bluuebunny/crossref_metadata_2025 huggingface dataset:
The Missing Reversioner: Reflections on the Status of Judea and Samaria
Authors: Blum Yehuda Z.
Published: July 2017

Two recent decisions handed down by the Hebron magistrate, Mr. Hussein El-Shajuchi, and by the Bethlehem magistrate, Mr. Tawfik El-Sakka, on February 5, 1968 and on February 27, 1968, respectively, have brought to the fore some interesting legal problems arising from the Six Day War of June, 1967 as a result of which Judea and Samaria (formerly known as the “West Bank” of the Kingdom of Jordan) have come under Israeli control.

The immediate cause that has given rise to the elaboration by the two learned magistrates of the problems to be dealt with in this paper was the promulgation by the Officer Commanding, Israel Defence Forces in Judea and Samaria, on October 23, 1967, of Order No. 145, concerning the status of Israeli advocates in the courts of Judea and Samaria. Article 2 of the said Order provides that “notwithstanding any existing provisions to the contrary, any party to civil proceedings and any defendant in criminal proceedings may authorise an Israeli advocate to represent him in such proceedings.” Article 4 of the same Order stipulates that the Order shall be in force for a period of six months from the date of its entry into force (i.e. October 23, 1967) unless it is terminated at an earlier date by the Officer Commanding, Israel Defence Forces in Judea and Samaria. In the preamble to the Order the reasons given for its promulgation are “to ensure the efficient maintenance of the law, to enable the uninterrupted functioning of the Courts in the District [of Judea and Samaria] and to make available the services of advocates to the local population.” As will be more fully explained later, the reason for promulgating this Order was the strike of Arab lawyers in Judea and Samaria, which threatened to deprive courts and clients there of legal services.
Mutual Fund Performance Evaluation and Best Clienteles
Authors: Chrétien Stéphane , Kammoun Manel
Published: July 2017

This paper investigates investor disagreement and clientele effects in performance evaluation by developing a measure that considers the best potential clienteles of mutual funds. In an incomplete market under law-of-one-price (LOP) and no-good-deal conditions, we obtain an upper bound on admissible performance measures that identifies the most favorable alpha. Empirically, we find that a reasonable investor disagreement leads to generally positive performance for the best clienteles. Performance disagreement by investors can be significant enough to change the average evaluation of mutual funds from negative to positive, depending on the clienteles.
Frontal Assessment Battery in Parkinson’s Disease: Validity and Morphological Correlates
Authors: Bezdicek Ondrej , Růžička Filip , Fendrych Mazancova Adela , Roth Jan , Dušek Pavel , Mueller Karsten , Růžička Evžen , Jech Robert
Published: July 2017

Objectives: Executive dysfunction is a common feature in Parkinson’s disease (PD). However, there is a lack of brief validated instruments for executive dysfunction in PD. Methods: The aim of the present study was to assess the relation of Frontal Assessment Battery (FAB) scores to age and education, to verify the utility of FAB in the evaluation of executive dysfunction in PD and to differentiate between controls (n=41), PD patients with normal cognition (PD-NC; n=41; Hoehn and Yahr stages 2–3) and PD with mild cognitive impairment (PD-MCI; n=32; Hoehn and Yahr stages 2–3). In addition, we studied the relation between voxel-based morphometric (VBM) data and FAB results in PD. Results: We found that FAB scores are significantly related to age and education. The FAB has shown discriminative validity for the differentiation of PD-MCI from PD-NC and controls (area under the curve >.80). Also, the VBM analysis revealed lower FAB scores are specifically related to lower gray matter density in the right ventromedial prefrontal areas and precuneus. Conclusions: The FAB can be recommended as a valid instrument for PD-MCI Level I screening. FAB is sensitive to frontal lobe involvement in PD as reflected by lower gray matter density in prefrontal areas. (JINS, 2017, 23, 675–684)
Trace fossils in Ordovician radiolarian chert successions in the Southern Uplands, Scotland
Authors: Kakuwa Yoshitaka , Floyd James D.
Published: July 2017

Radiolarian chert and associated siliceous claystone in the Southern Uplands of Scotland are examined, in order to study the Great Ordovician Biodiversification Event of benthic animals on the pelagic ocean bottom. Trace fossils which are uncommon, but convincing, are found in the grey chert and siliceous claystone of Gripps Cleuch. These observations constitute firm evidence that large benthic animals which could leave visible trace fossils had colonised the Iapetan Ocean by the late Middle Ordovician, confirming previous studies from Australia for Panthalassa, the other huge ocean. Red chert is, however, a poor recorder of trace fossils, probably because the highly oxidising environment breaks down organic matter, both inhibiting high-density activity of large benthic animals and removing clear traces of benthic animal life.
Beyond self-determination: norms contestation, constituent diplomacies and the co-production of sovereignty
Authors: CORNAGO NOÉ
Published: July 2017

