococcaeceae, Corynebacterium spp., Aggregatibacter pneumotropica were reduced in AgNS exposed group. Bacterial reductions correlated with select behavioral changes measured in the EPM. No significant histopathological changes were evident in the gastrointestinal system or brain. Findings suggest short-term exposure to AgNS or AgNC can lead to behavioral and gut microbiome changes.
The anti-cholesterolaemic effect of a consortium of probiotics: An acute study in C57BL/6J mice
Authors: Michael D. R. , Davies T. S. , Moss J. W. E. , Calvente D. Lama , Ramji D. P. , Marchesi J. R. , Pechlivanis A. , Plummer S. F. , Hughes T. R.
Published: May 2017

Hypercholesterolaemia is a major risk factor for cardiovascular disease and it has been found that some probiotic bacteria possess cholesterol-lowering capabilities. In this study, the ability of the Lab4 probiotic consortium to hydrolyse bile salts, assimilate cholesterol and regulate cholesterol transport by polarised Caco-2 enterocytes was demonstrated. Furthermore, in wild-type C57BL/6J mice fed a high fat diet, 2-weeks supplementation with Lab4 probiotic consortium plus Lactobacillusplantarum CUL66 resulted in significant reductions in plasma total cholesterol levels and suppression of diet-induced weight gain. No changes in plasma levels of very low-density lipoprotein/low-density lipoprotein, high-density lipoprotein, triglycerides, cytokines or bile acids were observed. Increased amounts of total and unconjugated bile acids in the faeces of the probiotic-fed mice, together with modulation of hepatic small heterodimer partner and cholesterol-7α-hydroxylase mRNA expression, implicates bile salt hydrolase activity as a potential mechanism of action. In summary, this study demonstrates the cholesterol-lowering efficacy of short-term feeding of the Lab4 probiotic consortium plus L. plantarum CUL66 in wild-type mice and supports further assessment in human trials.
A Central Small Amino Acid in the VAMP2 Transmembrane Domain Regulates the Fusion Pore in Exocytosis
Authors: Hastoy Benoît , Scotti Pier A. , Milochau Alexandra , Fezoua-Boubegtiten Zahia , Rodas Jorge , Megret Rémi , Desbat Bernard , Laguerre Michel , Castano Sabine , Perrais David , Rorsman Patrik , Oda Reiko , Lang Jochen
Published: May 2017

Exocytosis depends on cytosolic domains of SNARE proteins but the function of the transmembrane domains (TMDs) in membrane fusion remains controversial. The TMD of the SNARE protein synaptobrevin2/VAMP2 contains two highly conserved small amino acids, G100 and C103, in its central portion. Substituting G100 and/or C103 with the β-branched amino acid valine impairs the structural flexibility of the TMD in terms of α-helix/β-sheet transitions in model membranes (measured by infrared reflection-absorption or evanescent wave spectroscopy) during increase in protein/lipid ratios, a parameter expected to be altered by recruitment of SNAREs at fusion sites. This structural change is accompanied by reduced membrane fluidity (measured by infrared ellipsometry). The G100V/C103V mutation nearly abolishes depolarization-evoked exocytosis (measured by membrane capacitance) and hormone secretion (measured biochemically). Single-vesicle optical (by TIRF microscopy) and biophysical measurements of ATP release indicate that G100V/C103V retards initial fusion-pore opening, hinders its expansion and leads to premature closure in most instances. We conclude that the TMD of VAMP2 plays a critical role in membrane fusion and that the structural mobility provided by the central small amino acids is crucial for exocytosis by influencing the molecular re-arrangements of the lipid membrane that are necessary for fusion pore opening and expansion.
Rapamycin Attenuates Acute Seizure-induced Astrocyte Injury in Mice in Vivo
Authors: Guo Dongjun , Zou Jia , Wong Michael
Published: May 2017

