bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytoplasmic E2f4 forms organizing centres for initiation of centriole amplification during multiciliogenesis
Authors: Mori Munemasa , Hazan Renin , Danielian Paul S. , Mahoney John E. , Li Huijun , Lu Jining , Miller Emily S. , Zhu Xueliang , Lees Jacqueline A. , Cardoso Wellington V.
Published: July 2017

Abnormal development of multiciliated cells is a hallmark of a variety of human conditions associated with chronic airway diseases, hydrocephalus and infertility. Multiciliogenesis requires both activation of a specialized transcriptional program and assembly of cytoplasmic structures for large-scale centriole amplification that generates basal bodies. It remains unclear, however, what mechanism initiates formation of these multiprotein complexes in epithelial progenitors. Here we show that this is triggered by nucleocytoplasmic translocation of the transcription factor E2f4. After inducing a transcriptional program of centriole biogenesis, E2f4 forms apical cytoplasmic organizing centres for assembly and nucleation of deuterosomes. Using genetically altered mice and E2F4 mutant proteins we demonstrate that centriole amplification is crucially dependent on these organizing centres and that, without cytoplasmic E2f4, deuterosomes are not assembled, halting multiciliogenesis. Thus, E2f4 integrates nuclear and previously unsuspected cytoplasmic events of centriole amplification, providing new perspectives for the understanding of normal ciliogenesis, ciliopathies and cancer.
AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability
Authors: Brechet Aline , Buchert Rebecca , Schwenk Jochen , Boudkkazi Sami , Zolles Gerd , Siquier-Pernet Karine , Schaber Irene , Bildl Wolfgang , Saadi Abdelkrim , Bole-Feysot Christine , Nitschke Patrick , Reis Andre , Sticht Heinrich , Al-Sanna’a Nouriya , Rolfs Arndt , Kulik Akos , Schulte Uwe , Colleaux Laurence , Abou Jamra Rami , Fakler Bernd
Published: July 2017

AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function.
Crystal structure of E. coli apolipoprotein N-acyl transferase
Authors: Lu Guangyuan , Xu Yingzhi , Zhang Kai , Xiong Yong , Li He , Cui Lei , Wang Xianping , Lou Jizhong , Zhai Yujia , Sun Fei , Zhang Xuejun C.
Published: July 2017

In Gram-negative bacteria, lipid modification of proteins is catalysed in a three-step pathway. Apolipoprotein N-acyl transferase (Lnt) catalyses the third step in this pathway, whereby it transfers an acyl chain from a phospholipid to the amine group of the N-terminal cysteine residue of the apolipoprotein. Here, we report the 2.6-Å crystal structure of Escherichia coli Lnt. This enzyme contains an exo-membrane nitrilase domain fused to a transmembrane (TM) domain. The TM domain of Lnt contains eight TM helices which form a membrane-embedded cavity with a lateral opening and a periplasmic exit. The nitrilase domain is located on the periplasmic side of the membrane, with its catalytic cavity connected to the periplasmic exit of the TM domain. An amphipathic lid loop from the nitrilase domain interacts with the periplasmic lipid leaflet, forming an interfacial entrance from the lipid bilayer to the catalytic centre for both the lipid donor and acceptor substrates.
The evolution of host-symbiont dependence
Authors: Fisher Roberta M. , Henry Lee M. , Cornwallis Charlie K. , Kiers E. Toby , West Stuart A.
Published: July 2017

Organisms across the tree of life form symbiotic partnerships with microbes for metabolism, protection and resources. While some hosts evolve extreme dependence on their symbionts, others maintain facultative associations. Explaining this variation is fundamental to understanding when symbiosis can lead to new higher-level individuals, such as during the evolution of the eukaryotic cell. Here we perform phylogenetic comparative analyses on 106 unique host–bacterial symbioses to test for correlations between symbiont function, transmission mode, genome size and host dependence. We find that both transmission mode and symbiont function are correlated with host dependence, with reductions in host fitness being greatest when nutrient-provisioning, vertically transmitted symbionts are removed. We also find a negative correlation between host dependence and symbiont genome size in vertically, but not horizontally, transmitted symbionts. These results suggest that both function and population structure are important in driving irreversible dependence between hosts and symbionts.
Norrin-induced Frizzled4 endocytosis and endo-lysosomal trafficking control retinal angiogenesis and barrier function
Authors: Zhang Chi , Lai Maria B. , Khandan Lavan , Lee Lindsey A. , Chen Zhe , Junge Harald J.
Published: July 2017

Angiogenesis and blood–brain barrier formation are required for normal central nervous system (CNS) function. Both processes are controlled by Wnt or Norrin (NDP) ligands, Frizzled (FZD) receptors, and β-catenin-dependent signalling in vascular endothelial cells. In the retina, FZD4 and the ligand NDP are critical mediators of signalling and are mutated in familial exudative vitreoretinopathy. Here, we report that NDP is a potent trigger of FZD4 ubiquitination and induces internalization of the NDP receptor complex into the endo-lysosomal compartment. Inhibition of ubiquitinated cargo transport through the multivesicular body (MVB) pathway using a dominant negative ESCRT (endosomal sorting complexes required for transport) component VPS4 EQ strongly impairs NDP/FZD4 signalling in vitro and recapitulates CNS angiogenesis and blood-CNS-barrier defects caused by impaired vascular β-catenin signalling in mice. These findings provide evidence for an important role of FZD4 endocytosis in NDP/FZD4 signalling and in CNS vascular biology and disease.
Metabolic reprogramming underlies metastatic potential in an obesity-responsive murine model of metastatic triple negative breast cancer
Authors: O’Flanagan Ciara H. , Rossi Emily L. , McDonell Shannon B. , Chen Xuewen , Tsai Yi-Hsuan , Parker Joel S. , Usary Jerry , Perou Charles M. , Hursting Stephen D.
Published: July 2017