The idea of a perfect national political community, entirely confined within the contours of a corresponding state, is one of the foundational fictions of global modernity. Its formal crystallisation in the legal grammars of the right to self-determination has been however, particularly in the post-colonial era, highly problematic and full of ambiguities. Drawing on this background, this article contends that diplomacy offers frequently a more promising venue for dealing with the challenge of political pluralism than appealing to either the unstable grammars of the right to self-determination or a reified understanding of the principle of territorial integrity of states. In so doing, firstly, the right to self-determination is critically examined. Instead of attempting to articulate its formal content, the malleability of its legal grammars and political realities, will be emphasised. Secondly, based on the discussion of a variety of historical cases, the notion of ‘constituent diplomacies’ will be advanced, aiming to show how the agonistic accommodation of political and territorial pluralism through diplomacy was crucial not only in the formative processes of modern sovereign states but also nowadays. Finally, this relational understanding of the historical forms of governance of political pluralism within and beyond state boundaries will be re-examined, beyond its ethno-political dimensions, through the prism of the complex interplay between the material and ideational conditions for the co-production of sovereignty in the context of new global capitalism.
Non-equilibrium dissipative supramolecular materials with a tunable lifetime
Authors: Tena-Solsona Marta , Rieß Benedikt , Grötsch Raphael K. , Löhrer Franziska C. , Wanzke Caren , Käsdorf Benjamin , Bausch Andreas R. , Müller-Buschbaum Peter , Lieleg Oliver , Boekhoven Job
Published: July 2017

Many biological materials exist in non-equilibrium states driven by the irreversible consumption of high-energy molecules like ATP or GTP. These energy-dissipating structures are governed by kinetics and are thus endowed with unique properties including spatiotemporal control over their presence. Here we show man-made equivalents of materials driven by the consumption of high-energy molecules and explore their unique properties. A chemical reaction network converts dicarboxylates into metastable anhydrides driven by the irreversible consumption of carbodiimide fuels. The anhydrides hydrolyse rapidly to the original dicarboxylates and are designed to assemble into hydrophobic colloids, hydrogels or inks. The spatiotemporal control over the formation and degradation of materials allows for the development of colloids that release hydrophobic contents in a predictable fashion, temporary self-erasing inks and transient hydrogels. Moreover, we show that each material can be re-used for several cycles.
Non-canonical NOTCH3 signalling limits tumour angiogenesis
Authors: Lin Shuheng , Negulescu Ana , Bulusu Sirisha , Gibert Benjamin , Delcros Jean-Guy , Ducarouge Benjamin , Rama Nicolas , Gadot Nicolas , Treilleux Isabelle , Saintigny Pierre , Meurette Olivier , Mehlen Patrick
Published: July 2017

Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Here we describe an unexpected pro-apoptotic role of Notch3 in regulating tumour angiogenesis independently of the Notch canonical pathway. The Notch3 ligand Jagged-1 is upregulated in a fraction of human cancer and our data support the view that Jagged-1, produced by cancer cells, is inhibiting the apoptosis induced by the aberrant Notch3 expression in tumour vasculature. We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro-apoptotic activity is blocked by Jagged-1. Along this line, using Notch3 mutant mice, we demonstrate that tumour growth and angiogenesis are increased when Notch3 is silenced in the stroma. Consequently, we show that the well-documented anti-tumour effect mediated by γ-secretase inhibition is at least in part dependent on the apoptosis triggered by Notch3 in endothelial cells.
Ancient European dog genomes reveal continuity since the Early Neolithic
Authors: Botigué Laura R. , Song Shiya , Scheu Amelie , Gopalan Shyamalika , Pendleton Amanda L. , Oetjens Matthew , Taravella Angela M. , Seregély Timo , Zeeb-Lanz Andrea , Arbogast Rose-Marie , Bobo Dean , Daly Kevin , Unterländer Martina , Burger Joachim , Kidd Jeffrey M. , Veeramah Krishna R.
Published: July 2017

Europe has played a major role in dog evolution, harbouring the oldest uncontested Palaeolithic remains and having been the centre of modern dog breed creation. Here we sequence the genomes of an Early and End Neolithic dog from Germany, including a sample associated with an early European farming community. Both dogs demonstrate continuity with each other and predominantly share ancestry with modern European dogs, contradicting a previously suggested Late Neolithic population replacement. We find no genetic evidence to support the recent hypothesis proposing dual origins of dog domestication. By calibrating the mutation rate using our oldest dog, we narrow the timing of dog domestication to 20,000–40,000 years ago. Interestingly, we do not observe the extreme copy number expansion of the AMY2B gene characteristic of modern dogs that has previously been proposed as an adaptation to a starch-rich diet driven by the widespread adoption of agriculture in the Neolithic.
Physical limits to biomechanical sensing in disordered fibre networks
Authors: Beroz Farzan , Jawerth Louise M. , Münster Stefan , Weitz David A. , Broedersz Chase P. , Wingreen Ned S.
Published: July 2017

Cells actively probe and respond to the stiffness of their surroundings. Since mechanosensory cells in connective tissue are surrounded by a disordered network of biopolymers, their in vivo mechanical environment can be extremely heterogeneous. Here we investigate how this heterogeneity impacts mechanosensing by modelling the cell as an idealized local stiffness sensor inside a disordered fibre network. For all types of networks we study, including experimentally-imaged collagen and fibrin architectures, we find that measurements applied at different points yield a strikingly broad range of local stiffnesses, spanning roughly two decades. We verify via simulations and scaling arguments that this broad range of local stiffnesses is a generic property of disordered fibre networks. Finally, we show that to obtain optimal, reliable estimates of global tissue stiffness, a cell must adjust its size, shape, and position to integrate multiple stiffness measurements over extended regions of space.
Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus
Authors: Medina-Gomez Carolina , Kemp John P. , Dimou Niki L. , Kreiner Eskil , Chesi Alessandra , Zemel Babette S. , Bønnelykke Klaus , Boer Cindy G. , Ahluwalia Tarunveer S. , Bisgaard Hans , Evangelou Evangelos , Heppe Denise H. M. , Bonewald Lynda F. , Gorski Jeffrey P. , Ghanbari Mohsen , Demissie Serkalem , Duque Gustavo , Maurano Matthew T. , Kiel Douglas P. , Hsu Yi-Hsiang , C.J. van der Eerden Bram , Ackert-Bicknell Cheryl , Reppe Sjur , Gautvik Kaare M. , Raastad Truls , Karasik David , van de Peppel Jeroen , Jaddoe Vincent W. V. , Uitterlinden André G. , Tobias Jonathan H. , Grant Struan F.A. , Bagos Pantelis G. , Evans David M. , Rivadeneira Fernando
Published: July 2017