Astrocytes have been implicated in epileptogenesis and seizure-induced brain injury. Pathological studies reveal a variety of structural abnormalities in astrocytes, such as vacuolization and astrogliosis. While in vivo imaging methods have demonstrated rapid changes in astrocytes under a variety of physiological and pathological conditions, the acute effects of seizures on astrocyte morphology in vivo and corresponding mechanisms of seizure-induced astrocytic injury have not been documented. In this study, we utilized in vivo two-photon imaging to directly monitor the acute structural effects of kainate-induced seizures on cortical astrocytes. Kainate seizures cause an immediate, but transient, vacuolization of astrocytes, followed over several days by astrogliosis. These effects are prevented by pre- or post-treatment with rapamycin, indicating the mTOR pathway is involved in mediating seizure-induced astrocyte injury. These finding have clinical implications for mechanisms of seizure-induced astrocyte injury and potential therapeutic applications with mTOR inhibitors.
Statistical study of ductility-dip cracking induced plastic deformation in polycrystalline laser 3D printed Ni-based superalloy
Authors: Qian Dan , Xue Jiawei , Zhang Anfeng , Li Yao , Tamura Nobumichi , Song Zhongxiao , Chen Kai
Published: May 2017

Ductility-dip cracking in Ni-based superalloy, resulting from heat treatment, is known to cause disastrous failure, but its mechanism is still not completely clear. A statistical study of the cracking behavior as a function of crystal orientation in a laser 3D-printed DL125L Ni-based superalloy polycrystal is investigated here using the synchrotron X-ray microdiffraction. The dislocation slip system in each of the forty crystal grains adjacent to the 300 μm long crack has been analyzed through Laue diffraction peak shapes. In all these grains, edge-type geometrically necessary dislocations (GNDs) dominate, and their dislocation line directions are almost parallel to the crack plane. Based on Schmid’s law, the equivalent uniaxial tensile force direction is revealed normal to the trace of the crack. A qualitative mechanism is thus proposed. Thermal tensile stress perpendicular to the laser scanning direction is elevated due to a significant temperature gradient, and thus locations in the materials where the thermal stress exceeds the yield stress undergo plastic deformation mediated by GND activations. As the dislocations slip inside the crystal grains and pile up at the grain boundaries, local strain/stress keeps increasing, until the materials in these regions fail to sustain further deformation, leading to voids formation and cracks propagation.
Contributions of the maternal oral and gut microbiome to placental microbial colonization in overweight and obese pregnant women
Authors: Gomez-Arango Luisa F. , Barrett Helen. L. , McIntyre H. David , Callaway Leonie K. , Morrison Mark , Nitert Marloes Dekker
Published: May 2017

A distinct bacterial signature of the placenta was reported, providing evidence that the fetus does not develop in a sterile environment. The oral microbiome was suggested as a possible source of the bacterial DNA present in the placenta based on similarities to the oral non-pregnant microbiome. Here, the possible origin of the placental microbiome was assessed, examining the gut, oral and placental microbiomes from the same pregnant women. Microbiome profiles from 37 overweight and obese pregnant women were examined by 16SrRNA sequencing. Fecal and oral contributions to the establishment of the placental microbiome were evaluated. Core phylotypes between body sites and metagenome predictive functionality were determined. The placental microbiome showed a higher resemblance and phylogenetic proximity with the pregnant oral microbiome. However, similarity decreased at lower taxonomic levels and microbiomes clustered based on tissue origin. Core genera: Prevotella, Streptococcus and Veillonella were shared between all body compartments. Pathways encoding tryptophan, fatty-acid metabolism and benzoate degradation were highly enriched specifically in the placenta. Findings demonstrate that the placental microbiome exhibits a higher resemblance with the pregnant oral microbiome. Both oral and gut microbiomes contribute to the microbial seeding of the placenta, suggesting that placental colonization may have multiple niche sources.
Human dimethylarginine dimethylaminohydrolase 1 inhibition by proton pump inhibitors and the cardiovascular risk marker asymmetric dimethylarginine: in vitro and in vivo significance
Authors: Tommasi S. , Elliot D. J. , Hulin J. A. , Lewis B. C. , McEvoy M. , Mangoni A. A.
Published: May 2017

