bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurosurgical robotic arm drilling navigation system
Authors: Lin Chung‐Chih , Lin Hsin‐Cheng , Lee Wen‐Yo , Lee Shih‐Tseng , Wu Chieh‐Tsai
Published: December 2016

Background

The aim of this work was to develop a neurosurgical robotic arm drilling navigation system that provides assistance throughout the complete bone drilling process.

Methods

The system comprised neurosurgical robotic arm navigation combining robotic and surgical navigation, 3D medical imaging based surgical planning that could identify lesion location and plan the surgical path on 3D images, and automatic bone drilling control that would stop drilling when the bone was to be drilled‐through. Three kinds of experiment were designed.

Results

The average positioning error deduced from 3D images of the robotic arm was 0.502 ± 0.069 mm. The correlation between automatically and manually planned paths was 0.975. The average distance error between automatically planned paths and risky zones was 0.279 ± 0.401 mm. The drilling auto‐stopping algorithm had 0.00% unstopped cases (26.32% in control group 1) and 70.53% non‐drilled‐through cases (8.42% and 4.21% in control groups 1 and 2).

Conclusions

The system may be useful for neurosurgical robotic arm drilling navigation.
Transmission probability and energy distribution of electrons impinging on indium thin film targets
Authors: Hannachi M. , Rouabah Z. , Bouarissa N. , Champion C.
Published: December 2016

Based on a home‐made Monte Carlo simulation, the electron backscattering coefficient, mean penetration depth, transmission probability, and transmission energy distribution of 1–5 keV electron normally incident penetrating in indium thin film targets have been computed. The trend of all features of interest as a function of the indium film thickness at both nanometric scale region and bulk material region has been examined and discussed. The present predictions may be seen as the first investigation regarding 1–5 keV electrons impinging on indium thin film targets. Copyright © 2016 John Wiley & Sons, Ltd.
Antibodies Can Exploit Molecular Crowding to Bind New Antigens at Noncanonical Paratope Positions
Authors: Vashisht Sharad , Kumar Ashish , Kaur Kanwal J. , Salunke Dinakar M.
Published: December 2016

Despite having limited number of antibody molecules, it is still unclear how immune system recognizes surfeit of antigens. A novel mechanism of antigen recognition was deciphered from the crystallographic analysis of scFv 2D10 bound to disaccharide moiety. High‐resolution crystal structure of the complex reveals unusual binding of scFv 2D10 with α1‐6 mannobiose resembling supramolecular assemblies. The disaccharide interacts with the scFv 2D10 at two sites independent of canonical sugar binding positions, in two chemically distinct environments. At site A, α1‐6 mannobiose lies on two‐fold symmetry axis interacting through π‐stacking and water network. However, at site B, α1‐6 mannobiose exists in two orientations related by quasi‐symmetry with direct hydrogen bonds. Although individual one on one interactions are low at both sites, symmetry related molecules contribute significantly for stable binding of the disaccharides, indicated by 2–4 fold lower binding energies. These interactions are facilitated due to relatively high concentrations of receptor and ligand. We propose that the molecular crowding leading to supramolecular associations acts as a specificity determinant and could be naturally exploited to bind diverse antigens. This previously uncharacterized property will considerably enhance the recognition repertoire of antibodies and therefore allows the humoral response to deal with the threat posed by plethora of antigens.
Selective Synthesis of 4‐Chalcogenylmethyl‐1,3‐dioxolan‐2‐ones and 1,3‐Bis(organylchalcogenyl)propan‐2‐ols from 3‐O‐Tosyl Glycerol 1,2‐Carbonate
Authors: Perin Gelson , Silva Cristian M. , Borges Elton L. , Goulart Helen A. , Silva Rafaela B. , Jacob Raquel G. , Silva Márcio S. , Alves Diego , Schumacher Ricardo F.
Published: December 2016

We describe a selective method for synthesis of 4‐chalcogenylmethyl‐1,3‐dioxolan‐2‐ones and 1,3‐bis(organylchalcogenyl)propan‐2‐ols in a short reaction time through stoichiometric control. The use of 3‐O‐tosyl glycerol 1,2‐carbonate and a set of aryl and alkyl diorganyl dichalcogenides afforded the desired products in good to excellent yields. We also describe a synthetic application to 4‐chalcogenylmethyl‐1,3‐dioxolan‐2‐ones by base promoted the synthesis of 3‐(arylchalcogenyl)propane‐1,2‐diols in excellent yields.
Crystal Structures of Acyclic Nucleoside Phosphonates in Complex with Escherichia coli Hypoxanthine Phosphoribosyltransferase
Authors: Eng Wai Soon , Hocková Dana , Špaček Petr , Baszczyňski Ondřej , Janeba Zlatko , Naesens Lieve , Keough Dianne T. , Guddat Luke W.
Published: December 2016

Drug resistant uropathogenic E. coli associated with urinary tract infections (UTIs) are a serious and debilitating health threat. Therefore new drug targets to treat this disease need to be explored. One possible approach is to block the synthesis of the nucleoside monophosphates required for DNA/RNA production in these pathogens. In E. coli, the purine salvage pathway has two 6‐oxopurine phosphoribosyltransferases (PRTs), xanthine‐guanine PRT (EcXGPRT) and hypoxanthine PRT (EcHPRT). Here, we investigate acyclic nucleoside phosphonates (ANPs) as inhibitors of EcHPRT and have determined six crystal structures of EcHPRT in complex with ANPs. These data reveal the binding modes of these compounds and can assist in future rational structure‐based design efforts. It is suggested that a combination of inhibitors that block de novo and salvage pathways is a plausible approach to developing new antibiotics for E. coli UTIs. In addition, we provide details of a novel approach to accelerating the crystallization of this enzyme that may be of general applicability for rational drug discovery.
Antimicrobial behavior and photostability of polyvinyl chloride/1‐vinylimidazole nanocomposites loaded with silver or copper nanoparticles
Authors: Khalil Ahmed M. , Rabie Samira T.
Published: December 2016