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34–52%) for TBLH-BMD, and 39% (95% CI: 30–48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29–56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.
Let-7 microRNA-dependent control of leukotriene signaling regulates the transition of hematopoietic niche in mice
Authors: Jiang Xuan , Hawkins John S. , Lee Jerry , Lizama Carlos O. , Bos Frank L. , Zape Joan P. , Ghatpande Prajakta , Peng Yongbo , Louie Justin , Lagna Giorgio , Zovein Ann C. , Hata Akiko
Published: July 2017

Hematopoietic stem and progenitor cells arise from the vascular endothelium of the dorsal aorta and subsequently switch niche to the fetal liver through unknown mechanisms. Here we report that vascular endothelium-specific deletion of mouseDrosha(DroshacKO), an enzyme essential for microRNA biogenesis, leads to anemia and death. A similar number of hematopoietic stem and progenitor cells emerge from Drosha-deficient and control vascular endothelium, butDroshacKO-derived hematopoietic stem and progenitor cells accumulate in the dorsal aorta and fail to colonize the fetal liver. Depletion of thelet-7family of microRNAs is a primary cause of this defect, as it leads to activation of leukotriene B4 signaling and induction of the α4β1 integrin cell adhesion complex in hematopoietic stem and progenitor cells. Inhibition of leukotriene B4 or integrin rescues maturation and migration ofDroshacKOhematopoietic stem and progenitor cells to the fetal liver, while it hampers hematopoiesis in wild-type animals. Our study uncovers a previously undefined role of innate leukotriene B4 signaling as a gatekeeper of the hematopoietic niche transition.
Triggerable tough hydrogels for gastric resident dosage forms
Authors: Liu Jinyao , Pang Yan , Zhang Shiyi , Cleveland Cody , Yin Xiaolei , Booth Lucas , Lin Jiaqi , Lucy Lee Young-Ah , Mazdiyasni Hormoz , Saxton Sarah , Kirtane Ameya R. , Erlach Thomas von , Rogner Jaimie , Langer Robert , Traverso Giovanni
Published: July 2017

Systems capable of residing for prolonged periods of time in the gastric cavity have transformed our ability to diagnose and treat patients. Gastric resident systems for drug delivery, ideally need to be: ingestible, be able to change shape or swell to ensure prolonged gastric residence, have the mechanical integrity to withstand the forces associated with gastrointestinal motility, be triggerable to address any side effects, and be drug loadable and release drug over a prolonged period of time. Materials that have been primarily utilized for these applications have been largely restricted to thermoplastics and thermosets. Here we describe a novel set of materials, triggerable tough hydrogels, meeting all these requirement, supported by evaluation in a large animal model and ultimately demonstrate the potential of triggerable tough hydrogels to serve as prolonged gastric resident drug depots. Triggerable tough hydrogels may be applied in myriad of applications, including bariatric interventions, drug delivery, and tissue engineering.
Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity
Authors: Cao Jia , Peng Jinghua , An Hongying , He Qiyi , Boronina Tatiana , Guo Shaodong , White Morris F. , Cole Philip A. , He Ling
Published: July 2017

Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.
Thrombopoiesis is spatially regulated by the bone marrow vasculature
Authors: Stegner David , vanEeuwijk Judith M. M. , Angay Oğuzhan , Gorelashvili Maximilian G. , Semeniak Daniela , Pinnecker Jürgen , Schmithausen Patrick , Meyer Imke , Friedrich Mike , Dütting Sebastian , Brede Christian , Beilhack Andreas , Schulze Harald , Nieswandt Bernhard , Heinze Katrin G.
Published: July 2017

In mammals, megakaryocytes (MKs) in the bone marrow (BM) produce blood platelets, required for hemostasis and thrombosis. MKs originate from hematopoietic stem cells and are thought to migrate from an endosteal niche towards the vascular sinusoids during their maturation. Through imaging of MKs in the intact BM, here we show that MKs can be found within the entire BM, without a bias towards bone-distant regions. By combining in vivo two-photon microscopy and in situ light-sheet fluorescence microscopy with computational simulations, we reveal surprisingly slow MK migration, limited intervascular space, and a vessel-biased MK pool. These data challenge the current thrombopoiesis model of MK migration and support a modified model, where MKs at sinusoids are replenished by sinusoidal precursors rather than cells from a distant periostic niche. As MKs do not need to migrate to reach the vessel, therapies to increase MK numbers might be sufficient to raise platelet counts.
Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage
Authors: Schenk Arne , Ghallab Ahmed , Hofmann Ute , Hassan Reham , Schwarz Michael , Schuppert Andreas , Schwen Lars Ole , Braeuning Albert , Teutonico Donato , Hengstler Jan G. , Kuepfer Lars
Published: July 2017

