bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultra-strong nonlinear optical processes and trigonal warping in MoS2 layers
Authors: Säynätjoki Antti , Karvonen Lasse , Rostami Habib , Autere Anton , Mehravar Soroush , Lombardo Antonio , Norwood Robert A. , Hasan Tawfique , Peyghambarian Nasser , Lipsanen Harri , Kieu Khanh , Ferrari Andrea C. , Polini Marco , Sun Zhipei
Published: October 2017

Nonlinear optical processes, such as harmonic generation, are of great interest for various applications, e.g., microscopy, therapy, and frequency conversion. However, high-order harmonic conversion is typically much less efficient than low-order, due to the weak intrinsic response of the higher-order nonlinear processes. Here we report ultra-strong optical nonlinearities in monolayer MoS2 (1L-MoS2): the third harmonic is 30 times stronger than the second, and the fourth is comparable to the second. The third harmonic generation efficiency for 1L-MoS2 is approximately three times higher than that for graphene, which was reported to have a large χ(3). We explain this by calculating the nonlinear response functions of 1L-MoS2 with a continuum-model Hamiltonian and quantum mechanical diagrammatic perturbation theory, highlighting the role of trigonal warping. A similar effect is expected in all other transition-metal dichalcogenides. Our results pave the way for efficient harmonic generation based on layered materials for applications such as microscopy and imaging.
Targeted delivery of celastrol to mesangial cells is effective against mesangioproliferative glomerulonephritis
Authors: Guo Ling , Luo Shi , Du Zhengwu , Zhou Meiling , Li Peiwen , Fu Yao , Sun Xun , Huang Yuan , Zhang Zhirong
Published: October 2017

Mesangial cells-mediated glomerulonephritis is a frequent cause of end-stage renal disease. Here, we show that celastrol is effective in treating both reversible and irreversible mesangioproliferative glomerulonephritis in rat models, but find that its off-target distributions cause severe systemic toxicity. We thus target celastrol to mesangial cells using albumin nanoparticles. Celastrol-albumin nanoparticles crosses fenestrated endothelium and accumulates in mesangial cells, alleviating proteinuria, inflammation, glomerular hypercellularity, and excessive extracellular matrix deposition in rat anti-Thy1.1 nephritis models. Celastrol-albumin nanoparticles presents lower drug accumulation than free celastrol in off-target organs and tissues, thereby minimizing celastrol-related systemic toxicity. Celastrol-albumin nanoparticles thus represents a promising treatment option for mesangioproliferative glomerulonephritis and similar glomerular diseases.
Picosecond orientational dynamics of water in living cells
Authors: Tros Martijn , Zheng Linli , Hunger Johannes , Bonn Mischa , Bonn Daniel , Smits Gertien J. , Woutersen Sander
Published: October 2017

Cells are extremely crowded, and a central question in biology is how this affects the intracellular water. Here, we use ultrafast vibrational spectroscopy and dielectric-relaxation spectroscopy to observe the random orientational motion of water molecules inside living cells of three prototypical organisms: Escherichia coli, Saccharomyces cerevisiae (yeast), and spores of Bacillus subtilis. In all three organisms, most of the intracellular water exhibits the same random orientational motion as neat water (characteristic time constants ~9 and ~2 ps for the first-order and second-order orientational correlation functions), whereas a smaller fraction exhibits slower orientational dynamics. The fraction of slow intracellular water varies between organisms, ranging from ~20% in E. coli to ~45% in B. subtilis spores. Comparison with the water dynamics observed in solutions mimicking the chemical composition of (parts of) the cytosol shows that the slow water is bound mostly to proteins, and to a lesser extent to other biomolecules and ions.
A novel true random number generator based on a stochastic diffusive memristor
Authors: Jiang Hao , Belkin Daniel , Savel’ev Sergey E. , Lin Siyan , Wang Zhongrui , Li Yunning , Joshi Saumil , Midya Rivu , Li Can , Rao Mingyi , Barnell Mark , Wu Qing , Yang J. Joshua , Xia Qiangfei
Published: October 2017

The intrinsic variability of switching behavior in memristors has been a major obstacle to their adoption as the next generation of universal memory. On the other hand, this natural stochasticity can be valuable for hardware security applications. Here we propose and demonstrate a novel true random number generator utilizing the stochastic delay time of threshold switching in a Ag:SiO2 diffusive memristor, which exhibits evident advantages in scalability, circuit complexity, and power consumption. The random bits generated by the diffusive memristor true random number generator pass all 15 NIST randomness tests without any post-processing, a first for memristive-switching true random number generators. Based on nanoparticle dynamic simulation and analytical estimates, we attribute the stochasticity in delay time to the probabilistic process by which Ag particles detach from a Ag reservoir. This work paves the way for memristors in hardware security applications for the era of the Internet of Things.
A long-range cis-regulatory element for class I odorant receptor genes
Authors: Iwata Tetsuo , Niimura Yoshihito , Kobayashi Chizuru , Shirakawa Daichi , Suzuki Hikoyu , Enomoto Takayuki , Touhara Kazushige , Yoshihara Yoshihiro , Hirota Junji
Published: October 2017

