bluuebunny/crossref_metadata_2025 huggingface dataset:
Low‐Temperature Direct Catalytic Hydrothermal Conversion of Biomass Cellulose to Light Hydrocarbons over Pt/Zeolite Catalysts
Authors: Ogo Shuhei , Okuno Yutaro , Sekine Hikaru , Manabe Shota , Yabe Tomohiro , Onda Ayumu , Sekine Yasushi
Published: July 2017

Direct catalytic hydrothermal conversion of cellulose to C3+C4 hydrocarbons at a low temperature (443 K) over a Pt/zeolite catalyst without hydrogen or other expensive reagents was investigated. Pt supported on NH4+‐form ultra‐stable Y‐type (NH4‐USY) zeolite catalyst, which showed the highest activity among the tested Pt/zeolite catalysts, has appropriate acidity and a suitable active Pt site. The C3+C4 hydrocarbon yield reached 14.5 C‐% during the reaction over the Pt/NH4‐USY catalyst at 443 K after 72 h of the reaction. Results showed that the acid strength of the zeolite support was an important factor affecting the cellulose decomposition activity. Because of their structural sensitivity, Pt/zeolite catalysts with Pt particles larger than 5 nm, including Pt/NH4‐USY catalyst, showed higher TOF values than catalysts with Pt particles smaller than 5 nm.
A Novel Collaborative Protocol for Successful Management of Penile Pain Mediated by Radiculitis of Sacral Spinal Nerve Roots From Tarlov Cysts
Authors: Goldstein Irwin , Komisaruk Barry R. , Rubin Rachel S. , Goldstein Sue W. , Elliott Stacy , Kissee Jennifer , Kim Choll W.
Published: July 2017

Introduction

Since 14 years of age, the patient had experienced extreme penile pain within seconds of initial sexual arousal through masturbation. Penile pain was so severe that he rarely proceeded to orgasm or ejaculation. After 7 years of undergoing multiple unsuccessful treatments, he was concerned for his long-term mental health and for his future ability to have relationships.

Aim

To describe a novel collaboration among specialists in sexual medicine, neurophysiology, and spine surgery that led to successful management.

Methods

Collaborating health care providers conferred with the referring physician, patient, and parents and included a review of all medical records.

Main Outcome Measure

Elimination of postpubertal intense penile pain during sexual arousal.

Results

The patient presented to our sexual medicine facility at 21 years of age. The sexual medicine physician identifying the sexual health complaint noted a pelvic magnetic resonance imaging report of an incidental sacral Tarlov cyst. A subsequent sacral magnetic resonance image showed four sacral Tarlov cysts, with the largest measuring 18 mm. Neuro-genital testing result were abnormal. The neurophysiologist hypothesized the patient's pain at erection was produced by Tarlov cyst-induced neuropathic irritation of sensory fibers that course within the pelvic nerve. The spine surgeon directed a diagnostic injection of bupivacaine to the sacral nerve roots and subsequently morphine to the conus medullaris of the spinal cord. The bupivacaine produced general penile numbness; the morphine selectively decreased penile pain symptoms during sexual arousal without blocking penile skin sensation. The collaboration among specialties led to the conclusion that the Tarlov cysts were pathophysiologically mediating the penile pain symptoms during arousal. Long-term follow-up after surgical repair showed complete symptom elimination at 18 months after treatment.

Conclusion

This case provides evidence that (i) Tarlov cysts can cause sacral spinal nerve root radiculitis through sensory pelvic nerve and (ii) there are management benefits from collaboration among sexual medicine, neurophysiology, and spine surgery subspecialties.

Goldstein I, Komisaruk BR, Rubin RS, et al. A Novel Collaborative Protocol for Successful Management of Penile Pain Mediated by Radiculitis of Sacral Spinal Nerve Roots From Tarlov Cysts. Sex Med 2017;5:e203–e211.
Islam Instrumentalized
Authors: Platteau Jean-Philippe
Published: July 2017

In this book, economist Jean-Philippe Platteau addresses the question: does Islam, the religion of Muslims, bear some responsibility for a lack of economic development in the countries in which it dominates? In his nuanced approach, Platteau challenges the widespread view that the doctrine of Islam is reactionary in the sense that it defends tradition against modernity and individual freedom. He also questions the view that fusion between religion and politics is characteristic of Islam and predisposes it to theocracy. He disagrees with the substantivist view that Islam is a major obstacle to modern development because of a merging of religion and the state, or a fusion between the spiritual and political domains. But he also identifies how Islam's decentralized organization, in the context of autocratic regimes, may cause political instability and make reforms costly.
Dollars for Dixie
Authors: Jewell Katherine Rye
Published: July 2017

Organized in 1933, the Southern States Industrial Council's (SSIC) adherence to the South as a unique political and economic entity limited its members' ability to forge political coalitions against the New Deal. The SSIC's commitment to regional preferences, however, transformed and incorporated conservative thought in the post-World War II era, ultimately complementing the emerging conservative movement in the 1940s and 1950s. In response to New Dealers' attempts to remake the southern economy, the New South industrialists - heirs of C. Vann Woodward's 'new men' of the New South - effectively fused cultural traditionalism and free market economics into a brand of southern free enterprise that shaped the region's reputation and political culture. Dollars for Dixie demonstrates how the South emerged from this refashioning and became a key player in the modern conservative movement, with new ideas regarding free market capitalism, conservative fiscal policy, and limited bureaucracy.
Representation and Scepticism from Aquinas to Descartes
Authors: Adriaenssen Han Thomas
Published: July 2017