Polyvinyl chloride (PVC)/1‐vinylimidazole (VI) nanocomposites loaded with metal nanoparticles namely; silver Ag‐NPs and copper Cu‐NPs were synthesized via in situ reduction of their precursor salts. PVC/VI has been characterized by Fourier transform infrared and 1H NMR spectroscopic analyses. The morphologies of the tested nanocomposites loaded with the metal nanoparticles were identified. Photostability of PVC/VI was estimated with monitoring the discoloration for UV‐irradiated samples with the irradiation time. The antibacterial and antifungal activities of these polymeric nanocomposites elucidated the synergistic actions of both VI and the synthesized metal nanoparticles on PVC matrix leading to their explicit antimicrobial effect. J. VINYL ADDIT. TECHNOL., 23:E25–E33, 2017. © 2016 Society of Plastics Engineers
Safeguarding development and limiting vulnerability: India's stakes in the Paris Agreement
Authors: Dubash Navroz K.
Published: December 2016

India has a great deal at stake in the Paris Agreement. As a large and poor developing country, India stands to gain or lose from both obligations under the Agreement and its effectiveness in addressing climate change. This comment describes India as a premature power in climate politics, locates Indian climate negotiating positions in global context, and develops a balance sheet of India's gains and losses in the Paris Agreement. The Paris Agreement has received a lukewarm reaction in India because it runs against some key principles of Indian climate politics. However, the Paris Agreement requires assessment by a different set of metrics. Instead of principle‐driven changes in national actions, the Paris Agreement architecture relies on inducing changes through procedural commitments and supportive mechanisms. Viewed from this perspective, the Paris Agreement brings some signs of hope for India. The bottom‐up contributions should allow India to safeguard development and explore more linkages between development and climate objectives. Even while inadequate, the existing pledges do collectively set an upper bound on catastrophic climate change, although the introduction of a 1.5° goal induces cynicism among Indian stakeholders. The transparency, expert review, and stocktake processes, when combined with regular updates of nationally determined contributions, are designed to ramp up contributions over time. Whether this trajectory is feasible or wishful thinking depends a great deal on future country actions. The Paris Agreement provides a framework within which India could productively engage its interests, even while it by no means guarantees their realization. WIREs Clim Change 2017, 8:e444. doi: 10.1002/wcc.444

This article is categorized under:

Policy and Governance > International Policy Framework
Properties of embryoid bodies
Authors: Brickman Joshua M. , Serup Palle
Published: December 2016

Embryoid bodies (EBs) have been popular in vitro differentiation models for pluripotent stem cells for more than five decades. Initially, defined as aggregates formed by embryonal carcinoma cells, EBs gained more prominence after the derivation of karyotypically normal embryonic stem cells from early mouse blastocysts. In many cases, formation of EBs constitutes an important initial step in directed differentiation protocols aimed at generated specific cell types from undifferentiated stem cells. Indeed state‐of‐the‐art protocols for directed differentiation of cardiomyocytes still rely on this initial EB step. Analyses of spontaneous differentiation of embryonic stem cells in EBs have yielded important insights into the molecules that direct primitive endoderm differentiation and many of the lessons we have learned about the signals and transcription factors governing this differentiation event is owed to EB models, which later were extensively validated in studies of early mouse embryos. EBs show a degree of self‐organization that mimics some aspects of early embryonic development, but with important exceptions. Recent studies that employ modern signaling reporters and tracers of lineage commitment have revealed both the strengths and the weaknesses of EBs as a model of embryonic axis formation. In this review, we discuss the history, application, and future potential of EBs as an experimental model. WIREs Dev Biol 2017, 6:e259. doi: 10.1002/wdev.259

This article is categorized under:

Establishment of Spatial and Temporal Patterns > Cell Sorting and Boundary Formation

Gene Expression and Transcriptional Hierarchies > Cellular Differentiation

Signaling Pathways > Cell Fate Signaling
Uncertainty quantification of infinite aligned wind farm performance using non‐intrusive polynomial chaos and a distributed roughness model
Authors: Foti Daniel , Yang Xiaolei , Sotiropoulos Fotis
Published: December 2016

Uncertainty of wind farm parameters can have a significant effect on wind farm power output. Knowledge of the uncertainty‐produced stochastic distribution of the entire wind farm power output and the corresponding uncertainty propagation mechanisms is very important for evaluating the uncertainty effects on the wind farm performance during wind farm planning stage and providing insights on improving the performance of the existing wind farms. In this work, the propagation of uncertainties from surface roughness and induction factor in infinite aligned wind farms modeled by a modified distributed roughness model is investigated using non‐intrusive polynomial chaos. Stochastic analysis of surface roughness indicates that 30% uncertainty can propagate such that there is up a 8% uncertainty in the power output of the wind farm by affecting the uncertainty in the position of the individual wind turbines in the vertical boundary layer profile and uncertainty in vertical momentum fluxes which replenish energy in the wake in large wind farms. Induction factor uncertainty of the wind turbines can also have a significant effect on power output. Not only does its uncertainty substantially affect the vertical boundary layer profile, but the uncertainty in turbine wake growth which affects how neighboring turbine wakes interact. We found that optimal power output in terms of reduction of uncertainty closely correlates with the Betz limit and is dependent on the mean induction factor. Copyright © 2016 John Wiley & Sons, Ltd.
An Amorphous Phase of Zinc and Silicon at Composition Zn2Si5(:H, OH)
Authors: Feng Xianjuan , Böhme Bodo , Bobnar Matej , Simon Paul , Carrillo‐Cabrera Wilder , Burkhardt Ulrich , Schmidt Marcus , Schwarz Ulrich , Baitinger Michael , Straßner Thomas , Grin Yuri
Published: December 2016