Individual olfactory sensory neurons express a single odorant receptor gene from either class I genes residing in a single cluster on a single chromosome or class II genes spread over multiple clusters on multiple chromosomes. Here, we identify an enhancer element for mouse class I genes, the J element, that is conserved through mammalian species from the platypus to humans. The J element regulates most class I genes expression by exerting an effect over ~ 3 megabases within the whole cluster. Deletion of the trans J element increases the expression frequencies of class I genes from the intact J allele, indicating that the allelic exclusion of class I genes depends on the activity of the J element. Our data reveal a long-range cis-regulatory element that governs the singular class I gene expression and has been phylogenetically preserved to retain a single cluster organization of class I genes in mammals.
All-optical regenerator of multi-channel signals
Authors: Li Lu , Patki Pallavi G. , Kwon Young B. , Stelmakh Veronika , Campbell Brandon D. , Annamalai Muthiah , Lakoba Taras I. , Vasilyev Michael
Published: October 2017

One of the main reasons why nonlinear-optical signal processing (regeneration, logic, etc.) has not yet become a practical alternative to electronic processing is that the all-optical elements with nonlinear input–output relationship have remained inherently single-channel devices (just like their electronic counterparts) and, hence, cannot fully utilise the parallel processing potential of optical fibres and amplifiers. The nonlinear input–output transfer function requires strong optical nonlinearity, e.g. self-phase modulation, which, for fundamental reasons, is always accompanied by cross-phase modulation and four-wave mixing. In processing multiple wavelength-division-multiplexing channels, large cross-phase modulation and four-wave mixing crosstalks among the channels destroy signal quality. Here we describe a solution to this problem: an optical signal processor employing a group-delay-managed nonlinear medium where strong self-phase modulation is achieved without such nonlinear crosstalk. We demonstrate, for the first time to our knowledge, simultaneous all-optical regeneration of up to 16 wavelength-division-multiplexing channels by one device. This multi-channel concept can be extended to other nonlinear-optical processing schemes.
Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel
Authors: Kasuya Go , Yamaura Toshiaki , Ma Xiao-Bo , Nakamura Ryoki , Takemoto Mizuki , Nagumo Hiromitsu , Tanaka Eiichi , Dohmae Naoshi , Nakane Takanori , Yu Ye , Ishitani Ryuichiro , Matsuzaki Osamu , Hattori Motoyuki , Nureki Osamu
Published: October 2017

P2X receptors are non-selective cation channels gated by extracellular ATP, and the P2X7 receptor subtype plays a crucial role in the immune and nervous systems. Altered expression and dysfunctions of P2X7 receptors caused by genetic deletions, mutations, and polymorphic variations have been linked to various diseases, such as rheumatoid arthritis and hypertension. Despite the availability of crystal structures of P2X receptors, the mechanism of competitive antagonist action for P2X receptors remains controversial. Here, we determine the crystal structure of the chicken P2X7 receptor in complex with the competitive P2X antagonist, TNP-ATP. The structure reveals an expanded, incompletely activated conformation of the channel, and identified the unique recognition manner of TNP-ATP, which is distinct from that observed in the previously determined human P2X3 receptor structure. A structure-based computational analysis furnishes mechanistic insights into the TNP-ATP-dependent inhibition. Our work provides structural insights into the functional mechanism of the P2X competitive antagonist.
Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance
Authors: Patel Kashyap A. , Kettunen Jarno , Laakso Markku , Stančáková Alena , Laver Thomas W. , Colclough Kevin , Johnson Matthew B. , Abramowicz Marc , Groop Leif , Miettinen Päivi J. , Shepherd Maggie H. , Flanagan Sarah E. , Ellard Sian , Inagaki Nobuya , Hattersley Andrew T. , Tuomi Tiinamaija , Cnop Miriam , Weedon Michael N.
Published: October 2017

Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10−4). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10−5) and Finnish (n = 80, odds ratio = 22, P = 1 × 10−6) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.
The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases
Authors: Chen Chen , Song Xiaolei , Wei Weixia , Zhong Huanzi , Dai Juanjuan , Lan Zhou , Li Fei , Yu Xinlei , Feng Qiang , Wang Zirong , Xie Hailiang , Chen Xiaomin , Zeng Chunwei , Wen Bo , Zeng Liping , Du Hui , Tang Huiru , Xu Changlu , Xia Yan , Xia Huihua , Yang Huanming , Wang Jian , Wang Jun , Madsen Lise , Brix Susanne , Kristiansen Karsten , Xu Xun , Li Junhua , Wu Ruifang , Jia Huijue
Published: October 2017

Reports on bacteria detected in maternal fluids during pregnancy are typically associated with adverse consequences, and whether the female reproductive tract harbours distinct microbial communities beyond the vagina has been a matter of debate. Here we systematically sample the microbiota within the female reproductive tract in 110 women of reproductive age, and examine the nature of colonisation by 16S rRNA gene amplicon sequencing and cultivation. We find distinct microbial communities in cervical canal, uterus, fallopian tubes and peritoneal fluid, differing from that of the vagina. The results reflect a microbiota continuum along the female reproductive tract, indicative of a non-sterile environment. We also identify microbial taxa and potential functions that correlate with the menstrual cycle or are over-represented in subjects with adenomyosis or infertility due to endometriosis. The study provides insight into the nature of the vagino-uterine microbiome, and suggests that surveying the vaginal or cervical microbiota might be useful for detection of common diseases in the upper reproductive tract.
Coulomb spin liquid in anion-disordered pyrochlore Tb2Hf2O7
Authors: Sibille Romain , Lhotel Elsa , Ciomaga Hatnean Monica , Nilsen Gøran J. , Ehlers Georg , Cervellino Antonio , Ressouche Eric , Frontzek Matthias , Zaharko Oksana , Pomjakushin Vladimir , Stuhr Uwe , Walker Helen C. , Adroja Devashibhai T. , Luetkens Hubertus , Baines Chris , Amato Alex , Balakrishnan Geetha , Fennell Tom , Kenzelmann Michel
Published: October 2017