In this book Han Thomas Adriaenssen offers the first comparative exploration of the sceptical reception of representationalism in medieval and early modern philosophy. Descartes is traditionally credited with inaugurating a new kind of scepticism by saying that the direct objects of perception are images in the mind, not external objects, but Adriaenssen shows that as early as the thirteenth century, critics had already found similar problems in Aquinas's theory of representation. He charts the attempts of philosophers in both periods to grapple with these problems, and shows how in order to address the challenges of scepticism and representation, modern philosophers in the wake of Descartes often breathed new life into old ideas, remoulding them in ways that we are just beginning to understand. His book will be valuable for historians interested in the medieval background to early modern thought, and to medievalists looking at continuity with the early modern period.
Gentlemanly Terrorists
Authors: Ghosh Durba
Published: July 2017

In Gentlemanly Terrorists, Durba Ghosh uncovers the critical place of revolutionary terrorism in the colonial and postcolonial history of modern India. She reveals how so-called 'Bhadralok dacoits' used assassinations, bomb attacks, and armed robberies to accelerate the departure of the British from India and how, in response, the colonial government effectively declared a state of emergency, suspending the rule of law and detaining hundreds of suspected terrorists. She charts how each measure of constitutional reform to expand Indian representation in 1919 and 1935 was accompanied by emergency legislation to suppress political activism by those considered a threat to the security of the state. Repressive legislation became increasingly seen as a necessary condition to British attempts to promote civic society and liberal governance in India. By placing political violence at the center of India's campaigns to win independence, this book reveals how terrorism shaped the modern nation-state in India.
Misconceptions about Stroke: Causal Attributions for Stroke-Related Symptoms Reflect the Age of the Survivor
Authors: Wainwright Charlotte , McClure John , McDowall John
Published: July 2017

With visible disabilities, observers tend to overgeneralise from the disability. In contrast, with invisible disabilities such as traumatic brain injury and stroke, observers often fail to allow for challenges resulting from the disability. Persons who have suffered a stroke claim that people misunderstand their symptoms and stigmatise them as a result of these symptoms. This misunderstanding, which happens particularly with young survivors of stroke, may reflect people's causal attributions for symptoms that follow a stroke. Using a scenario design, this cross-sectional study examined whether people attribute ambiguous symptoms that may result from stroke to other causes (the stroke survivor's personality and age) and whether these attributions reflect the age of the stroke survivor. Participants (N= 120) read scenarios describing a male who was aged either 22, 72, or whose age was unstated and who showed four symptom changes: fatigue, depression, irritability and reduced friendships. For each symptom change, participants rated three causal attributions: the person's age, his personality and stroke. The age of the person in the scenario affected attributions; when the person in the scenario was 22, participants attributed his symptoms significantly more to his personality than to his age or stroke, whereas when he was 72, participants attributed his symptoms more to his age than to his personality or stroke and when his age was unstated, they attributed his symptoms equally to age, stroke and personality. Because misattributions for stroke symptoms hinder rehabilitation, therapy can target people's misattributions to enhance rehabilitation for survivors of stroke.
The future of subsidence modelling: compaction and subsidence due to gas depletion of the Groningen gas field in the Netherlands
Authors: van Thienen-Visser Karin , Fokker Peter A.
Published: July 2017

The Groningen gas field has shown considerable compaction and subsidence since starting production in the early 1960s. The behaviour is understood from the geomechanical response of the reservoir pressure depletion. By integrating surface movement measurements and modelling, the model parameters can be constrained and understanding of the subsurface behaviour can be improved. Such a procedure has been employed to formulate new compaction and subsidence forecasts. The results are put into the context of an extensive review of the work performed in this field, both in Groningen and beyond. The review is used to formulate a way forward designed to integrate all knowledge in a stochastic manner.
BREWING UP REASONS
Authors: Daly Paul
Published: July 2017

IT is trite law that good reasons must be given to justify infringements of fundamental rights protected by the European Convention on Human Rights, as incorporated into domestic law by the Human Rights Act 1998. But what reasons can one count as good reasons? In Re Brewster's Application [2017] UKSC 8; [2017] 1 W.L.R. 519, the United Kingdom Supreme Court addressed the question of how much deference courts should afford to post hoc rationalisations of decisions challenged for non-compliance with the Convention. The answer given by Lord Kerr, with whom Lady Hale, Lord Wilson, Lord Reed and Lord Dyson agreed, is interesting in its own terms and may have implications outside the confines of the Convention.
CONFIDENTIALITY AND PUBLIC AUTHORITIES: FUNDAMENTAL RIGHTS, LEGALITY AND DISCLOSURE FOR STATUTORY FUNCTIONS
Authors: Butler Oliver Michael
Published: July 2017

TAXPAYER confidentiality has a long history of protection in the UK. It is a fundamental part of the tax system. It has been considered invaluable by the executive for the efficient collection of taxation, protected by Parliament since the Income Tax Act 1799 and recognised by the courts as a “vital element in the working of the system” (Inland Revenue Commissioners v National Federation of Self-Employed and Small Businesses Ltd. [1982] A.C. 617, 633, per Lord Wilberforce).
Liquidity Constraints and Credit Card Delinquency: Evidence from Raising Minimum Payments
Authors: d’Astous Philippe , Shore Stephen H.
Published: July 2017