The vast majority of cancer-related deaths are due to metastatic disease, whereby primary tumor cells disseminate and colonize distal sites within the body. Triple negative breast cancer typically displays aberrant Wnt signaling, lacks effective targeted therapies, and compared with other breast cancer subtypes, is more likely to recur and metastasize. We developed a Wnt-driven lung metastasis model of triple negative breast cancer (metM-Wntlung) through serial passaging of our previously described, nonmetastatic, claudin-low M-Wnt cell line. metM-Wntlung cells displayed characteristics of epithelial-to-mesenchymal transition (e.g., increased invasiveness) with some re-epithealization (e.g., increased adhesion, tight colony formation, increased E-cadherin expression, and decreased Vimentin and Fibronectin expression). When orthotopically transplanted into syngeneic mice, metM-Wntlung cells readily formed tumors and metastasized in vivo, and tumor growth and metastasis were enhanced in obese mice compared with non-obese mice. Gene expression analysis revealed several genes and pathways altered in metM-Wntlung cells compared with M-Wnt cells, including multiple genes associated with epithelial-to-mesenchymal transition, energy metabolism and inflammation. Moreover, obesity caused significant transcriptomic changes, especially in metabolic pathways. Metabolic flux analyses showed greater metabolic plasticity, with heightened mitochondrial and glycolytic energetics in metM-Wntlung cells relative to M-Wnt cells. Similar metabolic profiles were found in a second triple negative breast cancer progression series, M6 and M6C cells. These findings suggest that metabolic reprogramming is a feature of metastatic potential in triple negative breast cancer. Thus, targeting metastases-associated metabolic perturbations may represent a novel strategy for reducing the burden of metastatic triple negative breast cancer, particularly in obese women.
Comparative phylogenetic analyses of recombinant noroviruses based on different protein-encoding regions show the recombination-associated evolution pattern
Authors: Xue Liang , Wu Qingping , Dong Ruimin , Cai Weicheng , Wu Haoming , Chen Moutong , Chen Gang , Wang Juan , Zhang Jumei
Published: July 2017

Noroviruses are the major cause of acute gastroenteritis worldwide, and recombination is recognized as the important mechanism for its continuous emergence. In this study, for the common GII.P12 and GII.3 recombinants, phylogenetic relationships based on different proteins in three ORFs were comparatively analyzed, focusing on the influence of intergenic recombination. By using newly designed primers, genomes of two GII.P12/GII.3 Guangzhou recombinants were firstly amplified. Combined with other reported sequences of GII.P12_ORF1 (n = 20), GII.3_ORF2 (n = 131), GII.3_ORF3 (n = 36), all GII.P12 and GII.3 strains could be divided into 6, 8, and 7 clusters based on different ORFs, which showed an obvious recombination-associated and temporally sequential evolution pattern (with the exception of GII.P12/GII.13 recombinants). Based on multiple alignments, 126 informative sites were identified in three ORFs (44, 54, and 28), and four proteins (p48, p22, VP1, and VP2) were found under positive selection. Furthermore, by using homology modeling, predicted epitopes were mapped on the P proteins of seven GII.3 representative strains, without one (Epi: 353–361) specific to the GII.4 VA387 strain. In summary, via the genome analyses, phylogenetic relationships of GII.P12 and GII.3 recombinants based on the different proteins presented a special temporally sequential evolution process associated with their recombinant types.
Material-Device-Circuit Co-optimization of 2D Material based FETs for Ultra-Scaled Technology Nodes
Authors: Agarwal Tarun kumar , Soree Bart , Radu Iuliana , Raghavan Praveen , Iannaccone Giuseppe , Fiori Gianluca , Dehaene Wim , Heyns Marc
Published: July 2017

Two-dimensional (2D) material based FETs are being considered for future technology nodes and high performance logic applications. However, a comprehensive assessment of 2D material based FETs has been lacking for high performance logic applications considering appropriate system level figure-of-merits (FOMs) e.g. delay, and energy-delay product. In this paper, we present guidelines for 2D material based FETs to meet sub-10 nm high performance logic requirements focusing on material requirement, device design, energy-delay optimization for the first time. We show the need for 2D materials with smaller effective mass in the transport direction and anisotropicity to meet the performance requirement for future technology nodes. We present novel device designs with one such 2D material (monolayer black-phosphorus) to keep Moore’s alive for the HP logic in sub-5 nm gate length regime. With these device proposals we show that below 5 nm gate lengths 2D electrostatistics arising from gate stack design becomes more of a challenge than direct source-to-drain tunneling for 2D material-based FETs. Therefore, it is challenging to meet both delay and energy-delay requirement in sub-5 nm gate length regime without scaling both supply voltage (V
DD
) and effective-oxide-thickness (EOT) below 0.5 V and 0.5 nm respectively.
Evaluate the effect of different mmps inhibitors on adhesive physical properties of dental adhesives, bond strength and mmp substarte activity
Authors: Zheng Pei , Chen Hui
Published: July 2017