Proton pump inhibitor (PPI)-induced inhibition of dimethylarginine dimethylaminohydrolase 1 (DDAH1), with consequent accumulation of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA), might explain the increased cardiovascular risk with PPI use. However, uncertainty exists regarding whether clinical PPI concentrations significantly inhibit DDAH1 under linear initial rate conditions, and whether PPI-induced DDAH1 inhibition significantly increases ADMA in humans. DDAH1 inhibition by esomeprazole, omeprazole, pantoprazole, lansoprazole and rabeprazole was determined by quantifying DDAH1-mediated L-citrulline formation in vitro. Plasma ADMA was measured in PPI users (n = 134) and non-users (n = 489) in the Hunter Community Study (HCS). At clinical PPI concentrations (0.1–10 μmol/L), DDAH1 retained >80% activity vs. baseline. A significant, reversible, time-dependent inhibition was observed with lansoprazole (66% activity at 240 min, P = 0.034) and rabeprazole (25% activity at 240 min, P < 0.001). In regression analysis, PPI use was not associated with ADMA in HCS participants (beta 0.012, 95% CI −0.001 to 0.025, P = 0.077). Furthermore, there were no differences in ADMA between specific PPIs (P = 0.748). At clinical concentrations, PPIs are weak, reversible, DDAH1 inhibitors in vitro. The lack of significant associations between PPIs and ADMA in HCS participants questions the significance of DDAH1 inhibition as a mechanism explaining the increased cardiovascular risk reported with PPI use.
Associations among ADHD, Abnormal Eating and Overweight in a non-clinical sample of Asian children
Authors: Tong Lian , Shi Huijing , Li Xiaoru
Published: May 2017

Attention-deficit/hyperactivity disorder (ADHD) has been found to be comorbid with obesity in adults, but the association in children is uncertain. Because the underlying mechanism of comorbidity in children has not been researched sufficiently, this study aims to explore the associations among ADHD, abnormal eating, and body mass index (BMI), as well as the mediating effect of depression in children. We conducted a cross-sectional study of 785 primary students in China. The parent-report version of ADHD Rating Scale-IV (ADHDRS-IV), the Child Eating Behaviour Questionnaire (CEBQ) and the Children’s Eating Attitude Test (ChEAT) were used to identify ADHD symptoms and abnormal eating. The Child Behavior Checklist (CBCL) was applied to assess depression. Structural Equation Modeling was carried out to clarify the associations between ADHD symptoms, depression, abnormal eating, and overweight of students. We found that ADHD positively contributed to emotional eating and Bulimia Nervosa symptoms. However, neither emotional eating nor Bulimia Nervosa symptoms was related to BMI in children. We also found that ADHD significantly contributed to depression, and depression directly predicted emotional eating. In conclusion, ADHD increased the risk of abnormal eating in children, while no significant relationship existed between ADHD and BMI. Comorbid depression raised the risk of emotional eating, rather than Bulimia Nervosa symptoms.
Insoluble (1 → 3), (1 → 4)-β-D-glucan is a component of cell walls in brown algae (Phaeophyceae) and is masked by alginates in tissues
Authors: Salmeán Armando A. , Duffieux Delphine , Harholt Jesper , Qin Fen , Michel Gurvan , Czjzek Mirjam , Willats William G. T. , Hervé Cécile
Published: May 2017

Brown algae are photosynthetic multicellular marine organisms. They belong to the phylum of Stramenopiles, which are not closely related to land plants and green algae. Brown algae share common evolutionary features with other photosynthetic and multicellular organisms, including a carbohydrate-rich cell-wall. Brown algal cell walls are composed predominantly of the polyanionic polysaccharides alginates and fucose-containing sulfated polysaccharides. These polymers are prevalent over neutral and crystalline components, which are believed to be mostly, if not exclusively, cellulose. In an attempt to better understand brown algal cell walls, we performed an extensive glycan array analysis of a wide range of brown algal species. Here we provide the first demonstration that mixed-linkage (1 → 3), (1 → 4)-β-d-glucan (MLG) is common in brown algal cell walls. Ultra-Performance Liquid Chromatography analyses indicate that MLG in brown algae solely consists of trisaccharide units of contiguous (1 → 4)-β-linked glucose residues joined by (1 → 3)-β-linkages. This regular conformation may allow long stretches of the molecule to align and to form well-structured microfibrils. At the tissue level, immunofluorescence studies indicate that MLG epitopes in brown algae are unmasked by a pre-treatment with alginate lyases to remove alginates. These findings are further discussed in terms of the origin and evolution of MLG in the Stramenopile lineage.
Retinol-binding protein-4 expression marks the short-term mortality of critically ill patients with underlying liver disease: Lipid, but not glucose, matters
Authors: Chen Wei-Ting , Lee Mu-Shien , Chang Chia-Lin , Chiu Cheng-Tang , Chang Ming-Ling
Published: May 2017