We use credit card data to estimate the impact of increasing minimum payments on delinquency, payments, spending, and write-offs. Our identification strategy exploits an unusual institutional feature: Borrowers can use their account to make purchases with both revolving loans (on which minimum payments increased) and term loans (on which there was no change). Payment increases by delinquent borrowers are insufficient to match increasing minimums, resulting in lower cure rates and an increase in write-offs. Affected borrowers migrate away from these accounts by decreasing charges and increasing payments, consequently lowering the interest earned by the bank.
Functional characterization of single-domain cystatin-like cysteine proteinase inhibitors expressed by the trematodeFasciola hepatica
Authors: CANCELA MARTÍN , CORVO ILEANA , DA SILVA EDILEUZA , TEICHMANN ALINE , ROCHE LEDA , DÍAZ ALVARO , TORT JOSÉ FRANSISCO , FERREIRA HENRIQUE B. , ZAHA ARNALDO
Published: July 2017

Cystatins are small, phylogenetically conserved proteins that are tight-binding inhibitors of cysteine proteinases. The liver flukeFasciola hepaticauses a diverse set of cysteine proteinases of the papain superfamily for host invasion, immune evasion and nutrition, but little is known about the regulation of these enzymes. The aim of this work is to characterize the cystatin repertoire ofF. hepatica. For this purpose, we first surveyed the available sequence databases, identifying three differentF. hepaticasingle-domain cystatins. In agreement with thein silicopredictions, at least three small proteins with cysteine proteinase binding activity were identified. Phylogenetic analyses showed that the three cystatins (named FhStf-1, -2 and -3) are members of the I25A subfamily (stefins). Whereas FhStf-1 grouped with classical stefins, FhStf-2 and 3 fell in a divergent stefin subgroup unusually featuring signal peptides. Recombinant rFhStf-1, -2 and -3 had potent inhibitory activity againstF. hepaticacathepsinLcysteine proteinases but differed in their capacity to inhibit mammalian cathepsinB,LandC. FhStf-1 was localized in theF. hepaticareproductive organs (testes and ovary), and at the surface lamella of the adult gut, where it may regulate cysteine proteinases related with reproduction and digestion, respectively. FhStf-1 was also detected amongF. hepaticaexcretion–secretion (E/S) products of adult flukes. This suggests that it is secreted by non-classical secretory pathway and that it may interact with host lysosomal cysteine proteinases.
The First Jewish Astronomers: Lunar Theory and Reconstruction of a Dead Sea Scroll
Authors: Ratzon Eshbal
Published: July 2017

Argument

The Astronomical Book of Enoch describes the passage of the moon through the gates of heaven, which stand at the edges of the earth. In doing so, the book describes the position of the rising and setting of the moon on the horizon. Otto Neugebauer, the historian of ancient science, suggested using the detailed tables found in later Ethiopic texts in order to reconstruct the path of the moon through the gates. This paper offers a new examination of earlier versions of the Astronomical Book, using a mathematical analysis of the figures and astronomical theories presented throughout the Aramaic Astronomical Book; the results fit both the data preserved in the scrolls and the mathematical approach and religious ideology of the scroll's authors better than the details found in the late Ethiopic texts. Among other new insights, this alternate theory also teaches about the process of the composition of the Astronomical Book in the first centuries of its composition.
Failed Histories of Electronic Music
Authors: Wilson Daniel R.
Published: July 2017

This article counters the canonical histories of electronic music that traditionally begin with Cahill’s Telharmonium and find their historical centre in the activities of the Paris and Cologne studios of the mid-twentieth century. The concept of ‘failed histories’ is introduced here with three important examples. The first chronicles the career of electromusical innovator Johann Baptist Schalkenbach (1824–1910). The second example examines Britain’s earliest electronic sound performance in 1895, signalling a rupture between electromusical bombast and the detailed, quiet work of the experimental laboratory. The third episode looks at the wireless oscillation outrages of the 1920s and 1930s, where electronic tone prematurely trespassed upon musical culture. Taken together, these failed histories offer an alternative narrative of electronic music finding its voice (and losing its voice) in turn-of-the-century Britain.
‘Nimble Fingers’ in Electronic Music: Rethinking sound through neo-colonial labour
Authors: Vágnerová Lucie
Published: July 2017

How can historians of electronic music address the factory labour of the global underclass of women building electronics used in sound technologies? How can we speak to the repetitive work of women who are racially and sexually stereotyped as having ‘nimble fingers’, being ‘detail oriented’ and ‘obedient’? Although women workers in electronics assembly are already de facto entangled in contemporary sound production, scholars have yet to enfold their lives and labour into histories of electronic music. I situate electronic sound technologies since the 1960s in the contexts of the global division of labour and the intimate disciplining of women’s bodies, and investigate the discursive fallout of transnational subcontracting in the electronics industry. I argue that rethinking the category ‘women in electronic music’ is a necessary step for sound studies and musicology, and I call for a new disciplinary understanding of electronic sound and audio as fundamentally neo-colonial.
Imaging and lipidomics methods for lipid analysis in metabolic and cardiovascular disease
Authors: Stevens K. G. , Bader C. A. , Sorvina A. , Brooks D. A. , Plush S. E. , Morrison J. L.
Published: July 2017