We have evaluated and compare the effect of different exogenous MMP inhibitors on adhesive physical properties of dental adhesives, bond strength, micro permeability and MMP substrate activity. 180-grit Sic paper was used to obtain the superficial dentin surface from each and every tooth after the wet grinding procedure. Dentin was exposed to four different MMP inhibitors to evaluate the effect on resin adhesive dentin interface. The four groups used in study were: 2% chlorhexidine digluconate, 2% doxycycline solution, 5% Proanthocyanidin (PR), Control Group. We evaluated and compared the four groups at each and every step of etching, bonding and resin application. Then, the immunolabeling was done with the help of the secondary antibodies with the pH of 7 and the dilution of 1:20. Amongst all the etching pretreatment groups, CHE group (Chlorhexidine etching group) revealed highest exposure to collagen fibrils than the other groups of etching. Then after the CHE group, the next group which has the second highest exposure DOE group. MMP inhibitor application for time duration of 1 minute after the etching procedures significantly improves the bond strength, exposure to collagen fibres and uniforms the dense form of dentin hybrid layer.
Integrated behavioural and stable isotope data reveal altered diet linked to low breeding success in urban-dwelling blue tits (Cyanistes caeruleus)
Authors: Pollock Christopher J. , Capilla-Lasheras Pablo , McGill Rona A. R. , Helm Barbara , Dominoni Davide M.
Published: July 2017

Animals often show reduced reproductive success in urban compared to adjacent natural areas. The lower availability and quality of natural food in cities is suggested as one key limiting factor. However, only few studies have provided conclusive support by simultaneously assessing food availability, diet and fitness. We consolidate this evidence by taking a holistic approach, comparing blue tits breeding in forest, suburban and urban areas. We (a) assessed arthropod availability, (b) investigated parental provisioning behaviour, (c) inferred diet through stable isotope analysis, and (d) measured reproductive success. At the urban site, we found a significant reduction in caterpillar availability, the main food source of blue tits, and consequently urban tits fed their offspring with fewer caterpillars than forest and suburban birds. Stable isotope analysis confirmed that diet in the urban area was fundamentally different than in the other sites. Reproductive success was lower in both urban and suburban sites compared to the forest site, and was positively associated with volume of provisioned caterpillars. Our findings provide strong integrative evidence that urban blue tit nestlings are not receiving a suitable diet, and this may be an important limiting factor for urban populations of this and potentially many other species.
Barcode ITS2: a useful tool for identifying Trachelospermum jasminoides and a good monitor for medicine market
Authors: Yu Ning , Wei Yu-long , Zhang Xin , Zhu Ning , Wang Yan-li , Zhu Yue , Zhang Hai-ping , Li Fen-mei , Yang Lan , Sun Jia-qi , Sun Ai-dong
Published: July 2017

Trachelospermum jasminoides is commonly used in traditional Chinese medicine. However, the use of the plant’s local alternatives is frequent, causing potential clinical problems. The T. jasminoides sold in the medicine market is commonly dried and sliced, making traditional identification methods difficult. In this study, the ITS2 region was evaluated on 127 sequences representing T. jasminoides and its local alternatives according to PCR and sequencing rates, intra- and inter-specific divergences, secondary structure, and discrimination capacity. Results indicated the 100% success rates of PCR and sequencing and the obvious presence of a barcoding gap. Results of BLAST 1, nearest distance and neighbor-joining tree methods showed that barcode ITS2 could successfully identify all the texted samples. The secondary structures of the ITS2 region provided another dimensionality for species identification. Two-dimensional images were obtained for better and easier identification. Previous studies on DNA barcoding concentrated more on the same family, genus, or species. However, an ideal barcode should be variable enough to identify closely related species. Meanwhile, the barcodes should also be conservative in identifying distantly related species. This study highlights the application of barcode ITS2 in solving practical problems in the distantly related local alternatives of medical plants.
Expression and regulation of drug transporters in vertebrate neutrophils
Authors: Foulkes Matthew J. , Henry Katherine M. , Rougeot Julien , Hooper-Greenhill Edward , Loynes Catherine A. , Jeffrey Phil , Fleming Angeleen , Savage Caroline O. , Meijer Annemarie H. , Jones Simon , Renshaw Stephen A.
Published: July 2017

There remains a need to identify novel pro-resolution drugs for treatment of inflammatory disease. To date, there are no neutrophil-specific anti-inflammatory treatments in clinical use, perhaps due to our lack of understanding of how drugs access this complex cell type. Here we present the first comprehensive description and expression of both major classes of drug transporters, SLC and ABC, in resting human blood neutrophils. Moreover, we have studied the expression of these carriers in the tractable model system, the zebrafish (Danio rerio), additionally examining the evolutionary relationship between drug transporters in zebrafish and humans. We anticipate that this will be a valuable resource to the field of inflammation biology and will be an important asset in future anti-inflammatory drug design.
Quantum sensing of noises in one and two dimensional quantum walks
Authors: Chen Tian , Zhang Xiong , Zhang Xiangdong
Published: July 2017

