bluuebunny/crossref_metadata_2025 huggingface dataset:
Inferring regulatory element landscapes and transcription factor networks from cancer methylomes
Authors: Yao Lijing , Shen Hui , Laird Peter W , Farnham Peggy J , Berman Benjamin P
Published: May 2015

Recent studies indicate that DNA methylation can be used to identify transcriptional enhancers, but no systematic approach has been developed for genome-wide identification and analysis of enhancers based on DNA methylation. We describe ELMER (Enhancer Linking by Methylation/Expression Relationships), an R-based tool that uses DNA methylation to identify enhancers and correlates enhancer state with expression of nearby genes to identify transcriptional targets. Transcription factor motif analysis of enhancers is coupled with expression analysis of transcription factors to infer upstream regulators. Using ELMER, we investigated more than 2,000 tumor samples from The Cancer Genome Atlas. We identified networks regulated by known cancer drivers such as GATA3 and FOXA1 (breast cancer), SOX17 and FOXA2 (endometrial cancer), and NFE2L2, SOX2, and TP63 (squamous cell lung cancer). We also identified novel networks with prognostic associations, including RUNX1 in kidney cancer. We propose ELMER as a powerful new paradigm for understanding the cis-regulatory interface between cancer-associated transcription factors and their functional target genes.
Longitudinal analysis of peripheral blood T cell receptor diversity in patients with systemic lupus erythematosus by next-generation sequencing
Authors: Thapa Dharma R , Tonikian Raffi , Sun Chao , Liu Mei , Dearth Andrea , Petri Michelle , Pepin Francois , Emerson Ryan O , Ranger Ann
Published: May 2015

Introduction

T cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Clonal expansion of T cells correlating with disease activity has been observed in peripheral blood (PB) of SLE subjects. Recently, next-generation sequencing (NGS) of the T cell receptor (TCR) β loci has emerged as a sensitive way to measure the T cell repertoire. In this study, we utilized NGS to assess whether changes in T cell repertoire diversity in PB of SLE patients correlate with or predict changes in disease activity.

Methods

Total RNA was isolated from the PB of 11 SLE patients. Each subject had three samples, collected at periods of clinical quiescence and at a flare. Twelve age-matched healthy controls (HC) were used for reference. NGS was used to profile the complementarity-determining region 3 (CDR3) of the rearranged TCR β loci.

Results

Relative to the HC, SLE patients (at quiescence) demonstrated a 2.2-fold reduction in repertoire diversity in a given PB volume (P <0.0002), a more uneven distribution of the repertoire (Gini coefficient, HC vs SLE, P = 0.015), and a trend toward increased percentage of expanded clones in the repertoire (clone size >1.0 %, HC vs SLE, P = 0.078). No significant correlation between the overall repertoire diversity and clinical disease activity was observed for most SLE patients with only two of eleven SLE patients showing a decreasing trend in repertoire diversity approaching the flare time point. We did not observe any overlap of CDR3 amino acid sequences or a preferential Vβ or Jβ gene usage among the top 100 expanded clones from all SLE patients. In both HC and SLE, the majority of the expanded clones were remarkably stable over time (HC = 5.5 ±0.5 months, SLE = 7.2 ±2.4 months).

Conclusions

A significant decrease in T cell repertoire diversity was observed in PB of SLE patients compared to HC. However, in most SLE patients, repertoire diversity did not change significantly with increases in disease activity to a flare. Thus, without a priori knowledge of disease-specific clones, monitoring TCR repertoire in PB from SLE patients is not likely to be useful to predict changes in disease activity.
The hard sphere view of the outer core
Authors: Helffrich George
Published: May 2015

The hard sphere model for liquids attempts to capture the physical behavior of a real liquid in a simple conceptual model: a fluid of fixed size spheres that only interact repulsively when they come into contact. Is the model good enough to use for modeling internal planetary structure? To answer this question, I survey variants of hard sphere liquid theory by applying them to the Earth’s outer core to determine which of them explains wavespeeds in the outer core best. The variants explored here are the Carnahan-Starling hard sphere model, the Mansoori-Carnahan-Starling-Leland extension to hard sphere mixtures, the transition metal hard sphere liquid, and the Lennard-Jones hard sphere liquid with attractive forces. With an empirical addition of a temperature dependence to the liquid’s hard sphere diameter, all of the variants explored can replicate wavespeeds in most of the radius range of the outer core. The hard sphere model for liquid transition metals explains the wavespeed best because it yields a mean liquid atomic weight of 48.8 g mol−1 at 10 wt% light element abundance in the core which is in good cosmochemical agreement with core light element models. Other variants also fit core wavespeeds but require implausibly low liquid mean atomic weight implying excessive incorporation of hydrogen or helium in the core. Applied to the detailed wavespeed structure of the Earth’s outermost outer core, the model suggests that the mean atomic weight could be reduced by up to 1.74% or the temperature could be increased by up to 400 K relative to an adiabatic profile, or there could be 8% fewer valence electrons in the liquid.
Low DICER1 expression is associated with attenuated neutrophil differentiation and autophagy of NB4 APL cells
Authors: Wampfler Julian , Federzoni Elena A , Torbett Bruce E , Fey Martin F , Tschan Mario P
Published: May 2015