Cardiometabolic diseases exhibit changes in lipid biology, which is important as lipids have critical roles in membrane architecture, signalling, hormone synthesis, homoeostasis and metabolism. However,Developmental Origins of Health and Diseasestudies of cardiometabolic disease rarely include analysis of lipids. This short review highlights some examples of lipid pathology and then explores the technology available for analysing lipids, focussing on the need to develop imaging modalities for intracellular lipids. Analytical methods for studying interactions between the complex endocrine and intracellular signalling pathways that regulate lipid metabolism have been critical in expanding our understanding of how cardiometabolic diseases develop in association with obesity and dietary factors. Biochemical methods can be used to generate detailed lipid profiles to establish links between lifestyle factors and metabolic signalling pathways and determine how changes in specific lipid subtypes in plasma and homogenized tissue are associated with disease progression. New imaging modalities enable the specific visualization of intracellular lipid traffic and distributionin situ. These techniques provide a dynamic picture of the interactions between lipid storage, mobilization and signalling, which operate during normal cell function and are altered in many important diseases. The development of methods for imaging intracellular lipids can provide a dynamic real-time picture of how lipids are involved in complex signalling and other cell biology pathways; and how they ultimately regulate metabolic function/homoeostasis during early development. Some imaging modalities have the potential to be adapted forin vivoapplications, and may enable the direct visualization of progression of pathogenesis of cardiometabolic disease after poor growth in early life.
Reversal of cancer gene expression correlates with drug efficacy and reveals therapeutic targets
Authors: Chen Bin , Ma Li , Paik Hyojung , Sirota Marina , Wei Wei , Chua Mei-Sze , So Samuel , Butte Atul J.
Published: July 2017

The decreasing cost of genomic technologies has enabled the molecular characterization of large-scale clinical disease samples and of molecular changes upon drug treatment in various disease models. Exploring methods to relate diseases to potentially efficacious drugs through various molecular features is critically important in the discovery of new therapeutics. Here we show that the potency of a drug to reverse cancer-associated gene expression changes positively correlates with that drug’s efficacy in preclinical models of breast, liver and colon cancers. Using a systems-based approach, we predict four compounds showing high potency to reverse gene expression in liver cancer and validate that all four compounds are effective in five liver cancer cell lines. The in vivo efficacy of pyrvinium pamoate is further confirmed in a subcutaneous xenograft model. In conclusion, this systems-based approach may be complementary to the traditional target-based approach in connecting diseases to potentially efficacious drugs.
Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5
Authors: Park Sungjun , Lee Seungwon , Lee Choong-Gu , Park Guk Yeol , Hong Hyebeen , Lee Jeon-Soo , Kim Young Min , Lee Sung Bae , Hwang Daehee , Choi Youn Soo , Fryer John D. , Im Sin-Hyeog , Lee Seung-Woo , Lee Yoontae
Published: July 2017

High-affinity antibody production through the germinal centre (GC) response is a pivotal process in adaptive immunity. Abnormal development of follicular helper T (TFH) cells can induce the GC response to self-antigens, subsequently leading to autoimmunity. Here we show the transcriptional repressor Capicua/CIC maintains peripheral immune tolerance by suppressing aberrant activation of adaptive immunity. CIC deficiency induces excessive development of TFH cells and GC responses in a T-cell-intrinsic manner. ETV5 expression is derepressed in Cic null TFH cells and knockdown of Etv5 suppresses the enhanced TFH cell differentiation in Cic-deficient CD4+ T cells, suggesting that Etv5 is a critical CIC target gene in TFH cell differentiation. Furthermore, we identify Maf as a downstream target of the CIC–ETV5 axis in this process. These data demonstrate that CIC maintains T-cell homeostasis and negatively regulates TFH cell development and autoimmunity.
Scalable variable-index elasto-optic metamaterials for macroscopic optical components and devices
Authors: Shin Dongheok , Kim Junhyun , Kim Changwook , Bae Kyuyoung , Baek Seunghwa , Kang Gumin , Urzhumov Yaroslav , Smith David R. , Kim Kyoungsik
Published: July 2017

Optical metamaterials with an artificial subwavelength structure offer new approaches to implement advanced optical devices. However, some of the biggest challenges associated with the development of metamaterials in the visible spectrum are the high costs and slow production speeds of the nanofabrication processes. Here, we demonstrate a macroscale (>35 mm) transformation-optics wave bender (293 mm2) and Luneburg lens (855 mm2) in the broadband white-light visible wavelength range using the concept of elasto-optic metamaterials that combines optics and solid mechanics. Our metamaterials consist of mesoscopically homogeneous chunks of bulk aerogels with superior, broadband optical transparency across the visible spectrum and an adjustable, stress-tuneable refractive index ranging from 1.43 down to nearly the free space index (∼1.074). The experimental results show that broadband light can be controlled and redirected in a volume of >105λ × 105λ × 103λ, which enables natural light to be processed directly by metamaterial-based optical devices without any additional coupling components.
Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program
Authors: Wang Ping , Wander Connor M. , Yuan Chao-Xing , Bereman Michael S. , Cohen Todd J.
Published: July 2017

TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. Surprisingly, it has been challenging to recapitulate this pathology, highlighting an incomplete understanding of TDP-43 regulatory mechanisms. Here we provide evidence supporting TDP-43 acetylation as a trigger for disease pathology. Using cultured cells and mouse skeletal muscle, we show that TDP-43 acetylation-mimics promote TDP-43 phosphorylation and ubiquitination, perturb mitochondria, and initiate degenerative inflammatory responses that resemble sporadic inclusion body myositis pathology. Analysis of functionally linked amyotrophic lateral sclerosis proteins revealed recruitment of p62, ubiquilin-2, and optineurin to TDP-43 aggregates. We demonstrate that TDP-43 acetylation-mimic pathology is potently suppressed by an HSF1-dependent mechanism that disaggregates TDP-43. Our study illustrates bidirectional TDP-43 processing in which TDP-43 aggregation is targeted by a coordinated chaperone response. Thus, activation or restoration of refolding mechanisms may alleviate TDP-43 aggregation in tissues that are uniquely susceptible to TDP-43 proteinopathies.
Plasmonically Enhanced Reflectance of Heat Radiation from Low-Bandgap Semiconductor Microinclusions
Authors: Tang Janika , Thakore Vaibhav , Ala-Nissila Tapio
Published: July 2017

Increased reflectance from the inclusion of highly scattering particles at low volume fractions in an insulating dielectric offers a promising way to reduce radiative thermal losses at high temperatures. Here, we investigate plasmonic resonance driven enhanced scattering from microinclusions of low-bandgap semiconductors (InP, Si, Ge, PbS, InAs and Te) in an insulating composite to tailor its infrared reflectance for minimizing thermal losses from radiative transfer. To this end, we compute the spectral properties of the microcomposites using Monte Carlo modeling and compare them with results from Fresnel equations. The role of particle size-dependent Mie scattering and absorption efficiencies, and, scattering anisotropy are studied to identify the optimal microinclusion size and material parameters for maximizing the reflectance of the thermal radiation. For composites with Si and Ge microinclusions we obtain reflectance efficiencies of 57–65% for the incident blackbody radiation from sources at temperatures in the range 400–1600 °C. Furthermore, we observe a broadbanding of the reflectance spectra from the plasmonic resonances due to charge carriers generated from defect states within the semiconductor bandgap. Our results thus open up the possibility of developing efficient high-temperature thermal insulators through use of the low-bandgap semiconductor microinclusions in insulating dielectrics.
Antiplasmodial Ealapasamines A-C,‘Mixed’ Naphthylisoquinoline Dimers from the Central African Liana Ancistrocladus ealaensis
Authors: Tshitenge Dieudonné Tshitenge , Feineis Doris , Mudogo Virima , Kaiser Marcel , Brun Reto , Bringmann Gerhard
Published: July 2017

Three unusual heterodimeric naphthylisoquinoline alkaloids, named ealapasamines A-C (1–3), were isolated from the leaves of the tropical plant Ancistrocladus ealaensis J. Léonard. These ‘mixed’, constitutionally unsymmetric dimers are the first stereochemically fully assigned cross-coupling products of a 5,8′- and a 7,8′-coupled naphthylisoquinoline linked via C-6′ in both naphthalene portions. So far, only two other West and Central Ancistrocladus species were known to produce dimers with a central 6,6″-axis, yet, in contrast to the ealapasamines, usually consisting of two 5,8′-coupled monomers, like e.g., in michellamine B. The new dimers 1–3 contain six elements of chirality, four stereogenic centers and the two outer axes, while the central biaryl axis is configurationally unstable. The elucidation of the complete stereostructures of the ealapasamines was achieved by the interplay of spectroscopic methods including HRESIMS, 1D and 2D NMR (in particular ROESY measurements), in combination with chemical (oxidative degradation) and chiroptical (electronic circular dichroism) investigations. The ealapasamines A-C display high antiplasmodial activities with excellent half-maximum inhibition concentration values in the low nanomolar range.
Chemical inhibitors of Candida albicans hyphal morphogenesis target endocytosis
Authors: Bar-Yosef Hagit , Vivanco Gonzalez Nora , Ben-Aroya Shay , Kron Stephen J. , Kornitzer Daniel
Published: July 2017

Candida albicans is an opportunistic pathogen, typically found as a benign commensal yeast living on skin and mucosa, but poised to invade injured tissue to cause local infections. In debilitated and immunocompromised individuals, C. albicans may spread to cause life-threatening systemic infections. Upon contact with serum and at body temperature, C. albicans performs a regulated switch to filamentous morphology, characterized by emergence of a germ tube from the yeast cell followed by mold-like growth of branching hyphae. The ability to switch between growth morphologies is an important virulence factor of C. albicans. To identify compounds able to inhibit hyphal morphogenesis, we screened libraries of existing drugs for inhibition of the hyphal switch under stringent conditions. Several compounds that specifically inhibited hyphal morphogenesis were identified. Chemogenomic analysis suggested an interaction with the endocytic pathway, which was confirmed by direct measurement of fluid-phase endocytosis in the presence of these compounds. These results suggest that the activity of the endocytic pathway, which is known to be particularly important for hyphal growth, represents an effective target for hyphae-inhibiting drugs.
Molecular tools for GABAA receptors: High affinity ligands for β1-containing subtypes
Authors: Simeone Xenia , Siebert David C. B. , Bampali Konstantina , Varagic Zdravko , Treven Marco , Rehman Sabah , Pyszkowski Jakob , Holzinger Raphael , Steudle Friederike , Scholze Petra , Mihovilovic Marko D. , Schnürch Michael , Ernst Margot
Published: July 2017