The implications of retinol-binding protein-4 (RBP4) expression in critically ill patients with underlying liver diseases remain unclear. A prospective cohort study involving 200 liver intensive care unit (ICU) patients was conducted, with 274 blood donors as controls. Patient outcomes were assessed using Cox and Kaplan-Meier analyses. Of the 200 ICU patients (mean age: 56.0 yrs), 79.5% were male, 72.5% were cirrhotic, 62% were septic, 29.5% were diabetic, and 29% expired in the ICU (median admission: 7.5 days). ICU patients had lower baseline RBP4 (25.6+/−18.4 vs. 43.8+/−35.0 mg/L, p < 0.001) and total cholesterol (TC) levels than controls. The surviving ICU patients had lower baseline international normalized ratios (INRs) of prothrombin time, model for end-stage liver disease (MELD) scores and sepsis rates, but higher estimated glomerular filtration rates (eGFRs) and RBP4 levels than non-surviving patients. eGFRs, INRs and TC levels were independently associated with RBP4 levels. Only surviving patients exhibited significantly increased RBP4 levels after ICU discharge. Baseline RBP4 levels and MELD scores predicted 21-day (≤10 mg/L) and 1-year (≥25) mortality, respectively. In critically ill patients with underlying liver disease, with a link to eGFRs, INRs and TC levels, the baseline RBP4 may serve as a marker for short-term mortality.
Ketogenic diet induces expression of the muscle circadian gene Slc25a25 via neural pathway that might be involved in muscle thermogenesis
Authors: Nakao Reiko , Shimba Shigeki , Oishi Katsutaka
Published: May 2017

We recently found that the mRNA expression of Slc25a25, a Ca2+-sensitive ATP carrier in the inner mitochondrial membrane, fluctuates in a circadian manner in mouse skeletal muscle. We showed here that the circadian expression of muscle Slc25a25 was damped in Clock mutant, muscle-specific Bmal1-deficient, and global Bmal1-deficient mice. Furthermore, a ketogenic diet (KD) that induces time-of-day-dependent hypothermia (torpor), induced Slc25a25 mRNA expression in skeletal muscle. Hypothermia induced by KD did not affect thermogenic genes such as Sarcolipin and Pgc1a in muscles and Ucp1 in adipose tissues. Sciatic denervation abolished circadian and KD-induced Slc25a25 expression, suggesting that the circadian clock regulates muscle Slc25a25 expression via neural pathways. We measured body temperature (Tb) in sciatic denervated mice fed with KD to determine the functional role of KD-induced Slc25a25 expression. Sciatic denervation abolished Slc25a25 expression and augmented KD-induced hypothermia compared with sham-operated mice, but did not affect Tb in mice given a normal diet. These findings suggest that KD feeding induces expression of the muscle circadian gene Slc25a25 via neural pathways, and that SLC25A25 might be involved in muscle thermogenesis under KD-induced hypothermia in mammals.
Heterogeneity of Diffusion-Weighted Imaging in Tumours and the Surrounding Stroma for Prediction of Ki-67 Proliferation Status in Breast Cancer
Authors: Fan Ming , He Ting , Zhang Peng , Zhang Juan , Li Lihua
Published: May 2017