Quantum walk (QW) provides a versatile platform for the realization of quantum algorithms. Due to the existence of the inevitable noises in the walk, the different quantum algorithms accommodating to different noises are demanded. Thus, the success of the algorithms based on the QW requires us to sense different noises in the walk. Until now, the way to distinguish different noises in the walk has been discussed rarely. Here, we propose an efficient way to sense the noises in the one and two dimensional QWs. The populations of the coin in the walk with or without decoherence are presented. By only detecting the populations of the coin in the QW, we can determine whether there exists the decoherence in the total QW system. Moreover, the non-Markovianity of the coin in the one and two dimensional QWs is revealed, in which the coin is taken as an open quantum system, and the other components of the QW system is taken as the large environment. With the measured value of the non-Markovianity for the coin, we can conjecture which kinds of noise emerges in the one and two dimensional QWs.
Seasonal variation modulates coral sensibility to heat-stress and explains annual changes in coral productivity
Authors: Scheufen Tim , Krämer Wiebke E. , Iglesias-Prieto Roberto , Enríquez Susana
Published: July 2017

The potential effects of seasonal acclimatization on coral sensitivity to heat-stress, has received limited attention despite differing bleaching thresholds for summer and winter. In this study, we examined the response of two contrasting phenotypes, termed winter and summer, of four Caribbean reef corals to similar light and heat-stress levels. The four species investigated were categorized into two groups: species with the ability to harbour large number of symbionts, Orbicella annularis and O. faveolata, and species with reduced symbiont density (Montastraea cavernosa and Pseudodiploria strigosa). The first group showed higher capacity to enhance photosynthetic rates per area (Pmax), while Pmax enhancement in the second group was more dependent on Symbiodinium performance (Psym). In summer all four species presented higher productivity, but also higher sensitivity to lose coral photosynthesis under heat-stress. In contrast, corals in winter exhibit symbionts with higher capacity to photoacclimate to the increased levels of light-stress elicited by heat-stress. Overall, our study supports the importance of the acclimatory coral condition in addition to the previous thermal history, to determine the severity of the impact of heat-stress on coral physiology, but also the dependence of this response on the particular structural and functional traits of the species.
Balancing Hole and Electron Conduction in Ambipolar Split-Gate Thin-Film Transistors
Authors: Yoo Hocheon , Ghittorelli Matteo , Lee Dong-Kyu , Smits Edsger C. P. , Gelinck Gerwin H. , Ahn Hyungju , Lee Han-Koo , Torricelli Fabrizio , Kim Jae-Joon
Published: July 2017

Complementary organic electronics is a key enabling technology for the development of new applications including smart ubiquitous sensors, wearable electronics, and healthcare devices. High-performance, high-functionality and reliable complementary circuits require n- and p-type thin-film transistors with balanced characteristics. Recent advancements in ambipolar organic transistors in terms of semiconductor and device engineering demonstrate the great potential of this route but, unfortunately, the actual development of ambipolar organic complementary electronics is currently hampered by the uneven electron (n-type) and hole (p-type) conduction in ambipolar organic transistors. Here we show ambipolar organic thin-film transistors with balanced n-type and p-type operation. By manipulating air exposure and vacuum annealing conditions, we show that well-balanced electron and hole transport properties can be easily obtained. The method is used to control hole and electron conductions in split-gate transistors based on a solution-processed donor-acceptor semiconducting polymer. Complementary logic inverters with balanced charging and discharging characteristics are demonstrated. These findings may open up new opportunities for the rational design of complementary electronics based on ambipolar organic transistors.
Nature Degradable, Flexible, and Transparent Conductive Substrates from Green and Earth-Abundant Materials
Authors: Yang Bing , Yao Chunhua , Yu Yanhao , Li Zhaodong , Wang Xudong
Published: July 2017

The rapid development of wearable and disposable electronic devices and the rising awareness of environmental sustainability impose growing new demands on the nature degradability of current electronic and energy systems. Here we report a new type of flexible transparent conductive paper completely made from green and earth abundant materials which are also fully degradable and recyclable. Aluminum-doped zinc oxide (AZO) was deposited by low-temperature atomic layer deposition (ALD) as the transparent conductive oxide (TCO) layer on transparent cellulose nanofibril (CNF) papers. The mesoporous structure of the CNF paper rendered strong adhesion of the AZO layer and exhibited excellent mechanical integrity and electrical conductivity within a wide range of tensile and compressive strains. The AZO-CNF paper could be completely dissolved in warm city water after one-hour stirring, demonstrating an excellent nature degradability. A flexible and transparent triboelectric nanogenerator (TENG) was further fabricated using such AZO-CNF papers with a performance that was comparable to other synthetic polymer-based systems. This work illustrated a new and promising strategy of utilizing 100% green and degradable materials in novel electronic and energy harvesting devices.
Revealing enterovirus infection in chronic human disorders: An integrated diagnostic approach
Authors: Genoni Angelo , Canducci Filippo , Rossi Agostino , Broccolo Francesco , Chumakov Konstantin , Bono Giorgio , Salerno-Uriarte Jorge , Salvatoni Alessandro , Pugliese Alberto , Toniolo Antonio
Published: July 2017