γ-Aminobutyric acid type A (GABAA) receptors are pentameric GABA-gated chloride channels that are, in mammalians, drawn from a repertoire of 19 different genes, namely α1-6, β1-3, γ1-3, δ, ε, θ, π and ρ1-3. The existence of this wide variety of subunits as well as their diverse assembly into different subunit compositions result in miscellaneous receptor subtypes. In combination with the large number of known and putative allosteric binding sites, this leads to a highly complex pharmacology. Recently, a novel binding site at extracellular α+/β− interfaces was described as the site of modulatory action of several pyrazoloquinolinones. In this study we report a highly potent ligand from this class of compounds with pronounced β1-selectivity that mainly lacks α-subunit selectivity. It constitutes the most potent β1-selective positive allosteric modulatory ligand with known binding site. In addition, a proof of concept pyrazoloquinolinone ligand lacking the additional high affinity interaction with the benzodiazepine binding site is presented. Ultimately, such ligands can be used as invaluable molecular tools for the detection of β1-containing receptor subtypes and the investigation of their abundance and distribution.
SNAP-tagged Chikungunya Virus Replicons Improve Visualisation of Non-Structural Protein 3 by Fluorescence Microscopy
Authors: Remenyi Roland , Roberts Grace C. , Zothner Carsten , Merits Andres , Harris Mark
Published: July 2017

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes febrile disease, muscle and joint pain, which can become chronic in some individuals. The non-structural protein 3 (nsP3) plays essential roles during infection, but a complete understanding of its function is lacking. Here we used a microscopy-based approach to image CHIKV nsP3 inside human cells. The SNAP system consists of a self-labelling enzyme tag, which catalyses the covalent linking of exogenously supplemented synthetic ligands. Genetic insertion of this tag resulted in viable replicons and specific labelling while preserving the effect of nsP3 on stress granule responses and co-localisation with GTPase Activating Protein (SH3 domain) Binding Proteins (G3BPs). With sub-diffraction, three-dimensional, optical imaging, we visualised nsP3-positive structures with variable density and morphology, including high-density rod-like structures, large spherical granules, and small, low-density structures. Next, we confirmed the utility of the SNAP-tag for studying protein turnover by pulse-chase labelling. We also revealed an association of nsP3 with cellular lipid droplets and examined the spatial relationships between nsP3 and the non-structural protein 1 (nsP1). Together, our study provides a sensitive, specific, and versatile system for fundamental research into the individual functions of a viral non-structural protein during infection with a medically important arthropod-borne virus (arbovirus).
Mapping and characterization of G-quadruplexes in Mycobacterium tuberculosis gene promoter regions
Authors: Perrone Rosalba , Lavezzo Enrico , Riello Erika , Manganelli Riccardo , Palù Giorgio , Toppo Stefano , Provvedi Roberta , Richter Sara N.
Published: July 2017

Mycobacterium tuberculosisis the causative agent of tuberculosis (TB), one of the top 10 causes of death worldwide in 2015. The recent emergence of strains resistant to all current drugs urges the development of compounds with new mechanisms of action. G-quadruplexes are nucleic acids secondary structures that may form in G-rich regions to epigenetically regulate cellular functions. Here we implemented a computational tool to scan the presence of putative G-quadruplex forming sequences in the genome ofMycobacterium tuberculosisand analyse their association to transcription start sites. We found that the most stable G-quadruplexes were in the promoter region of genes belonging to definite functional categories. Actual G-quadruplex folding of four selected sequences was assessed by biophysical and biomolecular techniques: all molecules formed stable G-quadruplexes, which were further stabilized by two G-quadruplex ligands. These compounds inhibitedMycobacterium tuberculosisgrowth with minimal inhibitory concentrations in the low micromolar range. These data support formation ofMycobacterium tuberculosisG-quadruplexesin vivoand their potential regulation of gene transcription, and prompt the use of G4 ligands to develop original antitubercular agents.
Predicting susceptibility to tuberculosis based on gene expression profiling in dendritic cells
Authors: Blischak John D. , Tailleux Ludovic , Myrthil Marsha , Charlois Cécile , Bergot Emmanuel , Dinh Aurélien , Morizot Gloria , Chény Olivia , Platen Cassandre Von , Herrmann Jean-Louis , Brosch Roland , Barreiro Luis B. , Gilad Yoav
Published: July 2017

Tuberculosis (TB) is a deadly infectious disease, which kills millions of people every year. The causative pathogen, Mycobacterium tuberculosis (MTB), is estimated to have infected up to a third of the world’s population; however, only approximately 10% of infected healthy individuals progress to active TB. Despite evidence for heritability, it is not currently possible to predict who may develop TB. To explore approaches to classify susceptibility to TB, we infected with MTB dendritic cells (DCs) from putatively resistant individuals diagnosed with latent TB, and from susceptible individuals that had recovered from active TB. We measured gene expression levels in infected and non-infected cells and found hundreds of differentially expressed genes between susceptible and resistant individuals in the non-infected cells. We further found that genetic polymorphisms nearby the differentially expressed genes between susceptible and resistant individuals are more likely to be associated with TB susceptibility in published GWAS data. Lastly, we trained a classifier based on the gene expression levels in the non-infected cells, and demonstrated reasonable performance on our data and an independent data set. Overall, our promising results from this small study suggest that training a classifier on a larger cohort may enable us to accurately predict TB susceptibility.
Distinct Top-down and Bottom-up Brain Connectivity During Visual Perception and Imagery
Authors: Dijkstra N. , Zeidman P. , Ondobaka S. , van Gerven M. A. J. , Friston K.
Published: July 2017