An amorphous phase at composition Zn2Si5(:H,OH) was prepared by oxidation of the precursor phase Li2ZnSi at 80 °C in the ionic liquid of n‐dodecyltrimethylammonium chloride (DTAC) and AlCl3 in 1:1 molar ratio, followed by removal of elemental zinc by dilute aqueous HCl. The product was structurally amorphous according to HRTEM, XRPD, and Raman spectroscopy. Zn2Si5(:H,OH) forms layers embedded in a matrix of a silica by‐product. On annealing at 150 °C, amorphous Zn2Si5(:H,OH) decomposed into crystalline Zn and α‐Si. The decomposition comes along with the release of H2 revealed by TG‐MS studies. IR and solid‐state NMR spectroscopy revealed that the Zn2Si5 bulk is terminated by Si‐OH and Si‐H groups. The absence of Knight shift in the 29Si NMR signal assigned to Zn2Si5(:H,OH) suggests semiconducting behavior.
A note on boundedness of solutions to a higher‐dimensional quasi–linear chemotaxis system with logistic source
Authors: Zheng Jiashan
Published: December 2016

We deal with the boundedness of solutions of a class of quasilinear chemotaxis systems generalizing the prototype
urn:x-wiley:00442267:media:zamm201600166:zamm201600166-math-0001where is a bounded domain with smooth boundary, , . It is showed that if , then for any sufficiently smooth initial data there exists a classical solution which is global in time and bounded. The novelty of the paper is that we use the boundedness of to estimate the boundedness of which is different from and . The results of this paper partly improve the results of and .
The Politics of Culture and the Culture of Politics: Examining the Role of Politics and Diplomacy in Cultural Property Disputes
Authors: Shehade Maria , Fouseki Kalliopi
Published: December 2016

This article constitutes the first systematic attempt to synthesize the role of politics as an affecting dynamic during the negotiation of cultural property disputes. The article limits its scope to disputes concerning the ownership of cultural artifacts between states and museums settled through negotiation and to the subsequent claims for the return of the contested objects. The discussion focuses on four ways in which the negotiation process is affected when states act as claimants, including the discourse and argumentation used, the available means to pressure the other party to negotiate, the possible political interventions, and the international political scene and its effect on the development of the dispute. Through the examination of multiple case studies, it is argued that in such disputes, several elements related to the role of politics are at interplay affecting the evolution of the negotiation process. Finally, it is also argued that the role of politics as an affecting dynamic during the negotiation process is multi-dimensional, consisting of many different interrelated dynamics that can potentially alter the course of the process.
Fatigue: neurobiologische, klinische und therapeutische Aspekte eines häufigen Symptoms
Authors: Valko Philipp O.
Published: December 2016

Zusammenfassung. Fatigue gehört zu den häufigsten Gründen eines Arztbesuchs; bei vielen Krankheiten leidet fast die Hälfte aller Betroffenen unter Fatigue. Trotz dieser Häufigkeit und trotz des ausgeprägten Leidensdrucks bleiben die neurobiologische Ursache von Fatigue unklar und die therapeutischen Möglichkeiten limitiert. Diese Übersichtsarbeit, in der die neurologische Perspektive einen grossen Raum einnimmt, fasst die wichtigsten klinischen und therapeutischen Aspekte von Fatigue zusammen, präsentiert Hypothesen zur Pathophysiologie und bietet Hilfe beim diagnostischen Vorgehen bei Patienten mit Fatigue.
CME: Umgang mit Angst-Patienten
Authors: Christen Brigitte , D’cunja Jaya Brigit
Published: December 2016

Zusammenfassung. Angststörungen gehören zu den häufigsten psychischen Erkrankungen, werden aber oft verpasst, da sich die Patienten vor allem mit körperlichen Symptomen präsentieren. Auch nach der Diagnosestellung können die betroffenen Patienten für den behandelnden Arzt eine grosse Herausforderung darstellen. Für die Patienten ist es schwierig, eine Angststörung als Diagnose zu akzeptieren, da sie vor allem körperliche Beschwerden wahrnehmen. In vielen Fällen ist zusätzlich eine akzentuierte Persönlichkeitsstruktur vorhanden, was die Arzt-Patienten-Beziehung zusätzlich erschwert. In dieser Arbeit werden Verhaltensregeln diskutiert, die den Umgang mit Angst-Patienten erleichtern können.
The prey’s scent – Volatile organic compound mediated interactions between soil bacteria and their protist predators
Authors: Schulz-Bohm Kristin , Geisen Stefan , Wubs E R Jasper , Song Chunxu , de Boer Wietse , Garbeva Paolina
Published: December 2016

