bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis
Authors: Pitroda Sean P. , Khodarev Nikolai N. , Huang Lei , Uppal Abhineet , Wightman Sean C. , Ganai Sabha , Joseph Nora , Pitt Jason , Brown Miguel , Forde Martin , Mangold Kathy , Xue Lai , Weber Christopher , Segal Jeremy P. , Kadri Sabah , Stack Melinda E. , Khan Sajid , Paty Philip , Kaul Karen , Andrade Jorge , White Kevin P. , Talamonti Mark , Posner Mitchell C. , Hellman Samuel , Weichselbaum Ralph R. 
Published: April 2018

AbstractThe oligometastasis hypothesis suggests a spectrum of metastatic virulence where some metastases are limited in extent and curable with focal therapies. A subset of patients with metastatic colorectal cancer achieves prolonged survival after resection of liver metastases consistent with oligometastasis. Here we define three robust subtypes of de novo colorectal liver metastasis through integrative molecular analysis. Patients with metastases exhibiting MSI-independent immune activation experience the most favorable survival. Subtypes with adverse outcomes demonstrateVEGFAamplification in concert with (i) stromal, mesenchymal, and angiogenic signatures, or (ii) exclusiveNOTCH1andPIK3C2Bmutations with E2F/MYC activation. Molecular subtypes complement clinical risk stratification to distinguish low-risk, intermediate-risk, and high-risk patients with 10-year overall survivals of 94%, 45%, and 19%, respectively. Our findings provide a framework for integrated classification and treatment of metastasis and support the biological basis of curable oligometastatic colorectal cancer. These concepts may be applicable to many patients with metastatic cancer.
The Role of Kainate Receptors in the Pathophysiology of Hypoxia-Induced Seizures in the Neonatal Mouse
Authors: Grosenbaugh Denise K. , Ross Brittany M. , Wagley Pravin , Zanelli Santina A. 
Published: April 2018

AbstractKainate receptors (KARs) are glutamate receptors with peak expression during late embryonic and early postnatal periods. Altered KAR-mediated neurotransmission and subunit expression are observed in several brain disorders, including epilepsy. Here, we examined the role of KARs in regulating seizures in neonatal C57BL/6 mice exposed to a hypoxic insult. We found that knockout of the GluK2 subunit, or blockade of KARs by UBP310 reduced seizure susceptibility during the period of reoxygenation. Following the hypoxic insult, we observed an increase in excitatory neurotransmission in hippocampal CA3 pyramidal cells, which was blocked by treatment with UBP310 prior to hypoxia. Similarly, we observed increased excitatory neurotransmission in CA3 pyramidal cells in an in vitro hippocampal slice model of hypoxic-ischemia. This increase was absent in slices from GluK2−/− mice and in slices treated with UBP310, suggesting that KARs regulate, at least in part, excitatory synaptic neurotransmission following in vivo hypoxia in neonatal mice. Data from these hypoxia models demonstrate that KARs, specifically those containing the GluK2 subunit, contribute to alterations in excitatory neurotransmission and seizure susceptibility, particularly during the reoxygenation period, in neonatal mice. Therapies targeting KARs may prove successful in treatment of neonates affected by hypoxic seizures.
Test-retest reliability of a computer-assisted self-administered questionnaire on early life exposure in a nasopharyngeal carcinoma case-control study
Authors: Mai Zhi-Ming , Lin Jia-Huang , Chiang Shing-Chun , Ngan Roger Kai-Cheong , Kwong Dora Lai-Wan , Ng Wai-Tong , Ng Alice Wan-Ying , Yuen Kam-Tong , Ip Kai-Ming , Chan Yap-Hang , Lee Anne Wing-Mui , Ho Sai-Yin , Lung Maria Li , Lam Tai-Hing 
Published: April 2018