Successful myeloid differentiation depends on the expression of a series of miRNAs. Thus, it is hardly surprising that miRNAs are globally repressed in AML, a disease mainly characterized by a block in cellular myeloid differentiation. Studies investigating the mechanisms for low miRNA expression in AML has mostly focused on altered transcriptional regulation or deletions, whereas defective miRNA processing has received less attention. In this study, we report that the expression of the key miRNA processing enzyme DICER1 is down-regulated in primary AML patient samples and healthy CD34+ progenitor cells as compared with granulocytes. In line with these findings, Dicer1 expression was induced significantly in AML cell lines upon neutrophil differentiation. The knocking down of DICER1 in AML cells significantly attenuated neutrophil differentiation, which was paralleled by decreased expression of miRNAs involved in this process. Moreover, we found that inhibiting DICER1 attenuated the activation of autophagy, a cellular recycling process that is needed for proper neutrophil differentiation of AML cells. Our results clearly indicate that DICER1 plays a novel role in neutrophil differentiation as well as in myeloid autophagy of AML cells.
Preweaning GH Treatment Normalizes Body Growth Trajectory and Reverses Metabolic Dysregulation in Adult Offspring After Maternal Undernutrition
Authors: Li Minglan , Reynolds Clare M. , Gray Clint , Vickers Mark H.
Published: May 2015

Maternal undernutrition (UN) results in growth disorders and metabolic dysfunction in offspring. Although dysregulation of the GH-IGF axis in offspring is a known consequence of maternal UN, little is known about the efficacy of GH treatment during the period of developmental plasticity on later growth and metabolic outcomes. The present study investigated the effect of preweaning GH treatment on growth, glucose metabolism, and the GH-IGF axis in adult male and female offspring after maternal UN. Female Sprague Dawley rats were fed either a chow diet ad libitum (control [CON]) or 50% of ad libitum (UN) throughout pregnancy. From postnatal day 3, CON and UN pups received either saline (CON-S and UN-S) or GH (2.5 μg/g·d CON-GH and UN-GH) daily throughout lactation. At weaning, male and female offspring were randomly selected from each litter and fed a standard chow diet for the remainder of the study. Preweaning GH treatment normalized maternal UN-induced alterations in postweaning growth trajectory and concomitant adiposity in offspring. Plasma leptin concentrations were increased in UN-S offspring and normalized in the UN-GH group. Hepatic GH receptor expression was significantly elevated in UN-S offspring and normalized with GH treatment. Hepatic IGF binding protein-2 gene expression and plasma IGF-1 to IGF binding protein-3 ratio was reduced in UN-S offspring and elevated with GH treatment. GH treatment during a critical developmental window prevented maternal UN-induced changes in postnatal growth patterns and related adiposity, suggesting that manipulation of the GH-IGF-1 axis in early development may represent a promising avenue to prevent adverse developmental programming effects in adulthood.
The Restoration of All Things: John Bradford’s Refutation of Aquinas on Animal Resurrection
Authors: Minnis Alastair
Published: May 2015

On July 1, 1555, John Bradford was burned at Smithfield, one of the Protestant divines executed during the reign of Mary Tudor. Shortly before his death he wrote a treatise entitled The Restoration of All Things to counsel a devout woman of his circle. This expounds Romans 8:21–22, where “the creature” is said to be groaning in pain, awaiting release from the bondage of corruption. Here Bradford follows the innovative exegesis of the exiled Strasbourg theologian Martin Bucer, with whom he had formed a close relationship at Cambridge. Contrary to centuries of Catholic theology, which held that all animal and plant life will perish after the Last Judgment and not be part of the promised “new heaven and new earth,” Bradford argues that creation in its entirety—not just humanity—will joyously be freed from the suffering it has endured since the Fall.
Rebellion from Below: Commonwealth and Community in The Life and Death of Jack Straw
Authors: Mathur Maya
Published: May 2015

The Life and Death of Jack Straw chronicles the main events of the 1381 Rising in England and has traditionally been viewed as a warning about the dangers of rebellion from below. While recent studies of the play have challenged this perspective, they have focused chiefly on the drama’s portrayal of the rebels and not on the relationship between elite and popular discourses in the text. This article bridges a gap in the existing criticism by investigating the references to commonwealth and community that are made by Jack Straw’s aristocrats and commoners respectively. The article argues that the conflict between the two groups stems from their divergent interpretation of these terms in their public speeches and private exchanges.
Differing roles of pyruvate dehydrogenase kinases during mouse oocyte maturation
Authors: Hou Xiaojing , Zhang Liang , Han Longsen , Ge Juan , Ma Rujun , Zhang Xuesen , Moley Kelle , Schedl Tim , Wang Qiang
Published: May 2015

Pyruvate dehydrogenase kinases (PDKs) modulate energy homeostasis in multiple tissues and cell types, under various nutrient conditions, through phosphorylation of the α subunit (PDHE1α, also known as PDHA1) of the pyruvate dehydrogenase (PDH) complex. However, the roles of PDKs in meiotic maturation are currently unknown. Here, by undertaking knockdown and overexpression analysis of PDK paralogs (PDK1–PDK4) in mouse oocytes, we established the site-specificity of PDKs towards the phosphorylation of three serine residues (Ser232, Ser293 and Ser300) on PDHE1α. We found that PDK3-mediated phosphorylation of Ser293-PDHE1α results in disruption of meiotic spindle morphology and chromosome alignment and decreased total ATP levels, probably through inhibition of PDH activity. Unexpectedly, we discovered that PDK1 and PDK2 promote meiotic maturation, as their knockdown disturbs the assembly of the meiotic apparatus, without significantly altering ATP content. Moreover, phosphorylation of Ser232-PDHE1α was demonstrated to mediate PDK1 and PDK2 action in meiotic maturation, possibly through a mechanism that is distinct from PDH inactivation. These findings reveal that there are divergent roles of PDKs during oocyte maturation and indicate a new mechanism controlling meiotic structure.
Visual phototransduction components in cephalopod chromatophores suggest dermal photoreception
Authors: Kingston Alexandra C. N. , Kuzirian Alan M. , Hanlon Roger T. , Cronin Thomas W.
Published: May 2015