Diseases and toxins may lead to death of active liver tissue, resulting in a loss of total clearance capacity at the whole-body level. However, it remains difficult to study, whether the loss of metabolizing tissue is sufficient to explain loss of metabolic capacity of the liver or whether the surviving tissue undergoes an adaptive response to compensate the loss. To understand the cellular impact of toxic liver damage in an in vivo situation, we here used physiologically-based pharmacokinetic modelling to investigate pharmacokinetics of a specifically designed drug cocktail at three different sampling sites of the body in healthy mice and mice treated with carbon tetrachloride (CCl4). Liver zonation was explicitly quantified in the models through immunostaining of cytochrome P450s enzymes. Comparative analyses between the simulated decrease in clearance capacity and the experimentally measured loss in tissue volume indicated that CCl4-induced impairment of metabolic functions goes beyond the mere loss of metabolically active tissue. The here established integrative modelling strategy hence provides mechanistic insights into functional consequences of toxic liver damage in an in vivo situation, which would not have been accessible by conventional methods.
Genetic and functional characterization of disease associations explains comorbidity
Authors: Rubio-Perez Carlota , Guney Emre , Aguilar Daniel , Piñero Janet , Garcia-Garcia Javier , Iadarola Barbara , Sanz Ferran , Fernandez-Fuentes Narcís , Furlong Laura I. , Oliva Baldo
Published: July 2017

Understanding relationships between diseases, such as comorbidities, has important socio-economic implications, ranging from clinical study design to health care planning. Most studies characterize disease comorbidity using shared genetic origins, ignoring pathway-based commonalities between diseases. In this study, we define the disease pathways using an interactome-based extension of known disease-genes and introduce several measures of functional overlap. The analysis reveals 206 significant links among 94 diseases, giving rise to a highly clustered disease association network. We observe that around 95% of the links in the disease network, though not identified by genetic overlap, are discovered by functional overlap. This disease network portraits rheumatoid arthritis, asthma, atherosclerosis, pulmonary diseases and Crohn’s disease as hubs and thus pointing to common inflammatory processes underlying disease pathophysiology. We identify several described associations such as the inverse comorbidity relationship between Alzheimer’s disease and neoplasms. Furthermore, we investigate the disruptions in protein interactions by mapping mutations onto the domains involved in the interaction, suggesting hypotheses on the causal link between diseases. Finally, we provide several proof-of-principle examples in which we model the effect of the mutation and the change of the association strength, which could explain the observed comorbidity between diseases caused by the same genetic alterations.
Myricetin improves endurance capacity and mitochondrial density by activating SIRT1 and PGC-1α
Authors: Jung Hoe-Yune , Lee Dongyeop , Ryu Hye Guk , Choi Bo-Hwa , Go Younghoon , Lee Namgyu , Lee Dohyun , Son Heehwa G. , Jeon Jongsu , Kim Seong-Hoon , Yoon Jong Hyuk , Park Seon-Min , Lee Seung-Jae V. , Lee In-Kyu , Choi Kwan Yong , Ryu Sung Ho , Nohara Kazunari , Yoo Seung-Hee , Chen Zheng , Kim Kyong-Tai
Published: July 2017

Robust mitochondrial respiration provides energy to support physical performance and physiological well-being, whereas mitochondrial malfunction is associated with various pathologies and reduced longevity. In the current study, we tested whether myricetin, a natural flavonol with diverse biological activities, may impact mitochondrial function and longevity. The mice were orally administered myricetin (50 mg/kg/day) for 3 weeks. Myricetin significantly potentiated aerobic capacity in mice, as evidenced by their increased running time and distance. The elevated mitochondrial function was associated with induction of genes for oxidative phosphorylation and mitochondrial biogenesis in metabolically active tissues. Importantly, myricetin treatment led to decreased PGC-1α acetylation through SIRT1 activation. Furthermore, myricetin significantly improved the healthspan and lifespan of wild-type, but notSir-2.1-deficient,C. elegans. These results demonstrate that myricetin enhances mitochondrial activity, possibly by activating PGC-1α and SIRT1, to improve physical endurance, strongly suggesting myricetin as a mitochondria-activating agent.
Enhanced figure of merit in nanostructured (Bi,Sb)2Te3 with optimized composition, prepared by a straightforward arc-melting procedure
Authors: Serrano-Sánchez F. , Gharsallah M. , Nemes N. M. , Biskup N. , Varela M. , Martínez J. L. , Fernández-Díaz M. T. , Alonso J. A.
Published: July 2017

Sb-doped Bi2Te3 is known since the 1950s as the best thermoelectric material for near-room temperature operation. Improvements in material performance are expected from nanostructuring procedures. We present a straightforward and fast method to synthesize already nanostructured pellets that show an enhanced ZT due to a remarkably low thermal conductivity and unusually high Seebeck coefficient for a nominal composition optimized for arc-melting: Bi0.35Sb1.65Te3. We provide a detailed structural analysis of the Bi2−xSbxTe3 series (0 ≤ x ≤ 2) based on neutron powder diffraction as a function of composition and temperature that reveals the important role played by atomic vibrations. Arc-melting produces layered platelets with less than 50 nm-thick sheets. The low thermal conductivity is attributed to the phonon scattering at the grain boundaries of the nanosheets. This is a fast and cost-effective production method of highly efficient thermoelectric materials.
Three-Dimensional Imaging of Biological Tissue by Cryo X-Ray Ptychography
Authors: Shahmoradian S. H. , Tsai E. H. R. , Diaz A. , Guizar-Sicairos M. , Raabe J. , Spycher L. , Britschgi M. , Ruf A. , Stahlberg H. , Holler M.
Published: July 2017

