bluuebunny/crossref_metadata_2025 huggingface dataset:
Gestational Diabetes Testing: Making Sense of the Controversy
Authors: Salmeen Kirsten
Published: February 2016

Evidence has demonstrated that even mild increases in maternal blood sugar are associated with worsening pregnancy outcomes, particularly macrosomia, and that reducing blood sugar improves outcomes. Euglycemia can often be achieved with dietary modification and exercise without a need for medication. Despite this evidence, there continues to be controversy over exactly who, when, and how to test for gestational diabetes mellitus (GDM), with various professional organizations and experts in the field suggesting different strategies or not making specific recommendations at all. Potential sources of this controversy may include differences in opinion about the clinical importance of the consequences of GDM and the benefits of available interventions. Further, dichotomously diagnosing disease when the disease‐defining characteristic is linear requires drawing a somewhat arbitrary line in the sand for diagnosis, which is likely to fall in a different place for different providers. Finally, given the resources and effort needed by both women and providers to address GDM, the availability of resources is likely to impact providers’ perspectives on the ideal testing strategy. Given the differences among patient characteristics and available resources that exist in different health care settings, identifying one best strategy for GDM testing is not necessarily appropriate. However, given the potential benefits of identifying pregnant women with hyperglycemia, providers should use the most sensitive testing strategy that their patient population and resources allow.
Parkinson's disease: acid‐glucocerebrosidase activity and alpha‐synuclein clearance
Authors: Blanz Judith , Saftig Paul
Published: February 2016

The role of mutations in the gene GBA1 encoding the lysosomal hydrolase β‐glucocerebrosidase for the development of synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, was only very recently uncovered. The knowledge obtained from the study of carriers or patients suffering from Gaucher disease (a common lysosomal storage disorder because of GBA1 mutations) is of particular importance for understanding the role of the enzyme and its catabolic pathway in the development of synucleinopathies. Decreased activity of β‐glucocerebrosidase leads to lysosomal dysfunction and the accumulation of its substrate glucosylceramide and related lipid derivatives. Glucosylceramide is suggested to stabilize toxic oligomeric forms of α‐synuclein that negatively influence the activity of β‐glucocerebrosidase and to partially block export of newly synthesized β‐glucocerebrosidase from the endoplasmic reticulum to late endocytic compartments, amplifying the pathological effects of α‐synuclein and ultimately resulting in neuronal cell death. This pathogenic molecular feedback loop and most likely other factors (such as impaired endoplasmic reticulum‐associated degradation, activation of the unfolded protein response and dysregulation of calcium homeostasis induced by misfolded GC mutants) are involved in shifting the cellular homeostasis from monomeric α‐synuclein towards oligomeric neurotoxic and aggregated forms, which contribute to Parkinson's disease progression. From a therapeutic point of view, strategies aiming to increase either the expression, stability or delivery of the β‐glucocerebrosidase to lysosomes are likely to decrease the α‐synuclein burden and may be useful for an in depth evaluation at the organismal level.

image

Lysosomes are critical for protein and lipid homeostasis. Recent research revealed that dysfunction of this organelle contributes to the development of neurodegenerative diseases such as Parkinson's disease (PD). Mutations in the lysosomal hydrolase β‐glucocerebrosidase (GBA1) are a major risk factor for the development of PD and the molecular events linked to the reduced activity of GBA1 and the pathological accumulation of lipids and α‐synuclein are just at the beginning to be understood. New therapeutic concepts in regards to how to increase the expression, stability, or delivery of β‐glucocerebrosidase to lysosomes are currently developed.