Cephalopod mollusks are renowned for their colorful and dynamic body patterns, produced by an assemblage of skin components that interact with light. These may include iridophores, leucophores, chromatophores and (in some species) photophores. Here, we present molecular evidence suggesting that cephalopod chromatophores – small dermal pigmentary organs that reflect various colors of light – are photosensitive. RT-PCR revealed the presence of transcripts encoding rhodopsin and retinochrome within the retinas and skin of the squid Doryteuthis pealeii, and the cuttlefish Sepia officinalis and Sepia latimanus. In D. pealeii, Gqα and squid TRP channel transcripts were present in the retina and in all dermal samples. Rhodopsin, retinochrome and Gqα transcripts were also found in RNA extracts from dissociated chromatophores isolated from D. pealeii dermal tissues. Immunohistochemical staining labeled rhodopsin, retinochrome and Gqα proteins in several chromatophore components, including pigment cell membranes, radial muscle fibers, and sheath cells. This is the first evidence that cephalopod dermal tissues, and specifically chromatophores, may possess the requisite combination of molecules required to respond to light.
Mosquitocidal properties of IgG targeting the glutamate-gated chloride channel in three mosquito disease vectors (Diptera: Culicidae)
Authors: Meyers Jacob I. , Gray Meg , Foy Brian D.
Published: May 2015

The glutamate-gated chloride channel (GluCl) is a highly sensitive insecticide target of the avermectin class of insecticides. As an alternative to using chemical insecticides to kill mosquitoes, we tested the effects of purified immunoglobulin G (IgG) targeting the extracellular domain of GluCl from Anopheles gambiae (AgGluCl) on the survivorship of three key mosquito disease vectors: Anopheles gambiae s.s., Aedes aegypti and Culex tarsalis. When administered through a single blood meal, anti-AgGluCl IgG reduced the survivorship of A. gambiae in a dose-dependent manner (LC50: 2.82 mg ml−1, range 2.68–2.96 mg ml−1) but not A. aegypti or C. tarsalis. We previously demonstrated that AgGluCl is only located in tissues of the head and thorax of A. gambiae. To verify that AgGluCl IgG is affecting target antigens found outside the midgut, we injected it directly into the hemocoel via intrathoracic injection. A single, physiologically relevant concentration of anti-AgGluCl IgG injected into the hemocoel equally reduced mosquito survivorship of all three species. To test whether anti-AgGluCl IgG was entering the hemocoel of each of these mosquitoes, we fed mosquitoes a blood meal containing anti-AgGluCl IgG and subsequently extracted their hemolymph. We only detected IgG in the hemolymph of A. gambiae, suggesting that resistance of A. aegypti and C. tarsalis to anti-AgGluCl IgG found in blood meals is due to deficient IgG translocation across the midgut. We predicted that anti-AgGluCl IgG's mode of action is by antagonizing GluCl activity. To test this hypothesis, we fed A. gambiae blood meals containing anti-AgGluCl IgG and the GluCl agonist ivermectin (IVM). Anti-AgGluCl IgG attenuated the mosquitocidal effects of IVM, suggesting that anti-AgGluCl IgG antagonizes IVM-induced activation of GluCl. Lastly, we stained adult, female A. aegypti and C. tarsalis for GluCl expression. Neuronal GluCl expression in these mosquitoes was similar to previously reported A. gambiae GluCl expression; however, we also discovered GluCl staining on the basolateral surface of their midgut epithelial cells, suggesting important physiological differences in Culicine and Anopheline mosquitoes.
Facile Synthesis of MgO Microspheres via Water-in-oil Emulsion Assisted with Homogeneous Precipitation
Authors: Chang Ying , Wang Hui , Wang Huihu , Yan Ming , Liu Bei , Dong Shijie
Published: May 2015

Water droplets containing MgCl2 and urea, as the water phase of xylene/water/span-80 water-in-oil (w/o) emulsion system, can act as microreactors where spherical MgO precursor powders with porous microstructure were obtained via homogeneous precipitation. By changing the volume ratio of span-80 to xylene, spherical powders with different sizes were synthesized, and the effect of span-80/xylene volume ratio on powder morphology was examined. The as-prepared powders as well as their precursors were characterized by means of field-emission scanning electron microscopy (FE-SEM), laser particle size analysis (LPS), N2-adsorption measurements (BET) and thermogravimetry and differential thermal analysis (TG-DTA). The TG-DTA result indicated that the optimal sintering temperature of precursor powders was 450 °C. The FE-SEM results showed that the span-80-to-xylene volume ratio had a marked effect on the morphology of powders. When the ratio was 1:40, the FE-SEM and LPS results confirmed the formation of the powder microspheres with a size range of 1–16 µm, and the surface area of the microspheres was about 75.7 m2 g−1 according to the BET result.
Best practice in supporting maternal and infant mental health
Authors: Luff Elaine
Published: May 2015