AbstractWe evaluated the reliability of early life nasopharyngeal carcinoma (NPC) aetiology factors in the questionnaire of an NPC case-control study in Hong Kong during 2014–2017. 140 subjects aged 18+ completed the same computer-assisted questionnaire twice, separated by at least 2 weeks. The questionnaire included most known NPC aetiology factors and the present analysis focused on early life exposure. Test-retest reliability of all the 285 questionnaire items was assessed in all subjects and in 5 subgroups defined by cases/controls, sex, time between 1st and 2nd questionnaire (2–29/≥30 weeks), education (secondary or less/postsecondary), and age (25–44/45–59/60+ years) at the first questionnaire. The reliability of items on dietary habits, body figure, skin tone and sun exposure in early life periods (age 6–12 and 13–18) was moderate-to-almost perfect, and most other items had fair-to-substantial reliability in all life periods (age 6–12, 13–18 and 19–30, and 10 years ago). Differences in reliability by strata of the 5 subgroups were only observed in a few items. This study is the first to report the reliability of an NPC questionnaire, and make the questionnaire available online. Overall, our questionnaire had acceptable reliability, suggesting that previous NPC study results on the same risk factors would have similar reliability.
Quantum conductance-temperature phase diagram of granular superconductor K
x
Fe2−ySe2
Authors: Soares C. C. , ElMassalami M. , Yanagisawa Y. , Tanaka M. , Takeya H. , Takano Y. 
Published: April 2018

AbstractIt is now well established that the microstructure of Fe-based chalcogenide K
x
Fe2−ySe2 consists of, at least, a minor (~15 percent), nano-sized, superconducting K
s
Fe2Se2 phase and a major (~85 percent) insulating antiferromagnetic K2Fe4Se5 matrix. Other intercalated A1−xFe2−ySe2 (A = Li, Na, Ba, Sr, Ca, Yb, Eu, ammonia, amide, pyridine, ethylenediamine etc.) manifest a similar microstructure. On subjecting each of these systems to a varying control parameter (e.g. heat treatment, concentration x,y, or pressure p), one obtains an exotic normal-state and superconducting phase diagram. With the objective of rationalizing the properties of such a diagram, we envisage a system consisting of nanosized superconducting granules which are embedded within an insulating continuum. Then, based on the standard granular superconductor model, an induced variation in size, distribution, separation and Fe-content of the superconducting granules can be expressed in terms of model parameters (e.g. tunneling conductance, g, Coulomb charging energy, E
c
, superconducting gap of single granule, Δ, and Josephson energy J = πΔg/2). We show, with illustration from experiments, that this granular scenario explains satisfactorily the evolution of normal-state and superconducting properties (best visualized on a $${\boldsymbol{g}}{\boldsymbol{-}}\frac{{{\boldsymbol{E}}}_{{\boldsymbol{c}}}}{{\boldsymbol{\Delta }}}{\boldsymbol{-}}{\boldsymbol{T}}$$
g
−

E

c

Δ

−
T
phase diagram) of A
x
Fe2−ySe2 when any of x, y, p, or heat treatment is varied.
The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells
Authors: Enerbäck C. , Sandin C. , Lambert S. , Zawistowski M. , Stuart P. E. , Verma D. , Tsoi L. C. , Nair R. P. , Johnston A. , Elder J. T. 
Published: April 2018

AbstractTyrosine kinase 2 (TYK2) belongs to the Janus kinase (JAK) family of tyrosine kinases, which transmit signals from activated cytokine receptors. GWAS have consistently implicated TYK2 in psoriasis susceptibility. We performed an in-depth association analysis of TYK2 using GWAS and resequencing data. Strong genetic association of three nonsynonymous variants in the exonic regions of the TYK2 gene (rs34536443, rs12720356, and rs2304256) were found. rs12720356 encoding I684S is predicted to be deleterious based on its location in the pseudokinase domain. We analyzed PBMCs from 29 individuals representing the haplotypes containing each of the significantly associated signals. STAT4 phosphorylation was evaluated by phospho-flow cytometry after CD3/CD28 activation of cells followed by IL-12 stimulation. Individuals carrying the protective I684S variant manifested significantly reduced p-STAT4 levels in CD4 + CD25 + CD45RO+ (mean Stimulation Index (S.I.) 48.08, n = 10) and CD8 + CD25 + CD45RO + cells (S.I. 55.71, n = 10), compared to controls homozygous for the ancestral haplotype (S.I. 68.19, n = 10 (p = 0.002) and 76.76 n = 10 (p = 0.0008) respectively). Reduced p-STAT4 levels were also observed in skin-homing, cutaneous lymphocyte associated antigen (CLA)-positive CD4 and CD8 cells from I684S carriers. No significant changes in p-STAT4 for the psoriasis-associated variant rs34536443 was found. These data establish the functional significance of the TYK2 I684S variant in psoriasis susceptibility.
Chronic features of allergic asthma are enhanced in the absence of resistin-like molecule-beta
Authors: LeMessurier Kim S. , Palipane Maneesha , Tiwary Meenakshi , Gavin Brian , Samarasinghe Amali E. 
Published: April 2018