The charge ordered structure of ions and vacancies characterizing rare-earth pyrochlore oxides serves as a model for the study of geometrically frustrated magnetism. The organization of magnetic ions into networks of corner-sharing tetrahedra gives rise to highly correlated magnetic phases with strong fluctuations, including spin liquids and spin ices. It is an open question how these ground states governed by local rules are affected by disorder. Here we demonstrate in the pyrochlore Tb2Hf2O7, that the vicinity of the disordering transition towards a defective fluorite structure translates into a tunable density of anion Frenkel disorder while cations remain ordered. Quenched random crystal fields and disordered exchange interactions can therefore be introduced into otherwise perfect pyrochlore lattices of magnetic ions. We show that disorder can play a crucial role in preventing long-range magnetic order at low temperatures, and instead induces a strongly fluctuating Coulomb spin liquid with defect-induced frozen magnetic degrees of freedom.
Binary temporal upconversion codes of Mn2+-activated nanoparticles for multilevel anti-counterfeiting
Authors: Liu Xiaowang , Wang Yu , Li Xiyan , Yi Zhigao , Deng Renren , Liang Liangliang , Xie Xiaoji , Loong Daniel T. B. , Song Shuyan , Fan Dianyuan , All Angelo H. , Zhang Hongjie , Huang Ling , Liu Xiaogang
Published: October 2017

Optical characteristics of luminescent materials, such as emission profile and lifetime, play an important role in their applications in optical data storage, document security, diagnostics, and therapeutics. Lanthanide-doped upconversion nanoparticles are particularly suitable for such applications due to their inherent optical properties, including large anti-Stokes shift, distinguishable spectroscopic fingerprint, and long luminescence lifetime. However, conventional upconversion nanoparticles have a limited capacity for information storage or complexity to prevent counterfeiting. Here, we demonstrate that integration of long-lived Mn2+ upconversion emission and relatively short-lived lanthanide upconversion emission in a particulate platform allows the generation of binary temporal codes for efficient data encoding. Precise control of the particle’s structure allows the excitation feasible both under 980 and 808 nm irradiation. We find that the as-prepared Mn2+-doped nanoparticles are especially useful for multilevel anti-counterfeiting with high-throughput rate of authentication and without the need for complex time-gated decoding instrumentation.
Bielectron vortices in two-dimensional Dirac semimetals
Authors: Downing C. A. , Portnoi M. E.
Published: October 2017

Searching for new states of matter and unusual quasi-particles in emerging materials and especially low-dimensional systems is one of the major trends in contemporary condensed matter physics. Dirac materials, which host quasi-particles which are described by ultrarelativistic Dirac-like equations, are of a significant current interest from both a fundamental and applied physics perspective. Here we show that a pair of two-dimensional massless Dirac–Weyl fermions can form a bound state independently of the sign of the inter-particle interaction potential, as long as this potential decays at large distances faster than Kepler’s inverse distance law. This leads to the emergence of a new type of energetically favorable quasiparticle: bielectron vortices, which are double-charged and reside at zero-energy. Their bosonic nature allows for condensation and may give rise to Majorana physics without invoking a superconductor. These novel quasi-particles arguably explain a range of poorly understood experiments in gated graphene structures at low doping.
Volcanic suppression of Nile summer flooding triggers revolt and constrains interstate conflict in ancient Egypt
Authors: Manning Joseph G. , Ludlow Francis , Stine Alexander R. , Boos William R. , Sigl Michael , Marlon Jennifer R.
Published: October 2017

Abstract

Volcanic eruptions provide tests of human and natural system sensitivity to abrupt shocks because their repeated occurrence allows the identification of systematic relationships in the presence of random variability. Here we show a suppression of Nile summer flooding via the radiative and dynamical impacts of explosive volcanism on the African monsoon, using climate model output, ice-core-based volcanic forcing data, Nilometer measurements, and ancient Egyptian writings. We then examine the response of Ptolemaic Egypt (305–30 BCE), one of the best-documented ancient superpowers, to volcanically induced Nile suppression. Eruptions are associated with revolt onset against elite rule, and the cessation of Ptolemaic state warfare with their great rival, the Seleukid Empire. Eruptions are also followed by socioeconomic stress with increased hereditary land sales, and the issuance of priestly decrees to reinforce elite authority. Ptolemaic vulnerability to volcanic eruptions offers a caution for all monsoon-dependent agricultural regions, presently including 70% of world population.
Heterogeneous integration for on-chip quantum photonic circuits with single quantum dot devices
Authors: Davanco Marcelo , Liu Jin , Sapienza Luca , Zhang Chen-Zhao , De Miranda Cardoso José Vinícius , Verma Varun , Mirin Richard , Nam Sae Woo , Liu Liu , Srinivasan Kartik
Published: October 2017