Protists are major predators of bacteria in soils. However, it remains unknown how protists sense their prey in this highly complex environment. Here, we investigated whether volatile organic compounds (VOCs) of six phylogenetic distinct soil bacteria affect the performance of three different soil protists and how that relates to direct feeding interactions. We observed that most bacteria affected protist activity by VOCs. However, the response of protists to the VOCs was strongly dependent on both the bacterial and protist interacting partner. Stimulation of protist activity by volatiles and in direct trophic interaction assays often coincided, suggesting that VOCs serve as signals for protists to sense suitable prey. Furthermore, bacterial terpene synthase mutants lost the ability to affect protists, indicating that terpenes represent key components of VOC-mediated communication. Overall, we demonstrate that volatiles are directly involved in protist−bacterial predator−prey interactions.
An integrated modelling framework from cells to organism based on a cohort of digital embryos
Authors: Villoutreix Paul , Delile Julien , Rizzi Barbara , Duloquin Louise , Savy Thierry , Bourgine Paul , Doursat René , Peyriéras Nadine
Published: December 2016

We conducted a quantitative comparison of developing sea urchin embryos based on the analysis of five digital specimens obtained by automatic processing of in toto 3D+ time image data. These measurements served the reconstruction of a prototypical cell lineage tree able to predict the spatiotemporal cellular organisation of a normal sea urchin blastula. The reconstruction was achieved by designing and tuning a multi-level probabilistic model that reproduced embryo-level dynamics from a small number of statistical parameters characterising cell proliferation, cell surface area and cell volume evolution along the cell lineage. Our resulting artificial prototype was embedded in 3D space by biomechanical agent-based modelling and simulation, which allowed a systematic exploration and optimisation of free parameters to fit the experimental data and test biological hypotheses. The spherical monolayered blastula and the spatial arrangement of its different cell types appeared tightly constrained by cell stiffness, cell-adhesion parameters and blastocoel turgor pressure.
Biomechanical Analysis of Normal Brain Development during the First Year of Life Using Finite Strain Theory
Authors: Kim Jeong Chul , Wang Li , Shen Dinggang , Lin Weili
Published: December 2016

The first year of life is the most critical time period for structural and functional development of the human brain. Combining longitudinal MR imaging and finite strain theory, this study aimed to provide new insights into normal brain development through a biomechanical framework. Thirty-three normal infants were longitudinally imaged using MRI from 2 weeks to 1 year of age. Voxel-wise Jacobian determinant was estimated to elucidate volumetric changes while Lagrange strains (both normal and shear strains) were measured to reveal directional growth information every 3 months during the first year of life. Directional normal strain maps revealed that, during the first 6 months, the growth pattern of gray matter is anisotropic and spatially inhomogeneous with higher left-right stretch around the temporal lobe and interhemispheric fissure, anterior-posterior stretch in the frontal and occipital lobes, and superior-inferior stretch in right inferior occipital and right inferior temporal gyri. In contrast, anterior lateral ventricles and insula showed an isotropic stretch pattern. Volumetric and directional growth rates were linearly decreased with age for most of the cortical regions. Our results revealed anisotropic and inhomogeneous brain growth patterns of the human brain during the first year of life using longitudinal MRI and a biomechanical framework.
Relationship between nanotopographical alignment and stem cell fate with live imaging and shape analysis
Authors: Newman Peter , Galenano-Niño Jorge Luis , Graney Pamela , Razal Joselito M. , Minett Andrew I. , Ribas João , Ovalle-Robles Raquel , Biro Maté , Zreiqat Hala
Published: December 2016

The topography of a biomaterial regulates cellular interactions and determine stem cell fate. A complete understanding of how topographical properties affect cell behavior will allow the rational design of material surfaces that elicit specified biological functions once placed in the body. To this end, we fabricate substrates with aligned or randomly organized fibrous nanostructured topographies. Culturing adipose-derived stem cells (ASCs), we explore the dynamic relationship between the alignment of topography, cell shape and cell differentiation to osteogenic and myogenic lineages. We show aligned topographies differentiate cells towards a satellite cell muscle progenitor state - a distinct cell myogenic lineage responsible for postnatal growth and repair of muscle. We analyze cell shape between the different topographies, using fluorescent time-lapse imaging over 21 days. In contrast to previous work, this allows the direct measurement of cell shape at a given time rather than defining the morphology of the underlying topography and neglecting cell shape. We report quantitative metrics of the time-based morphological behaviors of cell shape in response to differing topographies. This analysis offers insights into the relationship between topography, cell shape and cell differentiation. Cells differentiating towards a myogenic fate on aligned topographies adopt a characteristic elongated shape as well as the alignment of cells.
Engineering of a thermostable esterase Est816 to improve its quorum-quenching activity and the underlying structural basis
Authors: Liu Xiwen , Cao Li-chuang , Fan Xin-jiong , Liu Yu-huan , Xie Wei
Published: December 2016

N-acyl-homoserine lactones (AHLs) are small diffusible molecules called autoinducers that mediate cell-to-cell communications. Enzymatic degradation of AHLs is a promising bio-control strategy known as quorum-quenching. To improve the quorum-quenching activity of a thermostable esterase Est816, which had been previously cloned, we have engineered the enzyme by random mutagenesis. One of the mutants M2 with double amino acid substitutions (A216V/K238N) showed 3-fold improvement on catalytic efficiency. Based on the crystal structure determined at 2.64 Å, rational design of M2 was conducted, giving rise to the mutant M3 (A216V/K238N/L122A). The kcat/KM value of the mutant M3 is 21.6-fold higher than that of Est816. Furthermore, activity assays demonstrated that M3 reached 99% conversion of 10-μM N-octanoyl-DL-homoserine lactone (C8-HSL) to N-octanoyl- DL-homoserine (C8-Hse) in 20 min, in contrast to the 8 h required by wild type Est816. The dramatic activity enhancement may be attributed to the increased hydrophobic interactions with the lactone ring by the mutation A216V, and the reduced steric clashes between the long side chain of L122 and the aliphatic tail of HSL by the mutation L122A, according to the crystal structure. This study sheds lights on the activity-structure relationship of AHL-lactonases, and may provide useful information in engineering AHL-degrading enzymes.
The Association between Physical Activity During the Day and Long-Term Memory Stability
Authors: Pontifex Matthew B. , Gwizdala Kathryn L. , Parks Andrew C. , Pfeiffer Karin A. , Fenn Kimberly M.
Published: December 2016