Enteroviruses (EVs) causing persisting infection are characterized by minimal replication and genetic changes. Typing of these agents may complement disease assessment and shed light on pathogenesis. Here we report an integrated approach for EV detection in human samples that is based on pre-enrichment of virus in cell culture before search for the viral genome and viral antigens. Cases of post-polio syndrome, type 1 diabetes, and chronic cardiomyopathy were investigated. As tissue-based approaches require invasive procedures, information was mainly gleaned from virus in blood. Molecular assays targeting conserved genome regions of all EV types (5′UTR, 2 C, 3Dpol) were employed. As compared to direct assays of plasma or leukocytes, the EV detection rate was significantly enhanced by co-culture of leukocytes with cell lines prior to molecular and immunologic tests. Results of RT-PCR and sequencing were confirmed by staining cell cultures with a panel of EV-specific antibodies. Sequence and phylogenetic analysis showed that EVs of the C species (polioviruses) were associated with the post-polio syndrome, while members of the B species were found in type 1 diabetes and cardiomyopathy. The procedure may be used for investigating the possible association of different EVs with a variety of chronic neurologic, endocrine, and cardiac disorders.
Functional determinants of protein assembly into homomeric complexes
Authors: Bergendahl L. Therese , Marsh Joseph A.
Published: July 2017

Approximately half of proteins with experimentally determined structures can interact with other copies of themselves and assemble into homomeric complexes, the overwhelming majority of which (>96%) are symmetric. Although homomerisation is often assumed to a functionally beneficial result of evolutionary selection, there has been little systematic analysis of the relationship between homomer structure and function. Here, utilizing the large numbers of structures and functional annotations now available, we have investigated how proteins that assemble into different types of homomers are associated with different biological functions. We observe that homomers from different symmetry groups are significantly enriched in distinct functions, and can often provide simple physical and geometrical explanations for these associations in regards to substrate recognition or physical environment. One of the strongest associations is the tendency for metabolic enzymes to form dihedral complexes, which we suggest is closely related to allosteric regulation. We provide a physical explanation for why allostery is related to dihedral complexes: it allows for efficient propagation of conformational changes across isologous (i.e. symmetric) interfaces. Overall we demonstrate a clear relationship between protein function and homomer symmetry that has important implications for understanding protein evolution, as well as for predicting protein function and quaternary structure.
Sea ice breakup and marine melt of a retreating tidewater outlet glacier in northeast Greenland (81°N)
Authors: Bendtsen Jørgen , Mortensen John , Lennert Kunuk , K. Ehn Jens , Boone Wieter , Galindo Virginie , Hu Yu-bin , Dmitrenko Igor A. , Kirillov Sergei A. , Kjeldsen Kristian K. , Kristoffersen Yngve , G. Barber David , Rysgaard Søren
Published: July 2017

Rising temperatures in the Arctic cause accelerated mass loss from the Greenland Ice Sheet and reduced sea ice cover. Tidewater outlet glaciers represent direct connections between glaciers and the ocean where melt rates at the ice-ocean interface are influenced by ocean temperature and circulation. However, few measurements exist near outlet glaciers from the northern coast towards the Arctic Ocean that has remained nearly permanently ice covered. Here we present hydrographic measurements along the terminus of a major retreating tidewater outlet glacier from Flade Isblink Ice Cap. We show that the region is characterized by a relatively large change of the seasonal freshwater content, corresponding to ~2 m of freshwater, and that solar heating during the short open water period results in surface layer temperatures above 1 °C. Observations of temperature and salinity supported that the outlet glacier is a floating ice shelf with near-glacial subsurface temperatures at the freezing point. Melting from the surface layer significantly influenced the ice foot morphology of the glacier terminus. Hence, melting of the tidewater outlet glacier was found to be critically dependent on the retreat of sea ice adjacent to the terminus and the duration of open water.
A global classification of coastal flood hazard climates associated with large-scale oceanographic forcing
Authors: Rueda Ana , Vitousek Sean , Camus Paula , Tomás Antonio , Espejo Antonio , Losada Inigo J. , Barnard Patrick L. , Erikson Li H. , Ruggiero Peter , Reguero Borja G. , Mendez Fernando J.
Published: July 2017

Coastal communities throughout the world are exposed to numerous and increasing threats, such as coastal flooding and erosion, saltwater intrusion and wetland degradation. Here, we present the first global-scale analysis of the main drivers of coastal flooding due to large-scale oceanographic factors. Given the large dimensionality of the problem (e.g. spatiotemporal variability in flood magnitude and the relative influence of waves, tides and surge levels), we have performed a computer-based classification to identify geographical areas with homogeneous climates. Results show that 75% of coastal regions around the globe have the potential for very large flooding events with low probabilities (unbounded tails), 82% are tide-dominated, and almost 49% are highly susceptible to increases in flooding frequency due to sea-level rise.
Google Trends can improve surveillance of Type 2 diabetes
Authors: Tkachenko Nataliya , Chotvijit Sarunkorn , Gupta Neha , Bradley Emma , Gilks Charlotte , Guo Weisi , Crosby Henry , Shore Eliot , Thiarai Malkiat , Procter Rob , Jarvis Stephen
Published: July 2017