Elaine Luff describes how the health visiting team in her Trust established a new pathway for supporting perinatal mental health and wellbeing, known as the ‘4Rs’.
Advocating for children in a rapidly changing world
Authors: Murphy Madeleine
Published: May 2015

Integrated working was high on the agenda at the annual conference of the Royal College of Paediatrics and Child Health, held in Birmingham over 3 days in April.
In vitro-ex vivo model systems for nanosafety assessment
Authors: Wick Peter , Chortarea Savvina , Guenat Olivier T. , Roesslein Matthias , Stucki Janick D. , Hirn Stephanie , Petri-Fink Alke , Rothen-Rutishauser Barbara
Published: May 2015

Engineered nanomaterials have unique and novel properties enabling wide-ranging new applications in nearly all fields of research. As these new properties have raised concerns about potential adverse effects for the environment and human health, extensive efforts are underway to define reliable, cost- and time-effective, as well as mechanistic-based testing strategies to replace the current method of animal testing, which is still the most prevalent model used for the risk assessment of chemicals. Current approaches for nanomaterials follow this line. The aim of this review is to explore and qualify the relevance of new in vitro and ex vivo models in (nano)material safety assessment, a crucial prerequisite for translation into applications.
Patterns of Sexual Behaviour: The Law of Evidence: Back to the Future in Australia and England
Authors: Felicity Gerry Q. C. , Sjölin Catarina , Urbas Gregor
Published: May 2015

A recent Victorian Court of Appeal ruling
Warm Mix Asphalt For Australian Airports
Authors: White Greg
Published: May 2015

Warm Mix Asphalt (WMA) is a viable alternate to Hot Mix Asphalt (HMA) for airport surfacing in Australia. Limited experience with this technology at Australian airports has prevented its acceptance by airport owners and their designers. WMA does have a significant track record in Europe and the USA, where it has been demonstrated to provide significant environmental, safety, quality and construction flexibility benefits. Differences in available binders and the Australian tendency for thinner asphalt layers and less capable materials makes direct extrapolation of experience from Europe and the USA inappropriate.

The aim of this paper is to demonstrate the comparative performance of WMA (by foamed bitumen technology) to HMA as an airport surface layer. Comparison between HMA and WMA has been made during a number of projects at Australian airports since 2012. A formal trial was performed at a military airfield as part of a broader project in 2013. A combination of production verification, quality assurance and mix performance tests were used to make comparisons. Subject to ongoing monitoring and performance testing of the military airfield WMA trial section, WMA is now verified as a viable alternate surfacing material for Australian airport runways.
Development Of A Pavement Rutting Model Using Shakedown Theory
Authors: Boulbibane Mostapha , Collins Ian F.
Published: May 2015

The rutting of flexible pavements during their exploitation is considered to be one of the main problems in UK as well as worldwide. It is a serious mode of distress alongside fatigue in bituminous pavements that may lead to premature failure, as indicated by permanent deformation or rut depth along the wheel load path, and results in early and costly rehabilitation. This kind of pavement distress makes a negative impact to the serviceability characteristics of the flexible pavement, to the residual life of pavement structure and also to the safety and ride quality for traffic. Two design methods have been used to control rutting: one to limit the vertical compressive strain on the top of subgrade and the other to limit rutting to a tolerable amount usually around “12 mm”. Although experimental data and practical experience have been introduced into these design methods through empirical parameters, there is not a simple relationship between the elastic strain and the long-term plastic behaviour of pavement materials. This paper describes a method based on the kinematic shakedown theorem for constructing a mathematical model to predict the long-term behaviour of pavement structures under the action of repeated and cyclic loadings imposed by moving traffic. This method seeks the mechanism from within a class of mechanisms that minimises the shakedown limit load for pavement structures consisting of layers of Mohr-Coulomb materials. The model differs from extant models, in that the cyclic nature of the loading on a pavement is recognised from the outset, and the current method which is based upon foundation analysis, is replaced by a procedure employing shakedown theory that features the capabilities and applications of the developed technique for assessing rutting in flexible pavements. The basic concepts are outlined together with the most recent calculations of the critical design shakedown load. The influence of the design parameters such as, the strength, stiffness and depth of the granular base-course material as well as the consequences of traffic loading (number of equivalent standard axel loads – ESAL’s) are discussed.
Laboratory Trials Of Cold Recycled Foamed Bitumen Asphalt: Raf Waddington
Authors: Jiménez Helena Isabel Lacalle , Tuck Jessica
Published: May 2015

The Defence Infrastructure Organisation requested a pavement evaluation on RAF Waddington and the results indicated that runway rehabilitation and reprofiling was needed in order to meet the physical design requirements set out in the Manual of Aerodrome Design & Safeguarding. The presence of tar in a layer of the old pavement promoted the option of cold recycling this material into the new structure. This paper presents the results from a laboratory investigation into the suitability of cold recycled foamed bitumen asphalt to be used in the structural layers of an airfield pavement.

Laboratory mixture designs with foamed bitumen, incorporating asphalt planings from RAF Waddington runway, were produced in URS Infrastructure and Environment Ltd. laboratory. Specimens were used to assess mix performance and in order to add confidence to the design. The last objective of the research was to demonstrate that asphalt planings from RAF Waddington could be recycled into foamed asphalt for incorporation in the runway rehabilitation works. The optimum binder content was determined from Indirect Tensile Stiffness Modulus tests and Indirect Tensile Strength tests, concluding that the optimum binder content was 3.3% by mass. As a common practice in the UK, up to 1.5% by mass of cement was added to the mixture to improve early life performance. To assess the foamed bitumen samples’ performance with time, specimens were prepared and cured for 28, 180 and 360 days at different temperatures. Post curing, the specimens were tested for a range of performance criteria including fatigue, stiffness and durability.