AbstractAsthma is characterized by inflammation and architectural changes in the lungs. A number of immune cells and mediators are recognized as initiators of asthma, although therapeutics based on these are not always effective. The multifaceted nature of this syndrome necessitate continued exploration of immunomodulators that may play a role in pathogenesis. We investigated the role of resistin-like molecule-beta (RELM-β), a gut antibacterial, in the development and pathogenesis of Aspergillus-induced allergic airways disease. Age and gender matched C57BL/6J and Retnlb−/− mice rendered allergic to Aspergillus fumigatus were used to measure canonical markers of allergic asthma at early and late time points. Inflammatory cells in airways were similar, although Retnlb−/− mice had reduced tissue inflammation. The absence of RELM-β elevated serum IgA and pro-inflammatory cytokines in the lungs at homeostasis. Markers of chronic disease including goblet cell numbers, Muc genes, airway wall remodelling, and hyperresponsiveness were greater in the absence RELM-β. Specific inflammatory mediators important in antimicrobial defence in allergic asthma were also increased in the absence of RELM-β. These data suggest that while characteristics of allergic asthma develop in the absence of RELM-β, that RELM-β may reduce the development of chronic markers of allergic airways disease.
Propranolol sensitizes prostate cancer cells to glucose metabolism inhibition and prevents cancer progression
Authors: Brohée Laura , Peulen Olivier , Nusgens Betty , Castronovo Vincent , Thiry Marc , Colige Alain C. , Deroanne Christophe F. 
Published: April 2018

AbstractPropranolol, a widely used non-selective beta-adrenergic receptor blocker, was recently shown to display anticancer properties. Its potential to synergize with certain drugs has been also outlined. However, it is necessary to take into account all the properties of propranolol to select a drug that could be efficiently combined with. Propranolol was reported to block the late phase of autophagy. Hence, we hypothesized that in condition enhancing autophagy flux, cancer cells should be especially sensitive to propranolol. 2DG, a glycolysis inhibitor, is an anti-tumor agent having limited effect in monotherapy notably due to induction of pro-survival autophagy. Here, we report that treatment of cancer cells with propranolol in combination with the glycolysis inhibitor 2DG induced a massive accumulation of autophagosome due to autophagy blockade. The propranolol +2DG treatment efficiently prevents prostate cancer cell proliferation, induces cell apoptosis, alters mitochondrial morphology, inhibits mitochondrial bioenergetics and aggravates ER stress in vitro and also suppresses tumor growth in vivo. Our study underlines for the first time the interest to take advantage of the ability of propranolol to inhibit autophagy to design new anti-cancer therapies.
Heterogeneous network promotes species coexistence: metapopulation model for rock-paper-scissors game
Authors: Nagatani Takashi , Ichinose Genki , Tainaka Kei-ichi 
Published: April 2018

AbstractUnderstanding mechanisms of biodiversity has been a central question in ecology. The coexistence of three species in rock-paper-scissors (RPS) systems are discussed by many authors; however, the relation between coexistence and network structure is rarely discussed. Here we present a metapopulation model for RPS game. The total population is assumed to consist of three subpopulations (nodes). Each individual migrates by random walk; the destination of migration is randomly determined. From reaction-migration equations, we obtain the population dynamics. It is found that the dynamic highly depends on network structures. When a network is homogeneous, the dynamics are neutrally stable: each node has a periodic solution, and the oscillations synchronize in all nodes. However, when a network is heterogeneous, the dynamics approach stable focus and all nodes reach equilibriums with different densities. Hence, the heterogeneity of the network promotes biodiversity.
Specific features of human monocytes activation by monophosphoryl lipid A
Authors: Chentouh Ryme , Fitting Catherine , Cavaillon Jean-Marc 
Published: April 2018