High-throughput three-dimensional cryogenic imaging of thick biological specimens is valuable for identifying biologically- or pathologically-relevant features of interest, especially for subsequent correlative studies. Unfortunately, high-resolution imaging techniques at cryogenic conditions often require sample reduction through sequential physical milling or sectioning for sufficient penetration to generate each image of the 3-D stack. This study represents the first demonstration of using ptychographic hard X-ray tomography at cryogenic temperatures for imaging thick biological tissue in a chemically-fixed, frozen-hydrated state without heavy metal staining and organic solvents. Applied to mammalian brain, this label-free cryogenic imaging method allows visualization of myelinated axons and sub-cellular features such as age-related pigmented cellular inclusions at a spatial resolution of ~100 nanometers and thicknesses approaching 100 microns. Because our approach does not require dehydration, staining or reduction of the sample, we introduce the possibility for subsequent analysis of the same tissue using orthogonal approaches that are expected to yield direct complementary insight to the biological features of interest.
The resident pathobiont Staphylococcus xylosus in Nfkbiz-deficient skin accelerates spontaneous skin inflammation
Authors: Kim Yeji , Lee Yong-Soo , Yang Jin-Young , Lee Su-Hyun , Park Yun-Yong , Kweon Mi-Na
Published: July 2017

IκBζ, which is encoded by the Nfkbiz gene, is a member of the nuclear IκB family of proteins that act as transcriptional regulators via association with NF-κB. Nfkbiz-deficient (Nfkbiz−/−) mice develop spontaneous dermatitis; however, the underlying mechanism has yet to be elucidated. In our study, we found higher skin pathology scores and more serum IgE antibodies and trans-epidermal water loss in Nfkbiz−/− than in Nfkbiz-sufficient (Nfkbiz+/−) mice. There was also greater expansion of IFN-γ-, IL-17A-, and IL-22-secreting CD4+ T cells and of IL-17A-secreting γδ+ T cells in the skin of Nfkbiz−/− mice than in with Nfkbiz+/− mice. Pyrosequencing analysis showed decreased diversity of resident bacteria and markedly expanded Staphylococcus (S.) xylosus in the skin of Nfkbiz−/− mice. Oral administration of antibiotics including cephalexin and enrofloxacin ameliorated skin inflammation. Topical application of S. xylosus also resulted in the expansion of IL-17A-secreting CD4+ T cells along with high levels of pro-inflammatory cytokines and chemokines in the skin of Nfkbiz−/− mice. The expansion of commensal S. xylosus may be one cause of skin dysbiosis in Nfkbiz−/− mice and suggests that the Nfkbiz gene may play a regulatory role in the microbiota-skin immunity axis.
APOE genotype influences insulin resistance, apolipoprotein CII and CIII according to plasma fatty acid profile in the Metabolic Syndrome
Authors: Fallaize Rosalind , Carvalho-Wells Andrew L. , Tierney Audrey C. , Marin Carmen , Kieć-Wilk Beata , Dembińska-Kieć Aldona , Drevon Christian A. , DeFoort Catherine , Lopez-Miranda José , Risérus Ulf , Saris Wim H. , Blaak Ellen E. , Roche Helen M. , Lovegrove Julie A.
Published: July 2017

Metabolic markers associated with the Metabolic Syndrome (MetS) may be affected by interactions between the APOE genotype and plasma fatty acids (FA). In this study, we explored FA-gene interactions between the missense APOE polymorphisms and FA status on metabolic markers in MetS. Plasma FA, blood pressure, insulin sensitivity and lipid concentrations were determined at baseline and following a 12-week randomized, controlled, parallel, dietary FA intervention in 442 adults with MetS (LIPGENE study). FA-APOE gene interactions at baseline and following change in plasma FA were assessed using adjusted general linear models. At baseline E4 carriers had higher plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) compared with E2 carriers; and higher TC, LDL-C and apo B compared with E3/E3. Whilst elevated plasma n-3 polyunsaturated FA (PUFA) was associated with a beneficially lower concentration of apo CIII in E2 carriers, a high proportion of plasma C16:0 was associated with insulin resistance in E4 carriers. Following FA intervention, a reduction in plasma long-chain n-3 PUFA was associated with a reduction in apo CII concentration in E2 carriers. Our novel data suggest that individuals with MetS may benefit from personalized dietary interventions based on APOE genotype.
Angiopoietin-like 4 induces a β-catenin-mediated upregulation of ID3 in fibroblasts to reduce scar collagen expression
Authors: Teo Ziqiang , Chan Jeremy Soon Kiat , Chong Han Chung , Sng Ming Keat , Choo Chee Chong , Phua Glendon Zhi Ming , Teo Daniel Jin Rong , Zhu Pengcheng , Choong Cleo , Wong Marcus Thien Chong , Tan Nguan Soon
Published: July 2017