Recent studies demonstrate that people are increasingly looking online to assess their health, with reasons varying from personal preferences and beliefs to inability to book a timely appointment with their local medical practice. Records of these activities represent a new source of data about the health of populations, but which is currently unaccounted for by disease surveillance models. This could potentially be useful as evidence of individuals’ perception of bodily changes and self-diagnosis of early symptoms of an emerging disease. We make use of the Experian geodemographic Mosaic dataset in order to extract Type 2 diabetes candidate risk variables and compare their temporal relationships with the search keywords, used to describe early symptoms of the disease on Google. Our results demonstrate that Google Trends can detect early signs of diabetes by monitoring combinations of keywords, associated with searches for hypertension treatment and poor living conditions; Combined search semantics, related to obesity, how to quit smoking and improve living conditions (deprivation) can be also employed, however, may lead to less accurate results.
Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand
Authors: Dalton James A. R. , Pin Jean-Philippe , Giraldo Jesús
Published: July 2017

As class C GPCRs and regulators of synaptic activity, human metabotropic glutamate receptors (mGluRs) 4 and 5 are prime targets for allosteric modulation, with mGlu5 inhibition or mGlu4 stimulation potentially treating conditions like chronic pain and Parkinson’s disease. As an allosteric modulator that can bind both receptors, 2-Methyl-6-(phenylethynyl)pyridine (MPEP) is able to negatively modulate mGlu5 or positively modulate mGlu4. At a structural level, how it elicits these responses and how mGluRs undergo activation is unclear. Here, we employ homology modelling and 30 µs of atomistic molecular dynamics (MD) simulations to probe allosteric conformational change in mGlu4 and mGlu5, with and without docked MPEP. Our results identify several structural differences between mGlu4 and mGlu5, as well as key differences responsible for MPEP-mediated positive and negative allosteric modulation, respectively. A novel mechanism of mGlu4 activation is revealed, which may apply to all mGluRs in general. This involves conformational changes in TM3, TM4 and TM5, separation of intracellular loop 2 (ICL2) from ICL1/ICL3, and destabilization of the ionic-lock. On the other hand, mGlu5 experiences little disturbance when MPEP binds, maintaining its inactive state with reduced conformational fluctuation. In addition, when MPEP is absent, a lipid molecule can enter the mGlu5 allosteric pocket.
High Frequency Components of Hemodynamic Shear Stress Profiles are a Major Determinant of Shear-Mediated Platelet Activation in Therapeutic Blood Recirculating Devices
Authors: Consolo Filippo , Sheriff Jawaad , Gorla Silvia , Magri Nicolò , Bluestein Danny , Pappalardo Federico , Slepian Marvin J. , Fiore Gianfranco B. , Redaelli Alberto
Published: July 2017

We systematically analyzed the relative contributions of frequency component elements of hemodynamic shear stress waveforms encountered in cardiovascular blood recirculating devices as to overall platelet activation over time. We demonstrated that high frequency oscillations are the major determinants for priming, triggering and yielding activated “prothrombotic behavior” for stimulated platelets, even if the imparted shear stress has low magnitude and brief exposure time. Conversely, the low frequency components of the stress signal, with limited oscillations over time, did not induce significant activation, despite being of high magnitude and/or exposure time. In vitro data were compared with numerical predictions computed according to a recently proposed numerical model of shear-mediated platelet activation. The numerical model effectively resolved the correlation between platelet activation and the various frequency components examined. However, numerical predictions exhibited a different activation trend compared to experimental results for different time points of a stress activation sequence. With this study we provide a more fundamental understanding for the mechanobiological responsiveness of circulating platelets to the hemodynamic environment of cardiovascular devices, and the importance of these environments in mediating life-threatening thromboembolic complications associated with shear-mediated platelet activation. Experimental data will guide further optimization of the thromboresistance of cardiovascular implantable therapeutic devices.
Non-linear optical measurement of the twist elastic constant in thermotropic and DNA lyotropic chiral nematics
Authors: Lucchetti Liana , Fraccia Tommaso P. , Ciciulla Fabrizio , Bellini Tommaso
Published: July 2017

Throughout the whole history of liquid crystals science, the balancing of intrinsic elasticity with coupling to external forces has been the key strategy for most application and investigation. While the coupling of the optical field to the nematic director is at the base of a wealth of thoroughly described optical effects, a significant variety of geometries and materials have not been considered yet. Here we show that by adopting a simple cell geometry and measuring the optically induced birefringence, we can readily extract the twist elastic coefficient K22of thermotropic and lyotropic chiral nematics (N*). The value of K22we obtain for chiral doped 5CB thermotropic N* well matches those reported in the literature. With this same strategy, we could determine for the first time K22of the N* phase of concentrated aqueous solutions of DNA oligomers, bypassing the limitations that so far prevented measuring the elastic constants of this class of liquid crystalline materials. The present study also enlightens the significant nonlinear optical response of DNA liquid crystals.
Herbal formula YYJD inhibits tumor growth by inducing cell cycle arrest and senescence in lung cancer
Authors: Zheng Tingting , Que Zujun , Jiao Lijing , Kang Yani , Gong Yabin , Yao Jialin , Ma Chao , Bi Ling , Dong Qihan , Zhao Xiaodong , Xu Ling
Published: July 2017