This article is part of a special issue on Parkinson disease.
Walking the tightrope: proteostasis and neurodegenerative disease
Authors: Yerbury Justin J. , Ooi Lezanne , Dillin Andrew , Saunders Darren N. , Hatters Danny M. , Beart Philip M. , Cashman Neil R. , Wilson Mark R. , Ecroyd Heath
Published: February 2016

A characteristic of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), is the aggregation of specific proteins into protein inclusions and/or plaques in degenerating brains. While much of the aggregated protein consists of disease specific proteins, such as amyloid‐β, α‐synuclein, or superoxide dismutase1 (SOD1), many other proteins are known to aggregate in these disorders. Although the role of protein aggregates in the pathogenesis of neurodegenerative diseases remains unknown, the ubiquitous association of misfolded and aggregated proteins indicates that significant dysfunction in protein homeostasis (proteostasis) occurs in these diseases. Proteostasis is the concept that the integrity of the proteome is in fine balance and requires proteins in a specific conformation, concentration, and location to be functional. In this review, we discuss the role of specific mechanisms, both inside and outside cells, which maintain proteostasis, including molecular chaperones, protein degradation pathways, and the active formation of inclusions, in neurodegenerative diseases associated with protein aggregation.

image

A characteristic of many neurodegenerative diseases is the aggregation of specific proteins, which alone provides strong evidence that protein homeostasis is disrupted in these disease states. Proteostasis is the maintenance of the proteome in the correct conformation, concentration, and location by functional pathways such as molecular chaperones and protein degradation machinery. Here, we discuss the potential roles of quality control pathways, both inside and outside cells, in the loss of proteostasis during aging and disease.
Nurses as Leaders in Disaster Preparedness and Response—A Call to Action
Authors: Veenema Tener Goodwin , Griffin Anne , Gable Alicia R. , MacIntyre Linda , Simons RADM Nadine , Couig Mary Pat , Walsh John J. , Lavin Roberta Proffitt , Dobalian Aram , Larson Elaine
Published: February 2016

Purpose

To develop a vision for the future of disaster nursing, identify barriers and facilitators to achieving the vision, and develop recommendations for nursing practice, education, policy, and research.

Design and Methods

A series of semistructured conference calls were conducted with 14 national subject matter experts to generate relevant concepts regarding national nursing workforce preparedness. An invitational daylong workshop hosted by the Veterans Emergency Management Evaluation Center, U.S. Department of Veterans Affairs, was held in December 2014 to expand and refine these concepts. Workshop participants included 70 nurses, emergency managers, and a broad range of public health professionals. Conference call notes and audiotapes of the workshop were transcribed and thematic analysis conducted to outline a vision for the future of nursing in disaster preparedness and response, and to articulate an agenda for nursing practice, education, policy, and research to achieve that vision.

Findings

The group developed a vision for the future of disaster nursing, and identified current barriers and opportunities to advance professional disaster nursing. A broad array of recommendations for nursing practice, education, policy, and research, as well as implementation challenges, are summarized in this article.

Conclusions

This project represents an important step toward enhancing nurses’ roles as leaders, educators, responders, policymakers, and researchers in disaster preparedness and response. Nurses and the health and human service organizations that employ them are encouraged to engage in an expansive national dialogue regarding how to best incorporate the vision and recommendations into their individual lives and the organizations for which they work.

Clinical Relevance

Nurses comprise the largest healthcare workforce, and opportunities exist to strengthen disaster readiness, enhance national surge capacity, and build community resiliency to disasters.
The adenomatoid odontogenic tumour: an update of selected issues
Authors: Philipsen Hans Peter , Khongkhunthiang Pathawee , Reichart Peter A.
Published: February 2016

The aim of this update was to present the recent notable progress within remaining questions relating to the adenomatoid odontogenic tumour (AOT). Selected issues that were studied included the following: (i) AOT history and terminology, (ii) the so‐called peripheral AOT, (iii) AOT and the gubernaculum dentis and (iv) the so‐called adenomatoid odontogenic cyst (AOC). The earliest irrefutable European case of AOT was described in 1915 by Harbitz as ‘cystic adamantoma’. Recently, Ide et al. have traced two Japanese cases with irrefutable proof described by Nakayama in 1903. The so‐called peripheral (gingival) variant of AOT seems to cover a dual pathogenesis, both an ‘erupted intraosseous’ and an ‘extraosseous’ (gingival) one. In 1992, we theorized that the generally unnoticed gubernaculum dentis (cord and canal) seems to be involved in the development of AOT. Ide et al. have concluded that the dental lamina in the gubernacular cord seems to be an embryonic source of the vast majority of AOTs. The suggestion by Marx and Stern to change the nomenclature of AOT to adenomatoid odontogenic cyst (AOC) is critically discussed. The present authors agree on the background of the work of several groups of researchers and WHO/IARC classifications that the biology of the follicular variant of AOT is already fully explained and does not make room for any change in diagnostic terms. Further, there is no reason to change terminology in this case where improvements or conditions to better clinical management are not an issue.
Congressional Institutionalization: A Cross‐National Comparison
Authors: Palanza Valeria , Scartascini Carlos , Tommasi Mariano
Published: February 2016