Single-quantum emitters are an important resource for photonic quantum technologies, constituting building blocks for single-photon sources, stationary qubits, and deterministic quantum gates. Robust implementation of such functions is achieved through systems that provide both strong light–matter interactions and a low-loss interface between emitters and optical fields. Existing platforms providing such functionality at the single-node level present steep scalability challenges. Here, we develop a heterogeneous photonic integration platform that provides such capabilities in a scalable on-chip implementation, allowing direct integration of GaAs waveguides and cavities containing self-assembled InAs/GaAs quantum dots—a mature class of solid-state quantum emitter—with low-loss Si3N4 waveguides. We demonstrate a highly efficient optical interface between Si3N4 waveguides and single-quantum dots in GaAs geometries, with performance approaching that of devices optimized for each material individually. This includes quantum dot radiative rate enhancement in microcavities, and a path for reaching the non-perturbative strong-coupling regime.
Evidence of a chimpanzee-sized ancestor of humans but a gibbon-sized ancestor of apes
Authors: Grabowski Mark , Jungers William L.
Published: October 2017

Body mass directly affects how an animal relates to its environment and has a wide range of biological implications. However, little is known about the mass of the last common ancestor (LCA) of humans and chimpanzees, hominids (great apes and humans), or hominoids (all apes and humans), which is needed to evaluate numerous paleobiological hypotheses at and prior to the root of our lineage. Here we use phylogenetic comparative methods and data from primates including humans, fossil hominins, and a wide sample of fossil primates including Miocene apes from Africa, Europe, and Asia to test alternative hypotheses of body mass evolution. Our results suggest, contrary to previous suggestions, that the LCA of all hominoids lived in an environment that favored a gibbon-like size, but a series of selective regime shifts, possibly due to resource availability, led to a decrease and then increase in body mass in early hominins from a chimpanzee-sized LCA.
Chemical signal activation of an organocatalyst enables control over soft material formation
Authors: Trausel Fanny , Maity Chandan , Poolman Jos M. , Kouwenberg D. S. J. , Versluis Frank , van Esch Jan H. , Eelkema Rienk
Published: October 2017

Cells can react to their environment by changing the activity of enzymes in response to specific chemical signals. Artificial catalysts capable of being activated by chemical signals are rare, but of interest for creating autonomously responsive materials. We present an organocatalyst that is activated by a chemical signal, enabling temporal control over reaction rates and the formation of materials. Using self-immolative chemistry, we design a deactivated aniline organocatalyst that is activated by the chemical signal hydrogen peroxide and catalyses hydrazone formation. Upon activation of the catalyst, the rate of hydrazone formation increases 10-fold almost instantly. The responsive organocatalyst enables temporal control over the formation of gels featuring hydrazone bonds. The generic design should enable the use of a large range of triggers and organocatalysts, and appears a promising method for the introduction of signal response in materials, constituting a first step towards achieving communication between artificial chemical systems.
Effective purifying selection in ancient asexual oribatid mites
Authors: Brandt Alexander , Schaefer Ina , Glanz Julien , Schwander Tanja , Maraun Mark , Scheu Stefan , Bast Jens
Published: October 2017

Sex is beneficial in the long term because it can prevent mutational meltdown through increased effectiveness of selection. This idea is supported by empirical evidence of deleterious mutation accumulation in species with a recent transition to asexuality. Here, we study the effectiveness of purifying selection in oribatid mites which have lost sex millions of years ago and diversified into different families and species while reproducing asexually. We compare the accumulation of deleterious nonsynonymous and synonymous mutations between three asexual and three sexual lineages using transcriptome data. Contrasting studies of young asexual lineages, we find evidence for strong purifying selection that is more effective in asexual as compared to sexual oribatid mite lineages. Our results suggest that large populations likely sustain effective purifying selection and facilitate the escape of mutational meltdown in the absence of sex. Thus, sex per se is not a prerequisite for the long-term persistence of animal lineages.
Engineering species-like barriers to sexual reproduction
Authors: Maselko Maciej , Heinsch Stephen C. , Chacón Jeremy M. , Harcombe William R. , Smanski Michael J.
Published: October 2017

Controlling the exchange of genetic information between sexually reproducing populations has applications in agriculture, eradication of disease vectors, control of invasive species, and the safe study of emerging biotechnology applications. Here we introduce an approach to engineer a genetic barrier to sexual reproduction between otherwise compatible populations. Programmable transcription factors drive lethal gene expression in hybrid offspring following undesired mating events. As a proof of concept, we target theACT1promoter of the model organismSaccharomyces cerevisiaeusing a dCas9-based transcriptional activator. Lethal overexpression of actin results from mating this engineered strain with a strain containing the wild-typeACT1promoter.
The driver landscape of sporadic chordoma
Authors: Tarpey Patrick S. , Behjati Sam , Young Matthew D. , Martincorena Inigo , Alexandrov Ludmil B. , Farndon Sarah J. , Guzzo Charlotte , Hardy Claire , Latimer Calli , Butler Adam P. , Teague Jon W. , Shlien Adam , Futreal P. Andrew , Shah Sohrab , Bashashati Ali , Jamshidi Farzad , Nielsen Torsten O. , Huntsman David , Baumhoer Daniel , Brandner Sebastian , Wunder Jay , Dickson Brendan , Cogswell Patricia , Sommer Josh , Phillips Joanna J. , Amary M. Fernanda , Tirabosco Roberto , Pillay Nischalan , Yip Stephen , Stratton Michael R. , Flanagan Adrienne M. , Campbell Peter J.
Published: October 2017