AbstractWe deciphered the mechanisms of production of pro- and anti-inflammatory cytokines by adherent human blood mononuclear cells (PBMC) activated by lipopolysaccharide (LPS) or monophosphoryl lipid A (MPLA). Both LPS and MPLA induced tumor necrosis factor (TNF) production proved to be dependent on the production of interleukin-1β (IL-1β). Of note, MPLA induced IL-1β release in human adherent PBMCs whereas MPLA was previously reported to not induce this cytokine in murine cells. Both LPS and MPLA stimulatory effects were inhibited by Toll-like receptor-4 (TLR4) antagonists. Only monocytes activation by LPS was dependent on CD14. Other differences were noticed between LPS and MPLA. Among the different donors, a strong correlation existed in terms of the levels of TNF induced by different LPSs. In contrast, there was no correlation between the TNF productions induced by LPS and those induced by MPLA. However, there was a strong correlation when IL-6 production was analyzed. Blocking actin polymerization and internalization of the agonists inhibited MPLA induced TNF production while the effect on LPS induced TNF production depended on the donors (i.e. high TNF producersversuslow TNF producers). Finally, conventional LPS, tolerized adherent PBMCs to TLR2 agonists, while MPLA primed cells to further challenge with TLR2 agonists.
Fe Doped Magnetic Nanodiamonds Made by Ion Implantation as Contrast Agent for MRI
Authors: Lin Bo-Rong , Chen Chien-Hsu , Kunuku Srinivasu , Chen Tzung-Yuang , Hsiao Tung-Yuan , Niu Huan , Lee Chien-Ping 
Published: April 2018

AbstractWe report in this paper a new MRI contrast agent based on magnetic nanodiamonds fabricated by Fe ion implantation. The Fe atoms that are implanted into the nanodiamonds are not in direct contact with the outside world, enabling this new contrast agent to be free from cell toxicity. The image enhancement was shown clearly through T2 weighted images. The concentration dependence of the T2 relaxation time gives a relaxivity value that is about seven times that of the regular non-magnetic nanodiamonds. Cell viability study has also been performed. It was shown that they were nearly free from cytotoxicity independent of the particle concentration used. The imaging capability demonstrated here adds a new dimension to the medical application of nanodiamonds. In the future one will be able to combine this capability of magnetic nanodiamonds with other functions through surface modifications to perform drug delivery, targeted therapy, localized thermal treatment and diagnostic imaging at the same time.
Pathological conversion of regulatory T cells is associated with loss of allotolerance
Authors: Hua Jing , Inomata Takenori , Chen Yihe , Foulsham William , Stevenson William , Shiang Tina , Bluestone Jeffrey A. , Dana Reza 
Published: April 2018

AbstractCD4+CD25+Foxp3+ Regulatory T cells (Tregs) play a critical role in immune tolerance. The plasticity and functional adaptability of Tregs in an inflammatory microenvironment has been demonstrated in autoimmunity. Here, using a double transgenic mouse model that permits Foxp3 lineage tracing, we investigated the phenotypic plasticity of Foxp3+ Tregs in a well-characterized murine model of corneal transplantation. In order to subvert the normal immune privilege of the cornea and foster an inflammatory milieu, host mice were exposed to desiccating stress prior to transplantation. Treg frequencies and function were decreased following desiccating stress, and this corresponded to decreased graft survival. A fraction of Tregs converted to IL-17+ or IFNγ+ ‘exFoxp3’ T cells that were phenotypically indistinguishable from effector Th17 or Th1 cells, respectively. We investigated how Foxp3 expression is modulated in different Treg subsets, demonstrating that neuropilin-1− peripherally-derived Tregs are particularly susceptible to conversion to IL-17+/IFNγ+ exFoxp3 cells in response to cues from their microenvironment. Finally, we show that IL-6 and IL-23 are implicated in the conversion of Tregs to exFoxp3 cells. This report demonstrates that the pathological conversion of Tregs contributes to the loss of corneal immune privilege.
An Integrated Neural Framework for Dynamic and Static Face Processing
Authors: Bernstein Michal , Erez Yaara , Blank Idan , Yovel Galit 
Published: April 2018