Lung cancer represents a major cause of cancer-related death worldwide. Although various tactics and anti-tumor drugs have been used to improve curative effects, five-year survival rate of lung cancer patients remains poor. In this study, we investigated the action and underlying mechanisms of our recently optimized Chinese herbal formula Yangyinjiedu (YYJD) against lung cancer. YYJD significantly inhibits the proliferation of lung cancer cell lines (95-D, A549, H460 and H1975) by inducing cell cycle arrest and senescence in a dose-dependent manner. In particular, YYJD induces significant G2/M phase arrest and inhibits the colony formation of lung cancer cells. Moreover, we found that administration of YYJD could inhibit the growth of xenografted lung cancer cells in nude mice without loss in body weight. Our findings suggest that the herbal formula YYJD is a potential anti-tumor agent against lung cancer.
Self-assembled α-Tocopherol Transfer Protein Nanoparticles Promote Vitamin E Delivery Across an Endothelial Barrier
Authors: Aeschimann Walter , Staats Stefanie , Kammer Stephan , Olieric Natacha , Jeckelmann Jean-Marc , Fotiadis Dimitrios , Netscher Thomas , Rimbach Gerald , Cascella Michele , Stocker Achim
Published: July 2017

Vitamin E is one of the most important natural antioxidants, protecting polyunsaturated fatty acids in the membranes of cells. Among different chemical isoforms assimilated from dietary regimes, RRR-α-tocopherol is the only one retained in higher animals. This is possible thanks to α-Tocopherol Transfer Protein (α-TTP), which extracts α-tocopherol from endosomal compartments in liver cells, facilitating its distribution into the body. Here we show that, upon binding to its substrate, α-TTP acquires tendency to aggregation into thermodynamically stable high molecular weight oligomers. Determination of the structure of such aggregates by X-ray crystallography revealed a spheroidal particle formed by 24 protein monomers. Oligomerization is triggered by refolding of the N-terminus. Experiments with cultured cell monolayers demonstrate that the same oligomers are efficiently transported through an endothelial barrier (HUVEC) and not through an epithelial one (Caco-2). Discovery of a human endogenous transport protein with intrinsic capability of crossing endothelial tissues opens to new ways of drug delivery into the brain or other tissues protected by endothelial barriers.
Specificity Switching Pathways in Thermal and Mass Evaporation of Multicomponent Hydrocarbon Droplets: A Mesoscopic Observation
Authors: Nasiri Rasoul , Luo Kai H.
Published: July 2017

For well over one century, the Hertz–Knudsen equation has established the relationship between thermal – mass transfer coefficients through a liquid – vapour interface and evaporation rate. These coefficients, however, have been often separately estimated for one-component equilibrium systems and their simultaneous influences on evaporation rate of fuel droplets in multicomponent systems have yet to be investigated at the atomic level. Here we first apply atomistic simulation techniques and quantum/statistical mechanics methods to understand how thermal and mass evaporation effects are controlled kinetically/thermodynamically. We then present a new development of a hybrid method of quantum transition state theory/improved kinetic gas theory, for multicomponent hydrocarbon systems to investigate how concerted-distinct conformational changes of hydrocarbons at the interface affect the evaporation rate. The results of this work provide an important physical concept in fundamental understanding of atomistic pathways in topological interface transitions of chain molecules, resolving an open problem in kinetics of fuel droplets evaporation.
The glyceraldehyde-3-phosphate dehydrogenase GapDH of Corynebacterium diphtheriae is redox-controlled by protein S-mycothiolation under oxidative stress
Authors: Hillion Melanie , Imber Marcel , Pedre Brandán , Bernhardt Jörg , Saleh Malek , Loi Vu Van , Maaß Sandra , Becher Dörte , Astolfi Rosado Leonardo , Adrian Lorenz , Weise Christoph , Hell Rüdiger , Wirtz Markus , Messens Joris , Antelmann Haike
Published: July 2017

Mycothiol (MSH) is the major low molecular weight (LMW) thiol in Actinomycetes and functions in post-translational thiol-modification by protein S-mycothiolation as emerging thiol-protection and redox-regulatory mechanism. Here, we have used shotgun-proteomics to identify 26 S-mycothiolated proteins in the pathogen Corynebacterium diphtheriae DSM43989 under hypochlorite stress that are involved in energy metabolism, amino acid and nucleotide biosynthesis, antioxidant functions and translation. The glyceraldehyde-3-phosphate dehydrogenase (GapDH) represents the most abundant S-mycothiolated protein that was modified at its active site Cys153 in vivo. Exposure of purified GapDH to H2O2 and NaOCl resulted in irreversible inactivation due to overoxidation of the active site in vitro. Treatment of GapDH with H2O2 or NaOCl in the presence of MSH resulted in S-mycothiolation and reversible GapDH inactivation in vitro which was faster compared to the overoxidation pathway. Reactivation of S-mycothiolated GapDH could be catalyzed by both, the Trx and the Mrx1 pathways in vitro, but demycothiolation by Mrx1 was faster compared to Trx. In summary, we show here that S-mycothiolation can function in redox-regulation and protection of the GapDH active site against overoxidation in C. diphtheriae which can be reversed by both, the Mrx1 and Trx pathways.
Chronic lung inflammation primes humoral immunity and augments antipneumococcal resistance
Authors: Boehme Julia D. , Stegemann-Koniszewski Sabine , Autengruber Andrea , Peters Nicole , Wissing Josef , Jänsch Lothar , Jeron Andreas , Bruder Dunja
Published: July 2017