In adult skin wounds, collagen expression rapidly re-establishes the skin barrier, although the resultant scar is aesthetically and functionally inferior to unwounded tissue. Although TGFβ signaling and fibroblasts are known to be responsible for scar-associated collagen production, there are currently no prophylactic treatments for scar management. Fibroblasts in crosstalk with wound keratinocytes orchestrate collagen expression, although the precise paracrine pathways involved remain poorly understood. Herein, we showed that the matricellular protein, angiopoietin-like 4 (ANGPTL4), accelerated wound closure and reduced collagen expression in diabetic and ANGPTL4-knockout mice. Similar observations were made in wild-type rat wounds. Using human fibroblasts as a preclinical model for mechanistic studies, we systematically elucidated that ANGPTL4 binds to cadherin-11, releasing membrane-bound β-catenin which translocate to the nucleus and transcriptionally upregulate the expression of Inhibitor of DNA-binding/differentiation protein 3 (ID3). ID3 interacts with scleraxis, a basic helix-loop-helix transcription factor, to inhibit scar-associated collagen types 1α2 and 3α1 production by fibroblasts. We also showed ANGPTL4 interaction with cadherin-11 in human scar tissue. Our findings highlight a central role for matricellular proteins such as ANGPTL4 in the attenuation of collagen expression and may have a broader implication for other fibrotic pathologies.
CDKL5 localizes at the centrosome and midbody and is required for faithful cell division
Authors: Barbiero Isabella , Valente Davide , Chandola Chetan , Magi Fiorenza , Bergo Anna , Monteonofrio Laura , Tramarin Marco , Fazzari Maria , Soddu Silvia , Landsberger Nicoletta , Rinaldo Cinzia , Kilstrup-Nielsen Charlotte
Published: July 2017

The cyclin-dependent kinase-like 5 (CDKL5) gene has been associated with rare neurodevelopmental disorders characterized by the early onset of seizures and intellectual disability. The CDKL5 protein is widely expressed in most tissues and cells with both nuclear and cytoplasmic localization. In post-mitotic neurons CDKL5 is mainly involved in dendritic arborization, axon outgrowth, and spine formation while in proliferating cells its function is still largely unknown. Here, we report that CDKL5 localizes at the centrosome and at the midbody in proliferating cells. Acute inactivation of CDKL5 by RNA interference (RNAi) leads to multipolar spindle formation, cytokinesis failure and centrosome accumulation. At the molecular level, we observed that, among the several midbody components we analyzed, midbodies of CDKL5-depleted cells were devoid of HIPK2 and its cytokinesis target, the extrachromosomal histone H2B phosphorylated at S14. Of relevance, expression of the phosphomimetic mutant H2B-S14D, which is capable of overcoming cytokinesis failure in HIPK2-defective cells, was sufficient to rescue spindle multipolarity in CDKL5-depleted cells. Taken together, these results highlight a hitherto unknown role of CDKL5 in regulating faithful cell division by guaranteeing proper HIPK2/H2B functions at the midbody.
Novel Molecule Exhibiting Selective Affinity for GABAA Receptor Subtypes
Authors: Borghese Cecilia M. , Herman Melissa , Snell Lawrence D. , Lawrence Keri J. , Lee Hyun-Young , Backos Donald S. , Vanderlinden Lauren A. , Harris R. Adron , Roberto Marisa , Hoffman Paula L. , Tabakoff Boris
Published: July 2017

Aminoquinoline derivatives were evaluated against a panel of receptors/channels/transporters in radioligand binding experiments. One of these derivatives (DCUK-OEt) displayed micromolar affinity for brain γ-aminobutyric acid type A (GABAA) receptors. DCUK-OEt was shown to be a positive allosteric modulator (PAM) of GABA currents with α1β2γ2, α1β3γ2, α5β3γ2 and α1β3δ GABAA receptors, while having no significant PAM effect on αβ receptors or α1β1γ2, α1β2γ1, α4β3γ2 or α4β3δ receptors. DCUK-OEt modulation of α1β2γ2 GABAA receptors was not blocked by flumazenil. The subunit requirements for DCUK-OEt actions distinguished DCUK-OEt from other currently known modulators of GABA function (e.g., anesthetics, neurosteroids or ethanol). Simulated docking of DCUK-OEt at the GABAA receptor suggested that its binding site may be at the α + β- subunit interface. In slices of the central amygdala, DCUK-OEt acted primarily on extrasynaptic GABAA receptors containing the α1 subunit and generated increases in extrasynaptic “tonic” current with no significant effect on phasic responses to GABA. DCUK-OEt is a novel chemical structure acting as a PAM at particular GABAA receptors. Given that neurons in the central amygdala responding to DCUK-OEt were recently identified as relevant for alcohol dependence, DCUK-OEt should be further evaluated for the treatment of alcoholism.
Antisocial rewarding in structured populations
Authors: dos Santos Miguel , Peña Jorge
Published: July 2017

Cooperation in collective action dilemmas usually breaks down in the absence of additional incentive mechanisms. This tragedy can be escaped if cooperators have the possibility to invest in reward funds that are shared exclusively among cooperators (prosocial rewarding). Yet, the presence of defectors who do not contribute to the public good but do reward themselves (antisocial rewarding) deters cooperation in the absence of additional countermeasures. A recent simulation study suggests that spatial structure is sufficient to prevent antisocial rewarding from deterring cooperation. Here we reinvestigate this issue assuming mixed strategies and weak selection on a game-theoretic model of social interactions, which we also validate using individual-based simulations. We show that increasing reward funds facilitates the maintenance of prosocial rewarding but prevents its invasion, and that spatial structure can sometimes select against the evolution of prosocial rewarding. Our results suggest that, even in spatially structured populations, additional mechanisms are required to prevent antisocial rewarding from deterring cooperation in public goods dilemmas.
Evaluation of high resolution ultrasound as a tool for assessing the 3D volume of blood clots during in vitro thrombolysis
Authors: Auboire Laurent , Escoffre Jean-Michel , Fouan Damien , Jacquet Jean-René , Ossant Frédéric , Grégoire Jean-Marc , Bouakaz Ayache
Published: July 2017