AbstractFaces convey rich information including identity, gender and expression. Current neural models of face processing suggest a dissociation between the processing of invariant facial aspects such as identity and gender, that engage the fusiform face area (FFA) and the processing of changeable aspects, such as expression and eye gaze, that engage the posterior superior temporal sulcus face area (pSTS-FA). Recent studies report a second dissociation within this network such that the pSTS-FA, but not the FFA, shows much stronger response to dynamic than static faces. The aim of the current study was to test a unified model that accounts for these two functional characteristics of the neural face network. In an fMRI experiment, we presented static and dynamic faces while subjects judged an invariant (gender) or a changeable facial aspect (expression). We found that the pSTS-FA was more engaged in processing dynamic than static faces and changeable than invariant aspects, whereas the OFA and FFA showed similar response across all four conditions. These findings support an integrated neural model of face processing in which the ventral areas extract form information from both invariant and changeable facial aspects whereas the dorsal face areas are sensitive to dynamic and changeable facial aspects.
A Regional Scale Approach to Assessing Current and Potential Future Exposure to Tidal Inundation in Different Types of Estuaries
Authors: Hanslow David J. , Morris Bradley D. , Foulsham Edwina , Kinsela Michael A. 
Published: April 2018

AbstractBroad scale assessments of impacts associated with sea level rise have mainly been undertaken using ocean water level data from tide gauges located in harbours and ports assuming that these can be applied directly in mapping inundation throughout estuaries. On many coasts, however, exposure to sea level rise comes about through inundation adjacent to rivers and estuaries, in many instances far from the ocean. In this study, we examine the potential impacts of sea level rise within the diverse estuaries of South East Australia. We use an extensive and long-term water level data set, which show that water levels within the different types of estuaries vary from ocean water levels. We map potential inundation scenarios for each estuary using an approach which improves on the commonly used bath tub method by allowing for variation in tidal processes both between and along estuaries. We identify considerable exposure to future sea level rise, and variable suitability of the bath tub method within different estuaries. Exposure is particularly high around tidal lake systems, where reduced tidal ranges have allowed development to occur in relative proximity to present sea level, and around larger coastal rivers, which feature extensive low-lying plains exposed to potential inundation.
Cryo-EM of nucleosome core particle interactions in trans
Authors: Bilokapic Silvija , Strauss Mike , Halic Mario 
Published: April 2018

AbstractNucleosomes, the basic unit of chromatin, are repetitively spaced along DNA and regulate genome expression and maintenance. The long linear chromatin molecule is extensively condensed to fit DNA inside the nucleus. How distant nucleosomes interact to build tertiary chromatin structure remains elusive. In this study, we used cryo-EM to structurally characterize different states of long range nucleosome core particle (NCP) interactions. Our structures show that NCP pairs can adopt multiple conformations, but, commonly, two NCPs are oriented with the histone octamers facing each other. In this conformation, the dyad of both nucleosome core particles is facing the same direction, however, the NCPs are laterally shifted and tilted. The histone octamer surface and histone tails in trans NCP pairs remain accessible to regulatory proteins. The overall conformational flexibility of the NCP pair suggests that chromatin tertiary structure is dynamic and allows access of various chromatin modifying machineries to nucleosomes.
Topologically knotted deubiquitinases exhibit unprecedented mechanostability to withstand the proteolysis by an AAA+ protease
Authors: Sriramoju Manoj Kumar , Chen Yen , Lee Yun-Tzai Cloud , Hsu Shang-Te Danny 
Published: April 2018

AbstractMore than one thousand knotted protein structures have been identified so far, but the functional roles of these knots remain elusive. It has been postulated that backbone entanglement may provide additional mechanostability. Here, we employed a bacterial proteasome, ClpXP, to mechanically unfold 52-knotted human ubiquitin C-terminal hydrolase (UCH) paralogs from their C-termini, followed by processive translocation into the proteolytic chamber for degradation. Our results revealed unprecedentedly slow kinetics of ClpXP-mediated proteolysis for the proteasome-associated UCHL5: ten thousand times slower than that of a green fluorescence protein (GFP), which has a comparable size to the UCH domain but much higher chemical and thermal stabilities. The ClpXP-dependent mechanostability positively correlates with the intrinsic unfolding rates of the substrates, spanning over several orders of magnitude for the UCHs. The broad range of mechanostability within the same protein family may be associated with the functional requirements for their differential malleabilities.