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma.
Single-molecule study of oxidative enzymatic deconstruction of cellulose
Authors: Eibinger Manuel , Sattelkow Jürgen , Ganner Thomas , Plank Harald , Nidetzky Bernd
Published: October 2017

LPMO (lytic polysaccharide monooxygenase) represents a unique paradigm of cellulosic biomass degradation by an oxidative mechanism. Understanding the role of LPMO in deconstructing crystalline cellulose is fundamental to the enzyme’s biological function and will help to specify the use of LPMO in biorefinery applications. Here we show with real-time atomic force microscopy that C1 and C4 oxidizing types of LPMO from Neurospora crassa (NcLPMO9F, NcLPMO9C) bind to nanocrystalline cellulose with high preference for the very same substrate surfaces that are also used by a processive cellulase (Trichoderma reesei CBH I) to move along during hydrolytic cellulose degradation. The bound LPMOs, however, are immobile during their adsorbed residence time ( ~ 1.0 min for NcLPMO9F) on cellulose. Treatment with LPMO resulted in fibrillation of crystalline cellulose and strongly ( ≥ 2-fold) enhanced the cellulase adsorption. It also increased enzyme turnover on the cellulose surface, thus boosting the hydrolytic conversion.
EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop
Authors: Béguelin Wendy , Rivas Martín A. , Calvo Fernández María T. , Teater Matt , Purwada Alberto , Redmond David , Shen Hao , Challman Matt F. , Elemento Olivier , Singh Ankur , Melnick Ari M.
Published: October 2017

The EZH2 histone methyltransferase is required for B cells to form germinal centers (GC). Here we show that EZH2 mediates GC formation through repression of cyclin-dependent kinase inhibitor CDKN1A (p21Cip1). Deletion of Cdkn1a rescues the GC reaction in Ezh2−/− mice. Using a 3D B cell follicular organoid system that mimics the GC reaction, we show that depletion of EZH2 suppresses G1 to S phase transition of GC B cells in a Cdkn1a-dependent manner. GC B cells of Cdkn1a−/−Ezh2−/− mice have high levels of phospho-Rb, indicating that loss of Cdkn1a enables progression of cell cycle. Moreover, the transcription factor E2F1 induces EZH2 during the GC reaction. E2f1−/− mice manifest impaired GC responses, which is rescued by restoring EZH2 expression, thus defining a positive feedback loop in which EZH2 controls GC B cell proliferation by suppressing CDKN1A, enabling cell cycle progression with a concomitant phosphorylation of Rb and release of E2F1.
Hollow MnO2 as a tumor-microenvironment-responsive biodegradable nano-platform for combination therapy favoring antitumor immune responses
Authors: Yang Guangbao , Xu Ligeng , Chao Yu , Xu Jun , Sun Xiaoqi , Wu Yifan , Peng Rui , Liu Zhuang
Published: October 2017

Herein, an intelligent biodegradable hollow manganese dioxide (H-MnO2) nano-platform is developed for not only tumor microenvironment (TME)-specific imaging and on-demand drug release, but also modulation of hypoxic TME to enhance cancer therapy, resulting in comprehensive effects favoring anti-tumor immune responses. With hollow structures, H-MnO2 nanoshells post modification with polyethylene glycol (PEG) could be co-loaded with a photodynamic agent chlorine e6 (Ce6), and a chemotherapy drug doxorubicin (DOX). The obtained H-MnO2-PEG/C&D would be dissociated under reduced pH within TME to release loaded therapeutic molecules, and in the meantime induce decomposition of tumor endogenous H2O2 to relieve tumor hypoxia. As a result, a remarkable in vivo synergistic therapeutic effect is achieved through the combined chemo-photodynamic therapy, which simultaneously triggers a series of anti-tumor immune responses. Its further combination with checkpoint-blockade therapy would lead to inhibition of tumors at distant sites, promising for tumor metastasis treatment.
Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis
Authors: Dufton Neil P. , Peghaire Claire R. , Osuna-Almagro Lourdes , Raimondi Claudio , Kalna Viktoria , Chauhan Abhishek , Webb Gwilym , Yang Youwen , Birdsey Graeme M. , Lalor Patricia , Mason Justin C. , Adams David H. , Randi Anna M.
Published: October 2017

The role of the endothelium in protecting from chronic liver disease and TGFβ-mediated fibrosis remains unclear. Here we describe how the endothelial transcription factor ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGFβ-SMAD signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver fibrogenesis in EC-specific constitutive hemi-deficient (ErgcEC-Het) and inducible homozygous deficient mice (ErgiEC-KO), in a SMAD3-dependent manner. Acute administration of the TNF-α inhibitor etanercept inhibits carbon tetrachloride (CCL4)-induced fibrogenesis in an ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing EndMT in liver disease.
Phyllodes tumors with and without fibroadenoma-like areas display distinct genomic features and may evolve through distinct pathways
Authors: Pareja Fresia , Geyer Felipe C. , Kumar Rahul , Selenica Pier , Piscuoglio Salvatore , Ng Charlotte K. Y. , Burke Kathleen A. , Edelweiss Marcia , Murray Melissa P. , Brogi Edi , Weigelt Britta , Reis-Filho Jorge S.
Published: October 2017