The study found that asphalt sampled from the runway at RAF Waddington can be recycled into foamed asphalt, meeting the requirements of Defence Infrastructure Organisation Specification 050.
DFS70 antibodies – biomarkers for the exclusion of ANA-associated autoimmune rheumatic diseases
Authors: Conrad Karsten , Röber Nadja , Rudolph Sebastian , Mahler Michael
Published: May 2015

Despite the progress in the establishment of specific autoantibody assays, screening for antinuclear antibodies (ANA) by indirect immunofluorescence on HEp-2 cells for quality-oriented laboratory diagnosis of ANA associated rheumatic diseases (AARD) remains indispensable. Research results on the relevance of the dense fine speckled (DFS) pattern and DFS70 antibodies disclosed novel possibilities to optimize the serological stepwise diagnostics of AARD. The DFS pattern on HEp-2 cells is well differentiated from the classic “homogeneous” ANA pattern associated with dsDNA antibodies. In DFS pattern positive sera the most important detectable ANA specificity is the DFS70 antibody (synonym LEDGF antibody). This antibody is also the most frequent ANA specificity in ANA positive healthy persons. The prevalence of DFS70 antibodies in AARD patients is significantly lower compared with the prevalence in ANA-positive healthy individuals. There is a negative association between DFS70 antibodies and AARD, especially if no concomitant AARD-specific autoantibodies are found. Isolated DFS70 antibodies are detectable in <1% of AARD, but are detectable in 5%–11% of healthy individuals. In the presence of an isolated DFS70 antibody, the posttest probability for AARD is reduced significantly. DFS70 antibodies are valuable novel biomarkers for the improved interpretation of positive ANA but without detectable AARD associated autoantibodies and should be integrated in modified test algorithms to avoid unnecessary referrals and examinations of ANA-positive subjects.
Die Weimarer Militärbibliothek 1630 bis 1930 – klassische Ordnungsvorstellungen vom Krieg
Authors: Barnert Arno
Published: May 2015

During the World Wars, almost all German military libraries were destroyed or suffered heavy losses. One of the rare collections to have survived in its original form is the Weimar military library at the Duchess Anna Amalia Library. It was established about 1630 with books seized by Duke Bernard of Saxe-Weimar in the Thirty Years’ War. After 1787, when Duke Carl August of Saxe-Weimar-Eisenach took command of a Prussian regiment, the collection grew rapidly. Originally a department of the main library, it was separated from it in 1804. During the French Revolution and the Napoleonic Wars, the Weimar military library became a space of universal knowledge: apart from books, it also contained maps, globes, manuscripts and models of fortifications, holding about 15,000 items altogether. After Prussia’s defeat by Napoleon, Weimar was a social and literary centre for the military reformers of 1807-1813 who used and influenced the library. Since 1824, the collection has been kept in the library’s medieval tower. The shelving system goes back to ideas of Carl August and Johann Wolfgang Goethe. The collection is not limited to military literature, but is encyclopaedic in nature.
‘Switch-on’ DNA sensor based on poly (p-phenylene vinylenes) bound tentacle probes
Authors: Gulur Srinivas Anupama R. , Barker David , Travas-Sejdic Jadranka
Published: May 2015

The development of highly sensitive and selective DNA sensors has fuelled applications in a wide range of fields including medical diagnostics, forensics, biodefense, food contamination and environment monitoring. We demonstrate a novel superquenching based DNA sensor with “switch-on” readout using poly(p-phenylenevinylene) (PPV) coated magnetic beads (PPV-MagSi) and quencher functionalized tentacle probes (TP). The sensor design utilizes signal amplification properties of PPV and cooperativity of TPs to monitor hybridization of target oligonucleotides (ONs). The switch-on sensor exhibits excellent sensitivity and selectively discriminates mismatches in the target DNA sequence. Two novel anionic PPVs – poly (6,6′-((2-methyl-5-((E)-4-((E)-prop-1-en-1-yl)styryl)-1,4-phenylene)-bis(oxy) dihexanoic acid) (PMDH) and poly (6,6′-((2-((E)-2,5-bis(2-methoxyethoxy)-4-((E)-prop-1-en-1-yl)styryl)-5-methyl-1,4-phenylene)-bis-(oxy)) di-hexanoic acid) (PDMonoG) were tested and compared against each other as part of the sensor design. The employed hairpin TPs possess further advantages of avoiding labelling of target ON, increased selectivity and sensitivity; faster assay time, and capability of magnetically controlled deployment and separation of PPV-MagSi beads.
Neutron activation analysis of polyethylene from neutron shield of EDELWEISS experiment
Authors: Rakhimov Alimardon V. , Brudanin Viktor B. , Filosofov Dmitry V. , Loaiza Pia , Marinov Genko M. , Mirsagatova Adiba A. , Medvedev Dmitriy , Mukhamedshina Nuranya M. , Rozov Sergey V. , Sadikov Ilkham I. , Warot Guillaume , Yakushev Evgeniy A.
Published: May 2015