Despite positive associations between chronic physical activity and memory; we have little understanding of how best to incorporate physical activity during the day to facilitate the consolidation of information into memory, nor even how time spent physically active during the day relates to memory processes. The purpose of this investigation was to examine the relation between physical activity during the day and long-term memory. Ninety-two young adults learned a list of paired-associate items and were tested on the items after a 12-hour interval during which heart rate was recorded continuously. Although the percentage of time spent active during the day was unrelated to memory, two critical physical activity periods were identified as relating to the maintenance of long-term memory. Engaging in physical activity during the period 1 to 2-hours following the encoding of information was observed to be detrimental to the maintenance of information in long-term memory. In contrast, physical activity during the period 1-hour prior to memory retrieval was associated with superior memory performance, likely due to enhanced retrieval processing. These findings provide initial evidence to suggest that long-term memory may be enhanced by more carefully attending to the relative timing of physical activity incorporated during the day.
Highly Sensitive Detection of Minimal Cardiac Ischemia using Positron Emission Tomography Imaging of Activated Platelets
Authors: Ziegler Melanie , Alt Karen , Paterson Brett M. , Kanellakis Peter , Bobik Alex , Donnelly Paul S. , Hagemeyer Christoph E. , Peter Karlheinz
Published: December 2016

A reliable method for the diagnosis of minimal cardiac ischemia would meet a strong demand for the sensitive diagnosis of coronary artery disease in cardiac stress testing and risk stratification in patients with chest pain but unremarkable ECGs and biomarkers. We hypothesized that platelets accumulate early on in ischemic myocardium and a newly developed technology of non-invasive molecular PET imaging of activated platelets can thus detect minimal degrees of myocardial ischemia. To induce different degrees of minimal cardiac ischemia, the left anterior descending artery (LAD) was ligated for 10, 20 or 60 min. Mice were injected with a newly generated scFvanti-GPIIb/IIIa-64CuMeCOSar radiotracer, composed of a single-chain antibody that only binds to activated integrin GPIIb/IIIa (αIIbβIII) and thus to activated platelets, and a sarcophagine cage MeCOSar complexing the long half-life PET tracer copper-64. A single PET/CT scan was performed. Evans Blue/TTC staining to detect necrosis as well as classical serological biomarkers like Troponin I and heart-type fatty acid-binding protein (H-FABP) were negative, whereas PET imaging of activated platelets was able to detect small degrees of ischemia. Taken together, molecular PET imaging of activated platelets represents a unique and highly sensitive method to detect minimal cardiac ischemia.
Direct imaging of defect formation in strained organic flexible electronics by Scanning Kelvin Probe Microscopy
Authors: Cramer Tobias , Travaglini Lorenzo , Lai Stefano , Patruno Luca , de Miranda Stefano , Bonfiglio Annalisa , Cosseddu Piero , Fraboni Beatrice
Published: December 2016

The development of new materials and devices for flexible electronics depends crucially on the understanding of how strain affects electronic material properties at the nano-scale. Scanning Kelvin-Probe Microscopy (SKPM) is a unique technique for nanoelectronic investigations as it combines non-invasive measurement of surface topography and surface electrical potential. Here we show that SKPM in non-contact mode is feasible on deformed flexible samples and allows to identify strain induced electronic defects. As an example we apply the technique to investigate the strain response of organic thin film transistors containing TIPS-pentacene patterned on polymer foils. Controlled surface strain is induced in the semiconducting layer by bending the transistor substrate. The amount of local strain is quantified by a mathematical model describing the bending mechanics. We find that the step-wise reduction of device performance at critical bending radii is caused by the formation of nano-cracks in the microcrystal morphology of the TIPS-pentacene film. The cracks are easily identified due to the abrupt variation in SKPM surface potential caused by a local increase in resistance. Importantly, the strong surface adhesion of microcrystals to the elastic dielectric allows to maintain a conductive path also after fracture thus providing the opportunity to attenuate strain effects.
The Hha-TomB Toxin-Antitoxin System Shows Conditional Toxicity and Promotes Persister Cell Formation by Inhibiting Apoptosis-Like Death in S. Typhimurium
Authors: Jaiswal Sangeeta , Paul Prajita , Padhi Chandrashekhar , Ray Shilpa , Ryan Daniel , Dash Shantoshini , Suar Mrutyunjay
Published: December 2016