Thrombosis is a major cause of several diseases, i.e. myocardial infarction, cerebral stroke and pulmonary embolism. Thrombolytic therapies are required to induce fast and efficient recanalization of occluded vessels. To evaluate the in vitro efficacy of these thrombolytic strategies, measuring clot dissolution is essential. This study aimed to evaluate and validate high resolution ultrasound as a tool to assess the exact volume of clots in 3D and in real time during in vitro thrombolytic drug testing. This new method was validated by measuring the effects of concentration range of recombinant tissue type plasminogen activator on a blood clot during complete occlusion or 70% stenosis of a vessel. This study shows that high resolution ultrasound imaging allows for a real-time assessment of the 3D volume of a blood clot with negligible inter- and intra-operator variabilities. The conclusions drawn from this study demonstrate the promising potential of high resolution ultrasound imaging for the in vitro assessment of new thrombolytic drugs.
Functional correlates of TSH, fT3 and fT4 in Alzheimer disease: a F-18 FDG PET/CT study
Authors: Chiaravalloti Agostino , Ursini Francesco , Fiorentini Alessandro , Barbagallo Gaetano , Martorana Alessandro , Koch Giacomo , Tavolozza Mario , Schillaci Orazio
Published: July 2017

The present study was aimed to investigate the relationships between thyroid stimulating hormone (TSH), freeT3 (fT3) and freeT4 (fT4) and brain glucose consumption as detectable by means of 2-deoxy-2-(F-18) fluoro-D-glucose (F-18 FDG) Positron Emission Tomography/Computed Tomography (PET/CT) in a selected population with Alzheimer disease (AD). We evaluated 87 subjects (37 males and 50 females, mean age 70 (±6) years old) with AD. All of them were subjected to TSH, fT3 and fT4 assay and to cerebrospinal fluid amyloid (Aβ1-42) and tau [phosphorylated-tau (p-tau) and total-tau (t-tau)] assay prior PET/CT examination. Values for TSH, fT3 and fT4 were in the normal range. The relationships were evaluated by means of statistical parametric mapping (SPM8) using age, sex, MMSE, scholarship and CSF values of amyloid and tau as covariates. We found a significant positive correlation between TSH values and cortical glucose consumption in a wide portion of the anterior cingulate cortex bilaterally (BA32) and left frontal lobe (BA25) (p FWE-corr <0.001; p FDRcorr <0.000; cluster extent 66950). No significant relationships were found between cortical F-18 FDG uptake and T3 and T4 serum levels. The results of our study suggest that a cortical dysfunction in anterior cingulate and frontal lobes may affect serum values of TSH in AD patients.
Untangling the model muddle: Empirical tumour growth in Tasmanian devil facial tumour disease
Authors: Hamede Rodrigo K. , Beeton Nicholas J. , Carver Scott , Jones Menna E.
Published: July 2017

A pressing and unresolved topic in cancer research is how tumours grow in the absence of treatment. Despite advances in cancer biology, therapeutic and diagnostic technologies, there is limited knowledge regarding the fundamental growth and developmental patterns in solid tumours. In this ten year study, we estimated growth curves in Tasmanian devil facial tumours, a clonal transmissible cancer, in males and females with two different karyotypes (diploid, tetraploid) and facial locations (mucosal, dermal), using established differential equation models and model selection. Logistic growth was the most parsimonious model for diploid, tetraploid and mucosal tumours, with less model certainty for dermal tumours. Estimates of daily proportional tumour growth rate per day (95% Bayesian CIs) varied with ploidy and location [diploid 0.016 (0.014–0.020), tetraploid 0.026 (0.020–0.033), mucosal 0.013 (0.011–0.015), dermal 0.020 (0.016–0.024)]. Final tumour size (cm3) also varied, particularly the upper credible interval owing to host mortality as tumours approached maximum volume [diploid 364 (136–2,475), tetraploid 172 (100–305), dermal 226 (134–471)]. To our knowledge, these are the first empirical estimates of tumour growth in the absence of treatment in a wild population. Through this animal-cancer system our findings may enhance understanding of how tumour properties interact with growth dynamics in other types of cancer.
Predicting the spread of the Asian hornet (Vespa velutina) following its incursion into Great Britain
Authors: Keeling Matt J. , Franklin Daniel N. , Datta Samik , Brown Mike A. , Budge Giles E.
Published: July 2017