Research suggests that perception and imagination engage neuronal representations in the same visual areas. However, the underlying mechanisms that differentiate sensory perception from imagination remain unclear. Here, we examine the directed coupling (effective connectivity) between fronto-parietal and visual areas during perception and imagery. We found an increase in bottom-up coupling during perception relative to baseline and an increase in top-down coupling during both perception and imagery, with a much stronger increase during imagery. Modulation of the coupling from frontal to early visual areas was common to both perception and imagery. Furthermore, we show that the experienced vividness during imagery was selectively associated with increases in top-down connectivity to early visual cortex. These results highlight the importance of top-down processing in internally as well as externally driven visual experience.
Deep-ocean dissolved organic matter reactivity along the Mediterranean Sea: does size matter?
Authors: Martínez-Pérez Alba María , Álvarez-Salgado Xosé Antón , Arístegui Javier , Nieto-Cid Mar
Published: July 2017

Despite of the major role ascribed to marine dissolved organic matter (DOM) in the global carbon cycle, the reactivity of this pool in the dark ocean is still poorly understood. Present hypotheses, posed within the size-reactivity continuum (SRC) and the microbial carbon pump (MCP) conceptual frameworks, need further empirical support. Here, we provide field evidence of the soundness of the SRC model. We sampled the high salinity core-of-flow of the Levantine Intermediate Water along its westward route through the entire Mediterranean Sea. At selected sites, DOM was size-fractionated in apparent high (aHMW) and low (aLMW) molecular weight fractions using an efficient ultrafiltration cell. A percentage decline of the aHMW DOM from 68–76% to 40–55% was observed from the Levantine Sea to the Strait of Gibraltar in parallel with increasing apparent oxygen utilization (AOU). DOM mineralization accounted for 30 ± 3% of the AOU, being the aHMW fraction solely responsible for this consumption, verifying the SRC model in the field. We also demonstrate that, in parallel to this aHMW DOM consumption, fluorescent humic-like substances accumulate in both fractions and protein-like substances decline in the aLMW fraction, thus indicating that not only size matters and providing field support to the MCP model.
Olfactory bulb plasticity ensures proper olfaction after severe impairment in postnatal neurogenesis
Authors: Díaz D. , Muñoz-Castañeda R. , Ávila-Zarza C. , Carretero J. , Alonso J. R. , Weruaga E.
Published: July 2017

The olfactory bulb (OB) neurons establish a complex network that ensures the correct processing of the olfactory inputs. Moreover, the OB presents a lifelong addition of new neurons into its existing circuitry. This neurogenesis is considered essential for the OB function. However, its functional impact on physiology and behavior is still unclear. Here, we investigate the mechanisms of OB plasticity that underlie bulbar physiology in relation to severe damage of neurogenesis. The neurogenesis of young mice was altered by ionizing radiation. Afterwards, both multi-channel olfactometry and electrophysiological studies were performed. Furthermore, neurogenesis and differentiation of the newly formed cells were assessed using bromodeoxyuridine labeling combined with a wide battery of neuronal markers. Our results demonstrate a reduction in both neurogenesis and volume of the OB in irradiated animals. The number of neuroblasts reaching the OB was reduced and their differentiation rate into interneurons selectively changed; some populations were noticeably affected whereas others remained preserved. Surprisingly, both olfactory detection and discrimination as well as electrophysiology presented almost no alterations in irradiated mice. Our findings suggest that after damaging postnatal neurogenesis, the neurochemical fate of some interneurons changes within a new biological scenario, while maintaining homeostasis and olfaction.
Microbial turnover times in the deep seabed studied by amino acid racemization modelling
Authors: Braun Stefan , Mhatre Snehit S. , Jaussi Marion , Røy Hans , Kjeldsen Kasper U. , Pearce Christof , Seidenkrantz Marit-Solveig , Jørgensen Bo Barker , Lomstein Bente Aa.
Published: July 2017

The study of active microbial populations in deep, energy-limited marine sediments has extended our knowledge of the limits of life on Earth. Typically, microbial activity in the deep biosphere is calculated by transport-reaction modelling of pore water solutes or from experimental measurements involving radiotracers. Here we modelled microbial activity from the degree of D:L-aspartic acid racemization in microbial necromass (remains of dead microbial biomass) in sediments up to ten million years old. This recently developed approach (D:L-amino acid modelling) does not require incubation experiments and is highly sensitive in stable, low-activity environments. We applied for the first time newly established constraints on several important input parameters of the D:L-amino acid model, such as a higher aspartic acid racemization rate constant and a lower cell-specific carbon content of sub-seafloor microorganisms. Our model results show that the pool of necromass amino acids is turned over by microbial activity every few thousand years, while the turnover times of vegetative cells are in the order of years to decades. Notably, microbial turnover times in million-year-old sediment from the Peru Margin are up to 100-fold shorter than previous estimates, highlighting the influence of microbial activities on element cycling over geologic time scales.
Small chaperons and autophagy protected neurons from necrotic cell death
Authors: Lei Ye , Liu Kai , Hou Lin , Ding Lianggong , Li Yuhong , Liu Lei
Published: July 2017