Toxin-antitoxin (TA) modules are two component “addictive” genetic elements found on either plasmid or bacterial chromosome, sometimes on both. TA systems perform a wide range of functions like biofilm formation, persistence, programmed cell death, phage abortive infection etc. Salmonella has been reported to contain several such TA systems. However, the hemolysin expression modulating protein (Hha) and its adjacent uncharacterized hypothetical protein TomB (previously known as YbaJ), have not been listed as a TA module in Salmonella. In this study we established that Hha and TomB form a bonafide TA system where Hha serves as a toxin while TomB functions as an antitoxin. Interestingly, the toxicity of Hha was conditional causing cell death under acid stress. The antitoxin attenuated the toxicity of Hha by forming a TA complex through stable interactions. The Hha-TomB TA system was found to increase persistence and inhibit programmed cell death under antibiotic stress where a phenotypically diverse population expressing differential level of TA components was observed. Therefore we propose that Hha and TomB prevent cells from committing suicide thereby promoting persister cell formation.
PGC-1α dictates endothelial function through regulation of eNOS expression
Authors: Craige Siobhan M. , Kröller-Schön Swenja , Li Chunying , Kant Shashi , Cai Shenghe , Chen Kai , Contractor Mayur M. , Pei Yongmei , Schulz Eberhard , Keaney John F.
Published: December 2016

Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1α (PGC-1α) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1α in vascular function using mice with endothelial specific loss of function (PGC-1α EC KO) and endothelial specific gain of function (PGC-1α EC TG). Here we report that endothelial PGC-1α is suppressed in angiotensin-II (ATII)-induced hypertension. Deletion of endothelial PGC-1α sensitized mice to endothelial dysfunction and hypertension in response to ATII, whereas PGC-1α EC TG mice were protected. Mechanistically, PGC-1α promotes eNOS expression and activity, which is necessary for protection from ATII-induced dysfunction as mice either treated with an eNOS inhibitor (LNAME) or lacking eNOS were no longer responsive to transgenic endothelial PGC-1α expression. Finally, we determined that the orphan nuclear receptor, estrogen related receptor α (ERRα) is required to coordinate the PGC-1α -induced eNOS expression. In conclusion, endothelial PGC-1α expression protects from vascular dysfunction by promoting NO• bioactivity through ERRα induced expression of eNOS.
Dynamic Microenvironment Induces Phenotypic Plasticity of Esophageal Cancer Cells Under Flow
Authors: Calibasi Kocal Gizem , Güven Sinan , Foygel Kira , Goldman Aaron , Chen Pu , Sengupta Shiladitya , Paulmurugan Ramasamy , Baskin Yasemin , Demirci Utkan
Published: December 2016

Cancer microenvironment is a remarkably heterogeneous composition of cellular and non-cellular components, regulated by both external and intrinsic physical and chemical stimuli. Physical alterations driven by increased proliferation of neoplastic cells and angiogenesis in the cancer microenvironment result in the exposure of the cancer cells to elevated levels of flow-based shear stress. We developed a dynamic microfluidic cell culture platform utilizing eshopagael cancer cells as model cells to investigate the phenotypic changes of cancer cells upon exposure to fluid shear stress. We report the epithelial to hybrid epithelial/mesenchymal transition as a result of decreasing E-Cadherin and increasing N-Cadherin and vimentin expressions, higher clonogenicity and ALDH positive expression of cancer cells cultured in a dynamic microfluidic chip under laminar flow compared to the static culture condition. We also sought regulation of chemotherapeutics in cancer microenvironment towards phenotypic control of cancer cells. Such in vitro microfluidic system could potentially be used to monitor how the interstitial fluid dynamics affect cancer microenvironment and plasticity on a simple, highly controllable and inexpensive bioengineered platform.
Microtubule stabilising peptides rescue tau phenotypes in-vivo
Authors: Quraishe Shmma , Sealey Megan , Cranfield Louise , Mudher Amritpal
Published: December 2016

The microtubule cytoskeleton is a highly dynamic, filamentous network underpinning cellular structure and function. In Alzheimer’s disease, the microtubule cytoskeleton is compromised, leading to neuronal dysfunction and eventually cell death. There are currently no disease-modifying therapies to slow down or halt disease progression. However, microtubule stabilisation is a promising therapeutic strategy that is being explored. We previously investigated the disease-modifying potential of a microtubule-stabilising peptide NAP (NAPVSIPQ) in a well-established Drosophila model of tauopathy characterised by microtubule breakdown and axonal transport deficits. NAP prevented as well as reversed these phenotypes even after they had become established. In this study, we investigate the neuroprotective capabilities of an analogous peptide SAL (SALLRSIPA). We found that SAL mimicked NAP’s protective effects, by preventing axonal transport disruption and improving behavioural deficits, suggesting both NAP and SAL may act via a common mechanism. Both peptides contain a putative ‘SIP’ (Ser-Ile-Pro) domain that is important for interactions with microtubule end-binding proteins. Our data suggests this domain may be central to the microtubule stabilising function of both peptides and the mechanism by which they rescue phenotypes in this model of tauopathy. Our observations support microtubule stabilisation as a promising disease-modifying therapeutic strategy for tauopathies like Alzheimer’s disease.
Prostate Cancer Patients–Negative Biopsy Controls Discrimination by Untargeted Metabolomics Analysis of Urine by LC-QTOF: Upstream Information on Other Omics
Authors: Fernández-Peralbo M. A. , Gómez-Gómez E. , Calderón-Santiago M. , Carrasco-Valiente J. , Ruiz-García J. , Requena-Tapia M. J. , Luque de Castro M. D. , Priego-Capote F.
Published: December 2016