The yellow-legged or Asian hornet (Vespa velutina) is native to South-East Asia, and is a voracious predator of pollinating insects including honey bees. Since its accidental introduction into South-Western France in 2004, V. velutina has spread to much of western Europe. The presence of V. velutina in Great Britain was first confirmed in September 2016. The likely dynamics following an initial incursion are uncertain, especially the risk of continued spread, and the likely success of control measures. Here we extrapolate from the situation in France to quantify the potential invasion of V. velutina in Great Britain. We find that, without control, V. velutina could colonise the British mainland rapidly, depending upon how the Asian hornet responds to the colder climate in Britain compared to France. The announcement that a second hornet had been discovered in Somerset, increases the chance that the invasion first occurred before 2016. We therefore consider the likely site of first invasion and the probabilistic position of additional founding nests in late 2016 and early 2017. Given the potential dispersion of V. velutina, we conclude that vigilance is required over a large area to prevent the establishment of this threat to the pollinator population.
Safety and tolerability of topically administered autologous, apoptotic PBMC secretome (APOSEC) in dermal wounds: a randomized Phase 1 trial (MARSYAS I﻿)
Authors: Simader Elisabeth , Traxler Denise , Kasiri Mohammad Mahdi , Hofbauer Helmut , Wolzt Michael , Glogner Christoph , Storka Angela , Mildner Michael , Gouya Ghazaleh , Geusau Alexandra , Fuchs Carola , Eder Claudia , Graf Alexandra , Schaden Michaela , Golabi Bahar , Aretin Marie-Bernadette , Suessner Susanne , Gabriel Christian , Klepetko Walter , Tschachler Erwin , Ankersmit Hendrik Jan
Published: July 2017

Developing effective therapies against chronic wound healing deficiencies is a global priority. Thus we evaluated the safety of two different doses of topically administered autologous APOSEC, the secretome of apoptotic peripheral blood mononuclear cells (PBMCs), in healthy male volunteers with artificial dermal wounds. Ten healthy men were enrolled in a single-center, randomized, double-blinded, placebo-controlled phase 1 trial. Two artificial wounds at the upper arm were generated using a 4-mm punch biopsy. Each participant was treated with both topically applied APOSEC and placebo in NuGel for 7 consecutive days. The volunteers were randomized into two groups: a low-dose group (A) receiving the supernatant of 12.5 × 106 PBMCs and a high-dose group (B) receiving an equivalent of 25 × 106 PBMCs resuspended in NuGel Hydrogel. Irradiated medium served as placebo. The primary outcome was the tolerability of the topical application of APOSEC. All adverse events were recorded until 17 days after the biopsy. Local tolerability assessment was measured on a 4-point scale. Secondary outcomes were wound closure and epithelization at day 7. No therapy-related serious adverse events occurred in any of the participants, and both low- and high-dose treatments were well tolerated. Wound closure was not affected by APOSEC therapy.
Temporal dynamics of whole body residues of the neonicotinoid insecticide imidacloprid in live or dead honeybees
Authors: Schott Matthias , Bischoff Gabriela , Eichner Gerrit , Vilcinskas Andreas , Büchler Ralph , Meixner Marina Doris , Brandt Annely
Published: July 2017

In cases of acute intoxication, honeybees often lay in front of their hives for several days, exposed to sunlight and weather, before a beekeeper can take a sample. Beekeepers send samples to analytical laboratories, but sometimes no residues can be detected. Temperature and sun light could influence the decrease of pesticides in bee samples and thereby residues left for analysis. Moreover, samples are usually sent via normal postal services without cooling. We investigated the temporal dynamics of whole-body residues of imidacloprid in live or dead honeybees following a single-meal dietary exposure of 41 ng/bee under various environmental conditions, such as freezing, exposure to UV light or transfer of individuals through the mail system. Immobile, “dead” looking honeybees recovered from paralysis after 48 hours. The decrease of residues in living but paralysed bees was stopped by freezing (= killing). UV light significantly reduced residues, but the mode of transport did not affect residue levels. Group feeding increased the variance of residues, which is relevant for acute oral toxicity tests. In conclusion, elapsed time after poisoning is key for detection of neonicotinoids. Freezing before mailing significantly reduced the decrease of imidacloprid residues and may increase the accuracy of laboratory analysis for pesticides.
Mechanisms and Specificity of Phenazine Biosynthesis Protein PhzF
Authors: Diederich Christina , Leypold Mario , Culka Martin , Weber Hansjörg , Breinbauer Rolf , Ullmann G. Matthias , Blankenfeldt Wulf
Published: July 2017

Phenazines are bacterial virulence and survival factors with important roles in infectious disease. PhzF catalyzes a key reaction in their biosynthesis by isomerizing (2 S,3 S)-2,3-dihydro-3-hydroxy anthranilate (DHHA) in two steps, a [1,5]-hydrogen shift followed by tautomerization to an aminoketone. While the [1,5]-hydrogen shift requires the conserved glutamate E45, suggesting acid/base catalysis, it also shows hallmarks of a sigmatropic rearrangement, namely the suprafacial migration of a non-acidic proton. To discriminate these mechanistic alternatives, we employed enzyme kinetic measurements and computational methods. Quantum mechanics/molecular mechanics (QM/MM) calculations revealed that the activation barrier of a proton shuttle mechanism involving E45 is significantly lower than that of a sigmatropic [1,5]-hydrogen shift. QM/MM also predicted a large kinetic isotope effect, which was indeed observed with deuterated substrate. For the tautomerization, QM/MM calculations suggested involvement of E45 and an active site water molecule, explaining the observed stereochemistry. Because these findings imply that PhzF can act only on a limited substrate spectrum, we also investigated the turnover of DHHA derivatives, of which only O-methyl and O-ethyl DHHA were converted. Together, these data reveal how PhzF orchestrates a water-free with a water-dependent step. Its unique mechanism, specificity and essential role in phenazine biosynthesis may offer opportunities for inhibitor development.