This article explains variations in levels of institutionalization across legislatures of the world. It construes institutionalization as an equilibrium outcome that emerges from beliefs and investments made by political actors. Drawing insights from work on US congressional institutionalization and congressional organization, and on comparative party system institutionalization, it provides an index to measure congressional institutionalization. Using this index, it explores the constitutional factors that affect levels of congressional institutionalization. The empirical results raise a warning with respect to building comparative implications from an excessive focus on one particular case.
Tenoumer impact crater, Mauritania: Impact melt genesis from a lithologically diverse target
Authors: Schultze Dina Simona , Jourdan Fred , Hecht Lutz , Reimold Wolf Uwe , Schmitt Ralf‐Thomas
Published: February 2016

Impact melt rocks from the 1.9 km diameter, simple bowl‐shaped Tenoumer impact crater in Mauritania have been analyzed chemically and petrologically. They are heterogeneous and can be subdivided into three types based on melt matrix color, occurrence of lithic clast components, amount of vesiculation (melt degassing), different proportions of carbonate melt mingled into silicate melt, and bulk rock chemical composition. These heterogeneities have two main causes (1) due to the small size of the impact crater, there was probably no coherent melt pool where a homogeneous mixture of melts, derived from different target lithologies, could be created; and (2) melt rock heterogeneity occurring at the thin section scale is due to fast cooling during and after the dynamic ejection and emplacement process. The overall period of crystal growth from these diverse melts was extremely short, which provides a further indication that complete chemical equilibration of the phases could not be achieved in such short time. Melt mixing processes involved in the generation of impact melts are, thus, recorded in nonequilibrium growth features. Variable mixing processes between chemically different melt phases and the formation of hybrid melts can be observed even at millimeter scales. Due to extreme cooling rates, different mixing and mingling stages are preserved in the varied parageneses of matrix minerals and in the mineral chemistry of microlites. 40Ar39Ar step‐heating chronology on specimens from three melt rock samples yielded five concordant inverse isochron ages. The inverse isochron plots show that minute amounts of inherited 40Ar* are present in the system. We calculated a weighted mean age of 1.57 ± 0.14 Ma for these new results. This preferred age represents a refinement from the previous range of 21 ka to 2.5 Ma ages based on K/Ar and fission track dating.
Silencing of the tomato phosphatidylinositol‐phospholipase C2 (SlPLC2) reduces plant susceptibility to Botrytis cinerea
Authors: Gonorazky Gabriela , Guzzo María Carla , Abd‐El‐Haliem Ahmed M. , Joosten Matthieu H.A.J. , Laxalt Ana María
Published: February 2016

The tomato [Solanum lycopersicum (Sl)] phosphatidylinositol‐phospholipase C (PI‐PLC) gene family is composed of six members, named SlPLC1 to SlPLC6, differentially regulated on pathogen attack. We have previously shown that the fungal elicitor xylanase induces a raise of SlPLC2 and SlPLC5 transcripts and that SlPLC2, but not SlPLC5, is required for xylanase‐induced expression of defense‐related genes. In this work we studied the role of SlPLC2 in the interaction between tomato and the necrotrophic fungus Botrytis cinerea. Inoculation of tomato leaves with B. cinerea increases SlPLC2 transcript levels. We knocked‐down the expression of SlPLC2 by virus‐induced gene silencing and plant defense responses were analyzed upon B. cinerea inoculation. SlPLC2 silenced plants developed smaller necrotic lesions concomitantly with less proliferation of the fungus. Silencing of SlPLC2 resulted as well in a reduced production of reactive oxygen species. Upon B. cinerea inoculation, transcript levels of the salicylic acid (SA)‐defense pathway marker gene SlPR1a were diminished in SlPLC2 silenced plants compared to non‐silenced infected plants, while transcripts of the jasmonic acid (JA)‐defense gene markers Proteinase Inhibitor I and II (SlPI‐I and SlPI‐II) were increased. This implies that SlPLC2 participates in plant susceptibility to B. cinerea.
Application of cosmetic nail varnish does not affect the antifungal efficacy of amorolfine 5% nail lacquer in the treatment of distal subungual toenail onychomycosis: results of a randomised active‐controlled study and in vitro assays
Authors: Sigurgeirsson B. , Ghannoum M. A. , Osman‐Ponchet H. , Kerrouche N. , Sidou F.
Published: February 2016