Breast fibroepithelial lesions (fibroadenomas and phyllodes tumors) are underpinned by recurrent MED12 exon 2 mutations, which are more common in fibroadenomas and benign phyllodes tumors. TERT promoter hotspot mutations have been documented in phyllodes tumors, and found to be more frequent in borderline and malignant lesions. Several lines of evidence suggest that a subset of phyllodes tumors might arise from fibroadenomas. Here we sought to investigate the genetic differences between phyllodes tumors with fibroadenoma-like areas vs. those without. We retrieved data for 16 borderline/ malignant phyllodes tumors, including seven phyllodes tumors with fibroadenoma-like areas and nine phyllodes tumors without fibroadenoma-like areas, which had been previously subjected to targeted capture massively parallel sequencing. Whilst MED12 exon 2 mutations were significantly more frequent in tumors with fibroadenoma-like areas (71 vs. 11%), an enrichment in genetic alterations targeting bona fide cancer genes was found in those without fibroadenoma-like areas, in particular in EGFR mutations and amplifications (78 vs. 14%). No significant difference in the frequency of TERT genetic alterations was observed (71% in cases with fibroadenoma-like areas vs 56% in those without fibroadenoma-like areas). Our data suggest that the development of phyllodes tumors might follow two different evolutionary pathways: a MED12-mutant pathway that involves the progression from a fibroadenoma to a malignant phyllodes tumor; and a MED12-wild-type pathway, where malignant phyllodes tumors arise de novo through the acquisition of genetic alterations targeting cancer genes. Additional studies are warranted to confirm our observations and define whether the outcome differs between both pathways.
The measurement of the surface energy of solids using a laboratory drop tower
Authors: Calvimontes Alfredo
Published: October 2017

This work presents a technique for the study and measurement of the interfacial energies of solid–liquid–gas systems. The instrument and the evaluation method for the measurements obtained by it, allow the analysis of the energy changes of sessile drops submitted to microgravity. A mathematical model based on the thermodynamic of wetting is applied to evaluate the interfacial energies as a function of the drop shape changes due to the effect of the release of gravitation during the experiment. The presented model bases on the thermodynamic equilibrium of the interfaces and not on the balance of bi-dimensional tensors on the contour line. For this reason, the model does not follow Young’s equation as the current surface wetting characterization techniques usually do.
Single-cell analysis of the fate of c-kit-positive bone marrow cells
Authors: Czarna Anna , Sanada Fumihiro , Matsuda Alex , Kim Junghyun , Signore Sergio , Pereira João D. , Sorrentino Andrea , Kannappan Ramaswamy , Cannatà Antonio , Hosoda Toru , Rota Marcello , Crea Filippo , Anversa Piero , Leri Annarosa
Published: October 2017

The plasticity of c-kit-positive bone marrow cells (c-kit-BMCs) in tissues different from their organ of origin remains unclear. We tested the hypothesis that c-kit-BMCs are functionally heterogeneous and only a subgroup of these cells possesses cardiomyogenic potential. Population-based assays fall short of identifying the properties of individual stem cells, imposing on us the introduction of single cell-based approaches to track the fate of c-kit-BMCs in the injured heart; they included viral gene-tagging, multicolor clonal-marking and transcriptional profiling. Based on these strategies, we report that single mouse c-kit-BMCs expand clonally within the infarcted myocardium and differentiate into specialized cardiac cells. Newly-formed cardiomyocytes, endothelial cells, fibroblasts and c-kit-BMCs showed in their genome common sites of viral integration, providing strong evidence in favor of the plasticity of a subset of BMCs expressing the c-kit receptor. Similarly, individual c-kit-BMCs, which were infected with multicolor reporters and injected in infarcted hearts, formed cardiomyocytes and vascular cells organized in clusters of similarly colored cells. The uniform distribution of fluorescent proteins in groups of specialized cells documented the polyclonal nature of myocardial regeneration. The transcriptional profile of myogenic c-kit-BMCs and whole c-kit-BMCs was defined by RNA sequencing. Genes relevant for engraftment, survival, migration, and differentiation were enriched in myogenic c-kit-BMCs, a cell subtype which could not be assigned to a specific hematopoietic lineage. Collectively, our findings demonstrate that the bone marrow comprises a category of cardiomyogenic, vasculogenic and/or fibrogenic c-kit-positive cells and a category of c-kit-positive cells that retains an undifferentiated state within the damaged heart.
Protective efficacy of a novel simian adenovirus vaccine against lethal MERS-CoV challenge in a transgenic human DPP4 mouse model
Authors: Munster Vincent J. , Wells Daniel , Lambe Teresa , Wright Daniel , Fischer Robert J. , Bushmaker Trenton , Saturday Greg , van Doremalen Neeltje , Gilbert Sarah C. , de Wit Emmie , Warimwe George M.
Published: October 2017

Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel zoonotic virus that causes severe respiratory disease in humans with a case fatality rate close to 40%, but for which no vaccines are available. Here, we evaluated the utility of ChAdOx1, a promising replication-deficient simian adenovirus vaccine vector platform with an established safety profile in humans and dromedary camels, for MERS-CoV vaccine development. Using a transgenic lethal BALB/c MERS-CoV mouse model we showed that single dose intranasal or intramuscular immunisation with ChAdOx1 MERS, encoding full-length MERS-CoV Spike glycoprotein, is highly immunogenic and confers protection against lethal viral challenge. Immunogenicity and efficacy were comparable between immunisation routes. Together these data provide support for further evaluation of ChAdOx1 MERS vaccine in humans and dromedary camels, the animal reservoir of infection.
Erratum: One-month spaceflight compromises the bone microstructure, tissue-level mechanical properties, osteocyte survival and lacunae volume in mature mice skeletons
Authors: Gerbaix Maude , Gnyubkin Vasily , Farlay Delphine , Olivier Cécile , Ammann Patrick , Courbon Guillaume , Laroche Norbert , Genthial Rachel , Follet Hélène , Peyrin Françoise , Shenkman Boris , Gauquelin-Koch Guillemette , Vico Laurence
Published: October 2017

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
The Value of lncRNA NEAT1 as a Prognostic Factor for Survival of Cancer Outcome: A Meta-Analysis
Authors: Zhang Yunyuan , Lun Limin , Li Hui , Wang Qing , Lin Jieru , Tian Runhua , Pan Huazheng , Zhang Haiping , Chen Xian
Published: October 2017

The present meta-analysis aimed to analyze available data to identify the prognostic role of NEAT1 in multiple carcinomas. A systematic search was performed by using several computerized databases from inception to June 7, 2017. The quantity of the publications was assessed according to MOOSE checklist. Pooled HRs with 95% CI was calculated to summarize the effect. A total of 12 studies with 3,262 cancer patients were pooled in the analysis to evaluate the prognostic value of NEAT1 in multiple tumors. High expression levels of NEAT1 were demonstrated to be associated with poor OS (HR = 1.71, 95%CI: 1.37–2.14, P < 0.001) and tumor progression (III/IV vs. I/II: HR 1.76, 95%CI: 1.40–2.21, P < 0.00001). Subgroup analysis showed that NEAT1 detection method (qRT-PCR) and sample size (more or less than 100) did not alter the predictive value of NEAT1 on OS in various cancers. According to the meta-regression results, the large heterogeneity of meta-analysis may be attributed to the differences of NEAT1 detection method. Furthermore, elevated NEAT1 expression significantly predicted lymph node metastasis (HR: 2.10, 95%CI: 1.32–3.33, P = 0.002) and distant metastasis (HR: 2.80, 95%CI: 1.60–4.91, P = 0.0003) respectively. The results indicate that NEAT1 expression level is a prognostic biomarker for OS and metastasis in general tumors.
Observation of Contrary Thermo-responsive Trend for Single Crystal and Powder Samples in Mechano-, Thermo- and Solvato-responsive Luminescent Cubane [Ag4I4L4] Cluster
Authors: Li Shi-Li , Han Min , Wu Bin , Wang Jie , Zhang Fu-Qiang , Zhang Xian-Ming
Published: October 2017

A new silver(I) iodide cluster [Ag4I4(TMP)4] (TMP = tris(3-methylphenyl)-phosphine) 1 shows triply stimuli-responsive luminescent chromism, namely, mechano-, thermo- and solvent-responsive chromism, which is isostructural to our previously reported [Cu4I4(TMP)4] 2 but shows quite different luminescence in response to the external stimuli. Especially, during the mechanical grinding, the relative intensities of HE and LE of 1 varied with a concomitant hypsochromic shift, and when the temperature was decreased from 300 to 5 K, unprecedented contrary thermo-responsive trend for single crystal and powered samples (blueshift of single crystals and redshift of powdered samples) was observed. These distinct characters of 1 should be due to the different molecular packing modes, metallic interactions and the unique character of Ag(I) ion.
HLA and Histo-Blood Group Antigen Expression in Human Pluripotent Stem Cells and their Derivatives
Authors: Säljö Karin , Barone Angela , Mölne Johan , Rydberg Lennart , Teneberg Susann , Breimer Michael E.
Published: October 2017

One prerequisite for a successful clinical outcome of human pluripotent stem cell (hPSC) based therapies is immune compatibility between grafted cells/tissue and recipient. This study explores immune determinants of human embryonic stem cell lines (hESC) and induced human pluripotent stem cell (hiPSC) lines and hepatocyte- and cardiomyocyte-like cells derived from these cells. HLA class I was expressed on all pluripotent hPSC lines which upon differentiation into hepatocyte-like cells was considerably reduced in contrast to cardiomyocyte-like cells which retained class I antigens. No HLA class II antigens were found in the pluripotent or differentiated cells. Histo-blood group carbohydrate antigens SSEA-3/SSEA-4/SSEA-5, Globo H, A, Lex/Ley and sialyl-lactotetra were expressed on all hPSC lines. Blood group AB(O)H antigen expression was in accordance with ABO genotype. Interestingly, only a subpopulation of A1O1 cells expressed A. During differentiation of hPSC, some histo-blood group antigens showed congruent alteration patterns while expression of other antigens differed between the cell lines. No systematic difference in the hPSC cell surface tissue antigen expression was detected. In conclusion, hPSC and their derivatives express cell surface antigens that may cause an immune rejection. Furthermore, tissue antigen expression must be established for each individual stem cell line prior to clinical application.
Crystal structure of the flexible tandem repeat domain of bacterial cellulose synthesis subunit C
Authors: Nojima Shingo , Fujishima Ayumi , Kato Koji , Ohuchi Kayoko , Shimizu Nobutaka , Yonezawa Kento , Tajima Kenji , Yao Min
Published: October 2017