Instrumental neutron-activation analysis (INAA) was applied to estimate trace contaminations in polyethylene (PE) used as a neutron
shield for low background setup of the EDELWEISS Dark Matter search experiment. PE samples with masses of 1–10 grams each
were irradiated at the WWR-SM nuclear reactor by neutron flux of 1 · 1014 n/(cm2 s) for 5–48 h. The
radioactivity was measured by high-resolution γ-ray spectrometry. In PE samples of two types, more than 30 trace
elements were determined at a concentration level of 10−5 to 10
–11 g/g.
A Commitment Mechanism to Eliminate Willful Contract Litigation
Authors: Jacobi Osnat , Sher Noam
Published: May 2015

This paper concerns companies that sell commodities and are in their initial stages of formation and growth. Such companies will often face severe difficulties due to the banking system’s unwillingness to finance their activities before they are able to develop sufficient credit histories. When faced with a loss contract, such a company may prefer to breach and litigate simply in order to gain time before having to pay off its debt, thereby preventing immediate insolvency. We have designed a new financial tool to eliminate this incentive to willfully litigate. Under this mechanism, the seller undertakes an obligation to pay a bank the amount of the buyer’s damages if the seller does not deliver the good on delivery day in accordance with the contract and law. The bank, in turn, undertakes to pay the buyer the amount of her damages if received by the bank. The effect of this mechanism is to shift the buyer’s entitlement to the bank. This increases the seller’s cost of willful litigation: if the seller chooses to breach he will prefer paying the buyer’s damages to the bank in order to avoid any indication of default on the bank’s records, since such an indication will affect his credit rating and access to financial markets in the future. In addition, the mechanism gives the seller an incentive to breach the contract if and only if the contract becomes ex-post inefficient. We also demonstrate ex-ante benefits from the mechanism: by eliminating the risk of willful litigation, established buyers may be willing to raise the contract price, thereby increasing the probability of newcomers’ survival. The mechanism also enables the banking system to screen new companies according to their quality, and use their contracts as collateral. Ultimately, this can result in the newcomer achieving financial stability earlier.
Effect of Ambient Temperature on Pacing in Soccer Depends on Skill Level
Authors: Link Daniel , Weber Hendrik
Published: May 2015

Link, D and Weber, H. Effect of ambient temperature on pacing in soccer depends on skill level. J Strength Cond Res 31(7): 1766–1770, 2017—This study examines the influence ambient temperature has on the distances covered by players in soccer matches. For this purpose, 1,211 games from the top German professional leagues were analyzed over the course of the seasons 2011/12 and 2012/13 using an optical tracking system. Data show (a) significant differences in the total distance covered (TDC, in meters per 10 minutes) between the 1. Bundesliga (M = 1,225) and 2. Bundesliga (M = 1,201) and (b) a significant decrease in TDC from neutral (−4 to 13° C, M = 1,229) to warm (≥14° C, M = 1,217) environments. The size of the temperature effect is greater in the 1. Bundesliga (d = 0.30 vs. d = 0.16), although these players presumably have a higher level of fitness. This suggests that better players reduce their exertion level to a greater extent, thus preserving their ability to undertake the high-intensity activities when called upon. No reduction in running performance due to cold (≤5° C) temperatures was observed.
PKMζ, But Not PKCλ, Is Rapidly Synthesized and Degraded at the Neuronal Synapse
Authors: Palida Sakina F. , Butko Margaret T. , Ngo John T. , Mackey Mason R. , Gross Larry A. , Ellisman Mark H. , Tsien Roger Y.
Published: May 2015

Synthesizing, localizing, and stabilizing new protein copies at synapses are crucial factors in maintaining the synaptic changes required for storing long-term memories. PKMζ recently emerged as a molecule putatively responsible for maintaining encoded memories over time because its presence correlates with late LTP and because its inhibition disrupts LTPin vitroand long-term memory storagein vivo. Here we investigated PKMζ stability in rat neurons to better understand its role during information encoding and storage. We used TimeSTAMP reporters to track the synthesis and degradation of PKMζ as well as a related atypical PKC, PKCλ. These reporters revealed that both PKMζ and PKCλ were upregulated after chemical LTP induction; however, these new PKMζ copies exhibited more rapid turnover than basally produced PKMζ, particularly in dendritic spines. In contrast to PKMζ, new PKCλ copies exhibited elevated stability. Stable information storage over long periods of time is more challenging the shorter the metabolic lifetime of the candidate molecules.
Prdm13Regulates Subtype Specification of Retinal Amacrine Interneurons and Modulates Visual Sensitivity
Authors: Watanabe Satoshi , Sanuki Rikako , Sugita Yuko , Imai Wataru , Yamazaki Ryoji , Kozuka Takashi , Ohsuga Mizuki , Furukawa Takahisa
Published: May 2015