As onychomycosis is unsightly, this study clinically evaluated whether the antifungal efficacy of amorolfine 5% nail lacquer (NL) was affected by a masking, natural‐coloured, cosmetic nail varnish applied 24 h later; in vitro investigations were also performed. Subjects with mild‐to‐moderate distal subungual toenail onychomycosis were randomised to receive amorolfine 5% NL once weekly with or without cosmetic nail varnish applied 24 h later. After 12‐week treatment, antifungal activity of affected toenail clippings was assessed by measurement of zones of inhibition (ZOIs) on Trichophyton mentagrophytes seeded agar plates. Mean diameters were 53.5 mm for the amorolfine 5% NL‐alone group (n = 23) and 53.6 mm for amorolfine 5% NL plus cosmetic nail varnish group (n = 25). Also, mycological cultures of subungual debris at week 12 were negative for all subjects in both groups. Most subjects (88%) reported that cosmetic nail varnish masked their infected toenails. Additionally, cadaver human nails coated in vitro with or without cosmetic nail varnish 10 min or 24 h post amorolfine NL application all gave ZOIs on Trichophyton rubrum agar plates representing potent antifungal activity. In conclusion, cosmetic nail varnish applied post amorolfine had no effect on the subungual antifungal activity of amorolfine 5% NL or its penetration through toenails.
Immunolocalization of AMPA receptor subunits within the enteric nervous system of the mouse colon and the effect of their activation on spontaneous colonic contractions
Authors: Seifi M. , Swinny J. D.
Published: February 2016

Background

The appropriate expression of specific neurotransmitter receptors within the cellular networks that compose the enteric nervous system (ENS) is central to the regulation of gastrointestinal (GI) functions. While the ENS expression patterns of the neurotransmitter glutamate have been well documented, the localization of its receptors on ENS neurons remains to be fully characterized. We investigated the expression patterns of glutamate receptor AMPA subunits within ENS neurons of the mouse colon and the consequences of their pharmacological activation on spontaneous colonic contractility.

Methods

RT‐PCR was used to detect individual AMPA receptor (GluR 1‐4) subunit expression at the mRNA level in mouse colon tissue. Immunohistochemistry and confocal microscopy was used to localize the expression of the GluR1 and 4 subunits in colon tissue. Brain tissue was used as a positive control. Organ bath preparations were used to determine the effect of AMPA receptors activation on the force and frequency of colonic longitudinal smooth muscle spontaneous contractions.

Key Results

GluR1, 3, 4 mRNA was detected in the mouse colon. Immunoreactivity for GluR1 and 4 subunits was detected on the somatic and dendritic surfaces of subpopulations of neurochemically defined ENS neurons. The pharmacological activation of AMPA receptors increased the force but not frequency of spontaneous colonic contractions.