The existing clinical biomarkers for prostate cancer (PCa) diagnosis are far from ideal (e.g., the prostate specific antigen (PSA) serum level suffers from lack of specificity, providing frequent false positives leading to over-diagnosis). A key step in the search for minimum invasive tests to complement or replace PSA should be supported on the changes experienced by the biochemical pathways in PCa patients as compared to negative biopsy control individuals. In this research a comprehensive global analysis by LC–QTOF was applied to urine from 62 patients with a clinically significant PCa and 42 healthy individuals, both groups confirmed by biopsy. An unpaired t-test (p-value < 0.05) provided 28 significant metabolites tentatively identified in urine, used to develop a partial least squares discriminant analysis (PLS-DA) model characterized by 88.4 and 92.9% of sensitivity and specificity, respectively. Among the 28 significant metabolites 27 were present at lower concentrations in PCa patients than in control individuals, while only one reported higher concentrations in PCa patients. The connection among the biochemical pathways in which they are involved (DNA methylation, epigenetic marks on histones and RNA cap methylation) could explain the concentration changes with PCa and supports, once again, the role of metabolomics in upstream processes.
Methylmercury induces the expression of TNF-α selectively in the brain of mice
Authors: Iwai-Shimada Miyuki , Takahashi Tsutomu , Kim Min-Seok , Fujimura Masatake , Ito Hitoyasu , Toyama Takashi , Naganuma Akira , Hwang Gi-Wook
Published: December 2016

Methylmercury selectively damages the central nervous system (CNS). The tumor necrosis factor (TNF) superfamily includes representative cytokines that participate in the inflammatory response as well as cell survival, and apoptosis. In this study, we found that administration of methylmercury selectively induced TNF-α expression in the brain of mice. Although the accumulated mercury concentration in the liver and kidneys was greater than in the brain, TNF-α expression was induced to a greater extent in brain. Thus, it is possible that there may exist a selective mechanism by which methylmercury induces TNF-α expression in the brain. We also found that TNF-α expression was induced by methylmercury in C17.2 cells (mouse neural stem cells) and NF-κB may participate as a transcription factor in that induction. Further, we showed that the addition of TNF-α antagonist (WP9QY) reduced the toxicity of methylmercury to C17.2 cells. In contrast, the addition of recombinant TNF-α to the culture medium decreased the cell viability. We suggest that TNF-α may play a part in the selective damage of the CNS by methylmercury. Furthermore, our results indicate that the higher TNF-α expression induced by methylmercury maybe the cause of cell death, as TNF-α binds to its receptor after being released extracellularly.
Zn uptake behavior of rice genotypes and its implication on grain Zn biofortification
Authors: Johnson-Beebout Sarah E. , Goloran Johnvie Bayang , Rubianes Francis H. C. , Jacob Jack D. C. , Castillo Oliver B.
Published: December 2016

Understanding Zn uptake dynamics is critical to rice grain Zn biofortification. Here we examined soil Zn availability and Zn uptake pathways as affected by genotype (high-grain Zn varieties IR69428 and IR68144), Zn fertilization and water management in two pot experiments. Results showed significant interactions (P < 0.05) between genotypes and Zn fertilization on DTPA (diethylenetriaminepentaacetic acid)-extractable soil Zn from early tillering to flowering. DTPA-extractable Zn in soils grown with IR69428 was positively correlated with stem (r = 0.78, P < 0.01), flagleaf (r = 0.60, P < 0.01) and grain (r = 0.67, P < 0.01) Zn concentrations, suggesting improved soil Zn availability and continued soil Zn uptake by IR69428 even at maturity. Conversely for IR68144, DTPA-extractable Zn was positively correlated only with leaf Zn uptake (r = 0.60, P < 0.01) at active tillering, indicating dependence on remobilization for grain Zn loading. Furthermore, the highest grain Zn concentration (P < 0.05) was produced by a combination of IR69428 and Zn fertilization applied at panicle initiation (38.5 μg g−1) compared with other treatments (P < 0.05). The results highlight that Zn uptake behavior of a rice genotype determines the fate of Zn from the soil to the grain. This has implications on overcoming Zn translocation barriers between vegetative parts and grains, and achieving grain Zn biofortification targets (30.0 μg g−1).
Genomic variations leading to alterations in cell morphology of Campylobacter spp
Authors: Esson Diane , Mather Alison E. , Scanlan Eoin , Gupta Srishti , de Vries Stefan P. W. , Bailey David , Harris Simon R. , McKinley Trevelyan J. , Méric Guillaume , Berry Sophia K. , Mastroeni Pietro , Sheppard Samuel K. , Christie Graham , Thomson Nicholas R. , Parkhill Julian , Maskell Duncan J. , Grant Andrew J.
Published: December 2016

Campylobacter jejuni, the most common cause of bacterial diarrhoeal disease, is normally helical. However, it can also adopt straight rod, elongated helical and coccoid forms. Studying how helical morphology is generated, and how it switches between its different forms, is an important objective for understanding this pathogen. Here, we aimed to determine the genetic factors involved in generating the helical shape of Campylobacter. A C. jejuni transposon (Tn) mutant library was screened for non-helical mutants with inconsistent results. Whole genome sequence variation and morphological trends within this Tn library, and in various C. jejuni wild type strains, were compared and correlated to detect genomic elements associated with helical and rod morphologies. All rod-shaped C. jejuni Tn mutants and all rod-shaped laboratory, clinical and environmental C. jejuni and Campylobacter coli contained genetic changes within the pgp1 or pgp2 genes, which encode peptidoglycan modifying enzymes. We therefore confirm the importance of Pgp1 and Pgp2 in the maintenance of helical shape and extended this to a wide range of C. jejuni and C. coli isolates. Genome sequence analysis revealed variation in the sequence and length of homopolymeric tracts found within these genes, providing a potential mechanism of phase variation of cell shape.
Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H
Authors: Raymond Gerald V. , Pasquali Marzia , Polgreen Lynda E. , Dickson Patricia I. , Miller Weston P. , Orchard Paul J. , Lund Troy C.
Published: December 2016