Breast tissue heterogeneity is related to risk factors that lead to more aggressive tumour growth and worse prognosis, yet such heterogeneity has not been well characterized. The aim of this study is to reveal the heterogeneous signal patterns of the apparent diffusion coefficient (ADC) of a tumour and its surrounding stromal tissue and to predict the Ki-67 proliferation status in oestrogen receptor (ER)-positive breast cancer patients. A dataset of 82 patients who underwent diffusion-weighted imaging (DWI) examination was collected. The ADC map was segmented into regions comprising the tumour and the surrounding stromal shells. To reflect correlations between each region in terms of its mean ADC value, a functional graph was constructed consisting of nodes as regions and edges as interactions between two nodes. Analysis of the graph revealed a higher average degree in samples over-expressing Ki-67 than in samples with low Ki-67 expression. In the low-Ki-67 group, most of the identified edges represented correlations between adjacent regions, whereas additional edges representing correlations between non-adjacent regions were found in the high-Ki-67 group. The ADC signal in various breast stromal regions surrounding the tumour showed a discriminative pattern and would be valuable for estimating the Ki-67 proliferation status by DWI.
Maternal-placental-fetal biodistribution of multimodal polymeric nanoparticles in a pregnant rat model in mid and late gestation
Authors: Ho Diwei , Leong Joan W. , Crew Rachael C. , Norret Marck , House Michael J. , Mark Peter J. , Waddell Brendan J. , Iyer K. Swaminathan , Keelan Jeffrey A.
Published: May 2017

Multimodal polymeric nanoparticles have many exciting diagnostic and therapeutic applications, yet their uptake and passage by the placenta, and applications in the treatment of pregnancy complications have not been thoroughly investigated. In this work, the maternal-fetal-placental biodistribution of anionic and cationic multimodal poly(glycidyl methacrylate) (PGMA) nanoparticles in pregnant rats at mid (ED10) and late (ED20) gestation was examined. Fluorescently-labelled and superparamagnetic PGMA nanoparticles functionalized with/without poly(ethyleneimine) (PEI) were administered to pregnant rats at a clinically-relevant dose and biodistribution and tissue uptake assessed. Quantitative measurement of fluorescence intensity or magnetic resonance relaxometry in tissue homogenates lacked the sensitivity to quantify tissue uptake. Confocal microscopy, however, identified uptake by maternal organs and the decidua (ectoplacental cone) and trophoblast giant cells of conceptuses at ED10. At ED20, preferential accumulation of cationic vs. anionic nanoparticles was observed in the placenta, with PGMA-PEI nanoparticles localised mainly within the chorionic plate. These findings highlight the significant impact of surface charge and gestational age in the biodistribution of nanoparticles in pregnancy, and demonstrate the importance of using highly sensitive measurement techniques to evaluate nanomaterial biodistribution and maternal-fetal exposure.
Persistent effects of the Yellow River on the Chinese marginal seas began at least ~880 ka ago
Authors: Yao Zhengquan , Shi Xuefa , Qiao Shuqing , Liu Qingsong , Kandasamy Selvaraj , Liu Jianxing , Liu Yanguang , Liu Jihua , Fang Xisheng , Gao Jingjing , Dou Yanguang
Published: May 2017

The Yellow River (or Huanghe and also known as China’s Sorrow in ancient times), with the highest sediment load in the world, provides a key link between continental erosion and sediment accumulation in the western Pacific Ocean. However, the exact age of its influence on the marginal sea is highly controversial and uncertain. Here we present high-resolution records of clay minerals and lanthanum to samarium (La/Sm) ratio spanning the past ~1 million years (Myr) from the Bohai and Yellow Seas, the potential sedimentary sinks of the Yellow River. Our results show a climate-driven provenance shift from small, proximal mountain rivers-dominance to the Yellow River-dominance at ~880 ka, a time period consistent with the Mid-Pleistocene orbital shift from 41-kyr to 100-kyr cyclicity. We compare the age of this provenance shift with the available age data for Yellow River headwater integration into the marginal seas and suggest that the persistent influence of the Yellow River on the Chinese marginal seas must have occurred at least ~880 ka ago. To our knowledge, this study provides the first offshore evidence on the drainage history of the Yellow River within an accurate chronology framework.