Neuronal necrosis occurs during early phase of ischemic insult. However, our knowledge of neuronal necrosis is still inadequate. To study the mechanism of neuronal necrosis, we previously established a Drosophila genetic model of neuronal necrosis by calcium overloading through expression of a constitutively opened cation channel mutant. Here, we performed further genetic screens and identified a suppressor of neuronal necrosis, CG17259, which encodes a seryl-tRNA synthetase. We found that loss-of-function (LOF) CG17259 activated eIF2α phosphorylation and subsequent up-regulation of chaperons (Hsp26 and Hsp27) and autophagy. Genetically, down-regulation of eIF2α phosphorylation, Hsp26/Hsp27 or autophagy reduced the protective effect of LOF CG17259, indicating they function downstream of CG17259. The protective effect of these protein degradation pathways indicated activation of a toxic protein during neuronal necrosis. Our data indicated that p53 was likely one such protein, because p53 was accumulated in the necrotic neurons and down-regulation of p53 rescued necrosis. In the SH-SY5Y human cells, tunicamycin (TM), a PERK activator, promoted transcription of hsp27; and necrosis induced by glutamate could be rescued by TM, associated with reduced p53 accumulation. In an ischemic stroke model in rats, p53 protein was also increased, and TM treatment could reduce the p53 accumulation and brain damage.
Graphene microfiber as a scaffold for regulation of neural stem cells differentiation
Authors: Guo Weibo , Qiu Jichuan , Liu Jingquan , Liu Hong
Published: July 2017

We report the cytocompatibility and regulating effects of the nanostructured reduced graphene oxide (rGO) microfibers, which are synthesized through a capillary hydrothermal method, on neural differentiation of neural stem cells (NSCs). Our findings indicate that the flexible, mechanically strong, surface nanoporous, biodegradable, and cytocompatible nanostructured rGO microfibers not only offer a more powerful substrate for NSCs adhesion and proliferation compared with 2D graphene film and tissue cluture plate but also regulate the NSCs differentiation into neurons and form a dense neural network surrounding the microfiber. These results illustrate the great potential of nanostructured rGO microfibers as an artificial neural tissue engineering (NTE) scaffold for nerve regeneration.
Bulk vs. Surface Structure of 3d Metal Impurities in Topological Insulator Bi2Te3
Authors: Leedahl B. , Boukhvalov D. W. , Kurmaev E. Z. , Kukharenko A. , Zhidkov I. S. , Gavrilov N. V. , Cholakh S. O. , Le P. Huu , Luo C. Wei , Moewes A.
Published: July 2017

Topological insulators have become one of the most prominent research topics in materials science in recent years. Specifically, Bi2Te3 is one of the most promising for technological applications due to its conductive surface states and insulating bulk properties. Herein, we contrast the bulk and surface structural environments of dopant ions Cr, Mn, Fe, Co, Ni, and Cu in Bi2Te3 thin films in order to further elucidate this compound. Our measurements show the preferred oxidation state and surrounding crystal environment of each 3d-metal atomic species, and how they are incorporated into Bi2Te3. We show that in each case there is a unique interplay between structural environments, and that it is highly dependant on the dopant atom. Mn impurities in Bi2Te3 purely substitute into Bi sites in a 2+ oxidation state. Cr atoms seem only to reside on the surface and are effectively not able to be absorbed into the bulk. Whereas for Co and Ni, an array of substitutional, interstitial, and metallic configurations occur. Considering the relatively heavy Cu atoms, metallic clusters are highly favourable. The situation with Fe is even more complex, displaying a mix of oxidation states that differ greatly between the surface and bulk environments.
Structural and rheological properties conferring fertilization competence to Xenopus egg-coating envelope
Authors: Hanaue Mayu , Miwa Naofumi
Published: July 2017

The extracellular egg-coating envelope that comprises a meshwork of filaments polymerized by glycoproteins plays a pivotal role in species-selective sperm recognition and subsequent fertilization; however, the structural and rheological properties conferring fertilization competence to the egg-coating envelope remain poorly unveiled. Here we show several nanoscale-structural and viscoelastic properties of the egg-coat using the transmission electron microscopy and the quartz crystal microbalance experiments, following clamp of the egg-coat at either fertilization-competent or -incompetent statuses by short-term pretreatment with synthetic peptides. Individual filament of approximately 4.8 nm diameter crossed one another, forming several types of intersections. Higher competence-inducing treatment changed the proportion of V-, Y-, and T-type intersections, and induced more randomly deflected angles at intersections. Incompetence-inducing treatment increased the median of a Gaussian distribution of filament lengths that had a peak of 10–20 nm under control conditions; furthermore, this treatment created bumps in the 30–40 and 50–60 nm windows. Quartz crystal microbalance study revealed that viscoelasticity of the competent VE suspension was lower than that of incompetent VE, indicating that viscoelastic property required for successful fertilization resides within a specific range. These findings indicated that the architecture of the egg-coat is capable of rapid and dynamic remodeling, which determines fertilization efficiency.