Mucopolysaccharidosis (MPS) type-IH is a lysosomal storage disease that results from mutations in the IDUA gene causing the accumulation of glycosaminoglycans (GAGs). Historically, children with the severe phenotype, MPS-IH (Hurler syndrome) develop progressive neurodegeneration with death in the first decade due to cardio-pulmonary complications. New data suggest that inflammation may play a role in MPS pathophysiology. To date there is almost no information on the pathophysiologic changes within the cerebral spinal fluid (CSF) of these patients. We evaluated the CSF of 25 consecutive patients with MPS-IH. While CSF glucose and total protein were within the normal range, we found a significantly mean elevated CSF opening pressure at 24 cm H2O (range 14–37 cm H2O). We observed a 3-fold elevation in CSF heparan sulfate and a 3–8 fold increase in MPS-IH specific non-reducing ends, I0S0 and I0S6. Cytokine analyses in CSF of children with MPS-IH showed significantly elevated inflammatory markers including: MCP-1 SDF-1a, IL-Ra, MIP-1b, IL-8, and VEGF in comparison to unaffected children. This is the largest report of CSF characteristics in children with MPS-IH. Identification of key biomarkers may provide further insight into the inflammatory-mediated mechanisms related to MPS diseases and perhaps lead to improved targeted therapies.
Acute Effects of Nitrogen Dioxide on Cardiovascular Mortality in Beijing: An Exploration of Spatial Heterogeneity and the District-specific Predictors
Authors: Luo Kai , Li Runkui , Li Wenjing , Wang Zongshuang , Ma Xinming , Zhang Ruiming , Fang Xin , Wu Zhenglai , Cao Yang , Xu Qun
Published: December 2016

The exploration of spatial variation and predictors of the effects of nitrogen dioxide (NO2) on fatal health outcomes is still sparse. In a multilevel case-crossover study in Beijing, China, we used mixed Cox proportional hazard model to examine the citywide effects and conditional logistic regression to evaluate the district-specific effects of NO2 on cardiovascular mortality. District-specific predictors that could be related to the spatial pattern of NO2 effects were examined by robust regression models. We found that a 10 μg/m3 increase in daily mean NO2 concentration was associated with a 1.89% [95% confidence interval (CI): 1.33–2.45%], 2.07% (95% CI: 1.23–2.91%) and 1.95% (95% CI: 1.16–2.72%) increase in daily total cardiovascular (lag03), cerebrovascular (lag03) and ischemic heart disease (lag02) mortality, respectively. For spatial variation of NO2 effects across 16 districts, significant effects were only observed in 5, 4 and 2 districts for the above three outcomes, respectively. Generally, NO2 was likely having greater adverse effects on districts with larger population, higher consumption of coal and more civilian vehicles. Our results suggested independent and spatially varied effects of NO2 on total and subcategory cardiovascular mortalities. The identification of districts with higher risk can provide important insights for reducing NO2 related health hazards.
Protein expression from unintegrated HIV-1 DNA introduces bias in primary in vitro post-integration latency models
Authors: Bonczkowski Pawel , De Scheerder Marie-Angélique , Malatinkova Eva , Borch Alexandra , Melkova Zora , Koenig Renate , De Spiegelaere Ward , Vandekerckhove Linos
Published: December 2016

To understand the persistence of latently HIV-1 infected cells in virally suppressed infected patients, a number of in vitro models of HIV latency have been developed. In an attempt to mimic the in vivo situation as closely as possible, several models use primary cells and replication-competent viruses in combination with antiretroviral compounds to prevent ongoing replication. Latency is subsequently measured by HIV RNA and/or protein production after cellular activation. To discriminate between pre- and post-integration latency, integrase inhibitors are routinely used, preventing novel integrations upon cellular activation. Here, we show that this choice of antiretrovirals may still cause a bias of pre-integration latency in these models, as unintegrated HIV DNA can form and directly contribute to the levels of HIV RNA and protein production. We further show that the addition of reverse transcriptase inhibitors effectively suppresses the levels of episomal HIV DNA (as measured by 2-LTR circles) and decreases the levels of HIV transcription. Consequently, we show that latency levels described in models that only use integrase inhibitors may be overestimated. The inclusion of additional control conditions, such as 2-LTR quantification and the addition of reverse transcriptase inhibitors, is crucial to fully elucidate the actual levels of post-integration latency.
BHX Inhibits the Wnt Signaling Pathway by Suppressing β-catenin Transcription in the Nucleus
Authors: Ding Fengxia , Wang Meisa , Du Yibo , Du Shuangshuang , Zhu Zhongling , Yan Zhao
Published: December 2016

BHX (N-(4-hydroxybenzyl)-1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxamide), a Wnt signaling pathway inhibitor, effectively inhibits tumor cell growth, but the underlying mechanism is unclear. Thus, we aim to investigate the effects and associated mechanism of BHX action on A549 and MCF-7 cell lines. In our study, MTT(3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide) and xenograft model assay indicated that cell growth was inhibited by BHX at a range of concentrations in vitro and in vivo. The expression of β-catenin and Wnt signaling pathway downstream target genes were decreased evidently under BHX treatment. Flow cytometry also revealed that BHX treatment significantly induced G1 arrest. Further analysis showed that BHX lowered the transcriptional level of β-catenin. In conclusion, BHX inhibited the nuclear synthesis of β-catenin, thereby suppressing the Wnt signaling pathway and further inhibiting tumor growth and proliferation.