Amacrine interneurons, which are highly diversified in morphological, neurochemical, and physiological features, play crucial roles in visual information processing in the retina. However, the specification mechanisms and functions in vision for each amacrine subtype are not well understood. We found that the Prdm13 transcriptional regulator is specifically expressed in developing and mature amacrine cells in the mouse retina. Most Prdm13-positive amacrine cells are Calbindin- and Calretinin-positive GABAergic or glycinergic neurons. Absence ofPrdm13significantly reduces GABAergic and glycinergic amacrines, resulting in a specific defect of the S2/S3 border neurite bundle in the inner plexiform layer. Forced expression of Prdm13 distinctively induces GABAergic and glycinergic amacrine cells but not cholinergic amacrine cells, whereas Ptf1a, an upstream transcriptional regulator of Prdm13, induces all of these subtypes. Moreover,Prdm13-deficient mice showed abnormally elevated spatial, temporal, and contrast sensitivities in vision. Together, these results show that Prdm13 regulates development of a subset of amacrine cells, which newly defines an amacrine subtype to negatively modulate visual sensitivities. Our current study provides new insights into mechanisms of the diversification of amacrine cells and their function in vision.
Neurons in the Most Superficial Lamina of the Mouse Superior Colliculus Are Highly Selective for Stimulus Direction
Authors: Inayat Samsoon , Barchini Jad , Chen Hui , Feng Liang , Liu Xiaorong , Cang Jianhua
Published: May 2015

The superior colliculus (SC) is a layered midbrain structure important for multimodal integration and sensorimotor transformation. Its superficial layers are purely visual and receive depth-specific projections from distinct subtypes of retinal ganglion cells. Here we use two-photon calcium imaging to characterize the response properties of neurons in the most superficial lamina of the mouse SC, an undersampled population with electrophysiology. We find that these neurons have compact receptive fields with primarily overlapping ON and OFF subregions and are highly direction selective. The high selectivity is observed in both excitatory and inhibitory neurons. These neurons do not cluster according to their direction preference and lack orientation selectivity. In addition, we perform single-unit recordings and show that direction selectivity declines with depth in the SC. Together, our experiments reveal for the first time a highly specialized lamina in the most superficial SC for movement direction, a finding that has important implications for understanding signal transformation in the early visual system.
A Bidirectional Link between Brain Oscillations and Geometric Patterns
Authors: Mauro Federica , Raffone Antonino , VanRullen Rufin
Published: May 2015

Like hallucinogenic drugs, full-field flickering visual stimulation produces regular, geometric hallucinations such as radial or spiral patterns. Computational and theoretical models have revealed that the geometry of these hallucinations can be related to functional neuro-anatomy. However, while experimental evidence links both visual flicker and hallucinogenic drugs to upward and downward modulations of brain oscillatory activity, the exact relation between brain oscillations and geometric hallucinations remains a mystery. Here we demonstrate that, in human observers, this link is bidirectional. The same flicker frequencies that preferentially induced radial (<10 Hz) or spiral (10–20 Hz) hallucinations in a behavioral experiment involving full-field uniform flicker without any actual shape displayed, also showed selective oscillatory EEG enhancement when observers viewed a genuine static image of a radial or spiral pattern without any flicker. This bidirectional property constrains the possible neuronal events at the origin of visual hallucinations, and further suggests that brain oscillations, which are strictly temporal in nature, could nonetheless act as preferential channels for spatial information.
Noradrenaline and Dopamine Neurons in the Reward/Effort Trade-Off: A Direct Electrophysiological Comparison in Behaving Monkeys
Authors: Varazzani Chiara , San-Galli Aurore , Gilardeau Sophie , Bouret Sebastien
Published: May 2015

Motivation determines multiple aspects of behavior, including action selection and energization of behavior. Several components of the underlying neural systems have been examined closely, but the specific role of the different neuromodulatory systems in motivation remains unclear. Here, we compare directly the activity of dopaminergic neurons from the substantia nigra pars compacta and noradrenergic neurons from the locus coeruleus in monkeys performing a task manipulating the reward/effort trade-off. Consistent with previous reports, dopaminergic neurons encoded the expected reward, but we found that they also anticipated the upcoming effort cost in connection with its negative influence on action selection. Conversely, the firing of noradrenergic neurons increased with both pupil dilation and effort production in relation to the energization of behavior. Therefore, this work underlines the contribution of dopamine to effort-based decision making and uncovers a specific role of noradrenaline in energizing behavior to face challenges.
Blocking Stroke-Induced Immunodeficiency Increases CNS Antigen-Specific Autoreactivity But Does Not Worsen Functional Outcome after Experimental Stroke
Authors: Römer Christine , Engel Odilo , Winek Katarzyna , Hochmeister Sonja , Zhang Tian , Royl Georg , Klehmet Juliane , Dirnagl Ulrich , Meisel Christian , Meisel Andreas
Published: May 2015

Stroke-induced immunodepression (SIDS) is an essential cause of poststroke infections. Pharmacological inhibition of SIDS appears promising in preventing life-threatening infections in stroke patients. However, SIDS might represent an adaptive mechanism preventing autoreactive immune responses after stroke. To address this, we used myelin oligodendrocyte glycoprotein (MOG) T-cell receptor transgenic (2D2) mice where >80% of peripheral CD4+T cells express a functional receptor for MOG. We investigated in a murine model of middle cerebral artery occlusion the effect of blocking SIDS by inhibiting body's main stress axes, the sympathetic nervous system (SNS) with propranolol and the hypothalamic-pituitary-adrenal axis (HPA) with mifepristone. Blockade of both stress axes robustly reduced infarct volumes, decreased infection rate, and increased long-term survival of2D2and C57BL/6J wild-type mice. Despite these protective effects, blockade of SIDS increased CNS antigen-specific Type1 T helper cell (Th1) responses in the brains of2D2mice 14 d after middle cerebral artery occlusion. One month after experimental stroke,2D2mice developed signs of polyradiculitis, which were diminished by SIDS blockade. Adoptive transfer of CD4+T cells, isolated from2D2mice, into lymphocyte-deficientRag-1KOmice did not reveal differences between SIDS blockade and vehicle treatment in functional long-term outcome after stroke. In conclusion, inhibiting SIDS by pharmacological blockade of body's stress axes increases autoreactive CNS antigen-specific T-cell responses in the brain but does not worsen functional long-term outcome after experimental stroke, even in a mouse model where CNS antigen-specific autoreactive T-cell responses are boosted.
Connections between Intraparietal Sulcus and a Sensorimotor Network Underpin Sustained Tactile Attention
Authors: Goltz Dominique , Gundlach Christopher , Nierhaus Till , Villringer Arno , Müller Matthias , Pleger Burkhard
Published: May 2015