Bacterial cellulose (BC) is synthesized and exported through the cell membrane via a large protein complex (terminal complex) that consists of three or four subunits. BcsC is a little-studied subunit considered to export BC to the extracellular matrix. It is predicted to have two domains: a tetratrico peptide repeat (TPR) domain and a β-barrelled outer membrane domain. Here we report the crystal structure of the N-terminal part of BcsC-TPR domain (Asp24–Arg272) derived from Enterobacter CJF-002. Unlike most TPR-containing proteins which have continuous TPR motifs, this structure has an extra α-helix between two clusters of TPR motifs. Five independent molecules in the crystal had three different conformations that varied at the hinge of the inserted α-helix. Such structural feature indicates that the inserted α-helix confers flexibility to the chain and changes the direction of the TPR super-helix, which was also suggested by structural analysis of BcsC-TPR (Asp24–Leu664) in solution by size exclusion chromatography-small-angle X-ray scattering. The flexibility at the α-helical hinge may play important role for exporting glucan chains.
Co-inoculum of Beauveria brongniartii and B. bassiana shows in vitro different metabolic behaviour in comparison to single inoculums
Authors: Canfora L. , Abu-Samra N. , Tartanus M. , Łabanowska B. H. , Benedetti A. , Pinzari F. , Malusà E.
Published: October 2017

The use of entomopathogenic fungi for biocontrol of plant pests is recently receiving an increased interest due to the need of reducing the impact of agricultural practices on the environment. Biocontrol efficacy could be improved by co-inoculation of different microorganisms. However, interactions between the fungal species can trigger or depress the biocontrol activity. Co-inoculation of two entomopathogenic fungi (Beauveria bassiana and B. brongniartii) was performed in vitro to evaluate the effects of their joint behaviour on a range of different carbon sources in comparison to single inoculation. The two species showed a very different metabolic profile by Phenotype MicroArrayTM. B. bassiana showed a broader metabolism than B. brongniartii on a range of substrates. B. brongniartii showed a greater specificity in substrate utilization. Several carbon sources (L-Asparagine, L-Aspartic Acid, L- Glutamic Acid, m- Erythritol, D-Melezitose, D-Sorbitol) triggered the fungal metabolism in the co-inoculum. SSR markers and Real Time qPCR analysis showed that different substrates promoted either the growth of one or the other species, suggesting a form of interaction between the two fungi, related to their different ecological niches. The methodological approach that combines Phenotype MicroArrayTM and SSR genotyping appeared useful to assess the performance and potential competition of co-inoculated entomopathogenic fungi.
Origins and transformations of dissolved organic matter in large Arctic rivers
Authors: Kaiser Karl , Canedo-Oropeza Maria , McMahon Rachel , Amon Rainer M. W.
Published: October 2017

Arctic river watersheds are important components of the global climate system and show an amplified response to climate change. Here, we characterize origins and transformations of dissolved organic matter (DOM) in five major Arctic rivers (Kolyma, Lena, Yenisei, Ob, Mackenzie) over 3 years with seasonal sampling periods using measurements of carbohydrates, amino acids, bacterial biomarkers (D-amino acids), and plant protein biomarkers (hydroxyproline). A strong seasonal cycle of bioavailable DOM export was observed that correlated with discharge, vegetation, river morphology and water residence time. The chemical composition of bioavailable DOM was different among rivers reflecting unique characteristics of Arctic river watersheds. Trends in specific bacterial biomarkers were synchronous to changes in bacterial community compositions demonstrating that bacterial communities responded to the seasonal shifts in organic matter quality and chemical composition. Extensive heterotrophic processing of plant and soil-derived DOM resulted in major inputs of bacterial detritus, and bacterial organic matter accounted for 21–42% of DOC in all watersheds. Dissolved organic nitrogen sources were dominated by bacterially-derived nitrogen and important contributions of soluble plant protein during the Spring freshet. Overall, our results demonstrated the importance of watershed characteristics and bacterial metabolism in regulating DOM composition, reactivity and carbon fluxes in Arctic river watersheds.
MCPH1, mutated in primary microcephaly, is required for efficient chromosome alignment during mitosis
Authors: Arroyo M. , Kuriyama R. , Trimborn M. , Keifenheim D. , Cañuelo A. , Sánchez A. , Clarke D. J. , Marchal J. A.
Published: October 2017

MCPH1 gene, mutated in primary microcephaly, regulates cell progression into mitosis. While this role has been extensively investigated in the context of DNA damage, its function during unperturbed cell cycles has been given less attention. Here we have analyzed the dynamics of chromosome condensation and cell cycle progression in MCPH1 deficient cells under undamaging conditions. Our study demonstrates that chromosome condensation is uncoupled from cell cycle progression when MCPH1 function is lacking, resulting in cells that prematurely condense their chromosomes during mid G2-phase and delay decondensation at the completion of mitosis. However, mitosis onset occurs on schedule in MCPH1 deficient cells. We also revealed active Cdk1 to be mandatory for the premature onset of chromosome condensation during G2 and the maintenance of the condensed state thereafter. Interestingly, a novel cellular phenotype was observed while monitoring cell cycle progression in cells lacking MCPH1 function. Specifically, completion of chromosome alignment at the metaphase plate was significantly delayed. This deficiency reveals that MCPH1 is required for efficient chromosome biorientation during mitosis.