Airway epithelial cells (AECs) display remarkable plasticity in response to infectious stimuli and their functional adaptations are critical for antimicrobial immunity. However, the roles of AECs and humoral mediators to host defense in non-communicable lung inflammation remain elusive. We dissected pulmonary defense againstStreptococcus pneumoniaein hosts with pre-existing inflammatory conditions (SPC-HAxTCR-HA mice). Lung tissue transcriptomics and bronchoalveolar lavage fluid (BALF) proteomics revealed an induction of humoral defense mechanisms in inflamed lungs. Accordingly, besides antibacterial proteins and complement components being overrepresented in inflamed lungs, elevated polymeric immunoglobulin receptor (pIgR)-expression in AECs correlated with increased secretory immunoglobulin (SIg) transport. Consequently, opsonization assays revealed augmented pneumococcal coverage by SIgs present in the BALF of SPC-HAxTCR-HA mice, which was associated with enhanced antipneumococcal resistance. These findings emphasize the immunologic potential of AECs as well as their central role in providing antibacterial protection and put forward pIgR as potential target for therapeutic manipulation in infection-prone individuals.
Impacts of Early Life Stress on the Methylome and Transcriptome of Atlantic Salmon
Authors: Moghadam Hooman K. , Johnsen Hanne , Robinson Nicholas , Andersen Øivind , H. Jørgensen Even , Johnsen Helge K. , Bæhr Vegar J. , Tveiten Helge
Published: July 2017

Exposure to environmental stressors during early-life stages can change the rate and timing of various developmental processes. Epigenetic marks affecting transcriptional regulation can be altered by such environmental stimuli. To assess how stress might affect the methylome and transcriptome in salmon, fish were treated using cold-shock and air-exposure from the eye-stage until start-feeding. The fish were either stressed prior to hatching (E), post-hatching (PH), pre- and post-hatching (EPH) or not stressed (CO). Assessing transcriptional abundances just prior to start feeding, E and PH individuals were found to have modified the expression of thousands of genes, many with important functions in developmental processes. The EPH individuals however, showed expression similar to those of CO, suggesting an adaptive response to extended periods of stress. The methylome of stressed individuals differed from that of the CO, suggesting the importance of environment in shaping methylation signatures. Through integration of methylation with transcription, we identified bases with potential regulatory functions, some 10s of kb away from the targeted genes. We then followed fish growth for an additional year. Individuals in EPH showed superior growth compared to other treatment groups, highlighting how stress can potentially have long-lasting effects on an organism’s ability to adapt to environmental perturbations.
Melatonin alleviates chilling stress in cucumber seedlings by up-regulation of CsZat12 and modulation of polyamine and abscisic acid metabolism
Authors: Zhao Hailiang , Zhang Kai , Zhou Xiaoting , Xi Linjie , Wang Yuping , Xu Hongjun , Pan Tonghua , Zou Zhirong
Published: July 2017

To obtain new insights into the mechanisms of the positive effects of exogenous melatonin applications to cucumber seedlings during chilling, we investigated its role in regulating photosynthesis, the transcription level of csZat12 and the metabolism of polyamines (PAs) and of abscisic acid (ABA). The negative effects of chilling were clearly alleviated in cucumber seedlings by irrigation with 200 μM melatonin solution. This was evidenced by alleviation of the decline in net photosynthesis rate and also in electrolyte leakage in chilled plants. The reasons for this can be explained as follows. First, melatonin up-regulates CsZat12, an important stress-related gene. Second, melatonin increases the content of putrescine (Put) and spermidine (Spd) and stabilized spermine (Spm) by altering the activity of the PA metabolic enzymes. And, third, ABA is also involved in these effects as melatonin modulated the expression of the key ABA biosynthesis genes (CsNCED1 and CsNCED2) and also the key ABA catabolism genes (CsCYP707A1 and CsCYP707A2). This study provides new evidence suggesting melatonin mitigates chilling stress in cucumber by up-regulating the expression of CsZat12 and by modulating the metabolism of PAs and ABA.
Contrast-enhanced MR microscopy of amyloid plaques in five mouse models of amyloidosis and in human Alzheimer’s disease brains
Authors: Dudeffant Clémence , Vandesquille Matthias , Herbert Kelly , Garin Clément M. , Alves Sandro , Blanchard Véronique , Comoy Emmanuel E. , Petit Fanny , Dhenain Marc
Published: July 2017

Gadolinium (Gd)-stained MRI is based on Gd contrast agent (CA) administration into the brain parenchyma. The strong signal increase induced by Gd CA can be converted into resolution enhancement to record microscopic MR images. Moreover, inhomogeneous distribution of the Gd CA in the brain improves the contrast between different tissues and provides new contrasts in MR images. Gd-stained MRI detects amyloid plaques, one of the microscopic lesions of Alzheimer’s disease (AD), in APPSL/PS1M146Lmice or in primates. Numerous transgenic mice with various plaque typologies have been developed to mimic cerebral amyloidosis and comparison of plaque detection between animal models and humans with new imaging methods is a recurrent concern. Here, we investigated detection of amyloid plaques by Gd-stained MRI in five mouse models of amyloidosis (APPSL/PS1M146L, APP/PS1dE9, APP23, APPSwDI, and 3xTg) presenting with compact, diffuse and intracellular plaques as well as inpost mortemhuman-AD brains. The brains were then evaluated by histology to investigate the impact of size, compactness, and iron load of amyloid plaques on their detection by MRI. We show that Gd-stained MRI allows detection of compact amyloid plaques as small as 25 µm, independently of their iron load, in mice as well as in human-AD brains.