Previous studies on sustained tactile attention draw conclusions about underlying cortical networks by averaging over experimental conditions without considering attentional variance in single trials. This may have formed an imprecise picture of brain processes underpinning sustained tactile attention. In the present study, we simultaneously recorded EEG-fMRI and used modulations of steady-state somatosensory evoked potentials (SSSEPs) as a measure of attentional trial-by-trial variability. Therefore, frequency-tagged streams of vibrotactile stimulations were simultaneously presented to both index fingers. Human participants were cued to sustain attention to either the left or right finger stimulation and to press a button whenever they perceived a target pulse embedded in the to-be-attended stream. In-line with previous studies, a classical general linear model (GLM) analysis based on cued attention conditions revealed increased activity mainly in somatosensory and cerebellar regions. Yet, parametric modeling of the BOLD response using simultaneously recorded SSSEPs as a marker of attentional trial-by-trial variability quarried the intraparietal sulcus (IPS). The IPS in turn showed enhanced functional connectivity to a modality-unspecific attention network. However, this was only revealed on the basis of cued attention conditions in the classical GLM. By considering attentional variability as captured by SSSEPs, the IPS showed increased connectivity to a sensorimotor network, underpinning attentional selection processes between competing tactile stimuli and action choices (press a button or not). Thus, the current findings highlight the potential value by considering attentional variations in single trials and extend previous knowledge on the role of the IPS in tactile attention.
Relating Cerebellar Purkinje Cell Activity to the Timing and Amplitude of Conditioned Eyelid Responses
Authors: Halverson Hunter E. , Khilkevich Andrei , Mauk Michael D.
Published: May 2015

How Purkinje cell (PC) activity may be altered by learning is central to theories of the cerebellum. Pavlovian eyelid conditioning, because of how directly it engages the cerebellum, has helped reveal many aspects of cerebellar learning and the underlying mechanisms. Theories of cerebellar learning assert that climbing fiber inputs control plasticity at synapses onto PCs, and thus PCs control the expression of learned responses. We tested this assertion by recording 184 eyelid PCs and 240 non-eyelid PCs during the expression of conditioned eyelid responses (CRs) in well trained rabbits. By contrasting the responses of eyelid and non-eyelid PCs and by contrasting the responses of eyelid PCs under conditions that produce differently timed CRs, we test the hypothesis that learning-related changes in eyelid PCs contribute to the learning and adaptive timing of the CRs. We used a variety of analyses to test the quantitative relationships between eyelid PC responses and the kinematic properties of the eyelid CRs. We find that the timing of eyelid PC responses varies systematically with the timing of the behavioral CRs and that there are differences in the magnitude of eyelid PC responses between larger-CR, smaller-CR, and non-CR trials. However, eyelid PC activity does not encode any single kinematic property of the behavioral CRs at a fixed time lag, nor does it linearly encode CR amplitude. Even so, the results are consistent with the hypothesis that learning-dependent changes in PC activity contribute to the adaptively timed expression of conditioned eyelid responses.
Inducible Activation of ERK5 MAP Kinase Enhances Adult Neurogenesis in the Olfactory Bulb and Improves Olfactory Function
Authors: Wang Wenbin , Lu Song , Li Tan , Pan Yung-Wei , Zou Junhui , Abel Glen M. , Xu Lihong , Storm Daniel R. , Xia Zhengui
Published: May 2015

Recent discoveries have suggested that adult neurogenesis in the subventricular zone (SVZ) and olfactory bulb (OB) may be required for at least some forms of olfactory behavior in mice. However, it is unclear whether conditional and selective enhancement of adult neurogenesis by genetic approaches is sufficient to improve olfactory function under physiological conditions or after injury. Furthermore, specific signaling mechanisms regulating adult neurogenesis in the SVZ/OB are not fully defined. We previously reported that ERK5, a MAP kinase selectively expressed in the neurogenic regions of the adult brain, plays a critical role in adult neurogenesis in the SVZ/OB. Using a site-specific knock-in mouse model, we report here that inducible and targeted activation of the endogenous ERK5 in adult neural stem/progenitor cells enhances adult neurogenesis in the OB by increasing cell survival and neuronal differentiation. This conditional ERK5 activation also improves short-term olfactory memory and odor-cued associative olfactory learning under normal physiological conditions. Furthermore, these mice show enhanced recovery of olfactory function and have more adult-born neurons after a zinc sulfate-induced lesion of the main olfactory epithelium. We conclude that ERK5 MAP kinase is an important endogenous signaling pathway regulating adult neurogenesis in the SVZ/OB, and that conditional activation of endogenous ERK5 is sufficient to enhance adult neurogenesis in the OB thereby improving olfactory function both under normal conditions and after injury.