Conclusions & Inferences

Molecularly distinct AMPA receptor subtypes are differentially expressed within the neural networks of the mouse colon and have a direct role in motility. These data provide the rationale for the development of AMPA‐selective ligands for the therapeutic delivery to the GIT in motility disorders.
Radiologic Improvement After Early Medical Intervention in Localised Facial Morphea
Authors: Khan Muhammad Amjad , Shaw Lindsay , Eleftheriou Despina , Prabhakar Prab , Chong Wui K. , Glover Mary
Published: February 2016

We report the case of a young girl who presented with hemiparesis, seizures, and subtle features consistent with a linear form of facial morphea (en coup de sabre). She was treated with pulsed parenteral steroids and oral steroids and started on methotrexate. Magnetic resonance imaging results and neurologic problems improved after 6 months. Switching off inflammation early in the course of disease seemed to reverse some of the central nervous system changes. Assessment of children with unexplained hemiparesis and seizures should include careful examination of the face and scalp, looking for subtle signs of skin change and asymmetry. This is one of the few reported cases of neuroradiologic improvement after immunosuppressive treatment in a child with en coup de sabre.
Transplant related ocular surface disorders: Advanced techniques for ocular surface rehabilitation after ocular complications secondary to hematopoietic stem cell transplantation
Authors: Stahl Erin D. , Mahomed Faheem , Hans Amneet K. , Dalal Jignesh D.
Published: February 2016

HSCT has been linked to the development of an assortment of ocular surface complications with the potential to lead to permanent visual impairment if left untreated or if not treated early in the course of disease. Strategies for therapy include maintenance of lubrication and tear preservation, prevention of evaporation, decreasing inflammation, and providing epithelial support. The ultimate aim of treatment is to prevent permanent ocular sequelae through prompt ophthalmology consultation and the use of advanced techniques for ocular surface rehabilitation. We describe several rehabilitation options of ocular surface complications occurring secondarily during the post‐HSCT course.
Ecological restoration success: a policy analysis understanding
Authors: Baker Susan , Eckerberg Katarina
Published: February 2016

This article discusses how ecological restoration success can be understood and evaluated using a policy analysis lens. First, this article details a conceptual tool that helps to develop a more encompassing set of criteria to assess restoration activities that provide socioeconomic benefits. Second, by broadening the understanding of restoration success and how it can be evaluated, it allows a more critical view of evaluation itself and its uses as a policy tool. A table is presented that can help practitioners reveal preferences and clarify the aims and objectives of particular initiatives. The table also sensitizes practitioners to the complexity of the links between restoration rationales and evaluation criteria, which in turn may open up much needed discussion and dialogue between restoration participants about the underlying values an actor may wish to promote. It heightens awareness of the fact that evaluation methods need to recognize that restoration is driven by multiple rationales often in the same project, both process driven and output oriented, which in turn can change over time. Adding process and output criteria together may also raise issues of priority. Evaluation criteria thus need to be assigned in ways that reflect these multiplicities, while at the same time recognizing that some restoration values might be conflictual and that there may be winners and losers. Furthermore, judgement about “failure” of a project can change as new goals emerge in delivery and implementation. Ecological restoration evaluation should therefore be ongoing, contextual, and not a one‐off event.
Probability Distribution Functions of Freak Waves: Nonlinear Versus Linear Model
Authors: Dyachenko Alexander I. , Kachulin Dmitriy I. , Zakharov Vladimir E.
Published: February 2016

Presented are the results of numerical experiments on calculation of probability distribution functions (PDFs) for surface elevations of water waves arising during the evolution of statistically homogeneous wave field. Extreme waves or freak waves are an integral part of ocean waving, and PDFs are compared both for nonlinear and linear models. Obviously, linear model demonstrates the Rayleigh distribution of surface elevations while PDFs for nonlinear equation have tails for large elevations similar to Rayleigh distribution, but with much larger σ.
Fragile X mental retardation protein controls ion channel expression and activity
Authors: Ferron Laurent
Published: February 2016

Fragile X‐associated disorders are a family of genetic conditions resulting from the partial or complete loss of fragile X mental retardation protein (FMRP). Among these disorders is fragile X syndrome, the most common cause of inherited intellectual disability and autism. FMRP is an RNA‐binding protein involved in the control of local translation, which has pleiotropic effects, in particular on synaptic function. Analysis of the brain FMRP transcriptome has revealed hundreds of potential mRNA targets encoding postsynaptic and presynaptic proteins, including a number of ion channels. FMRP has been confirmed to bind voltage‐gated potassium channels (Kv3.1 and Kv4.2) mRNAs and regulates their expression in somatodendritic compartments of neurons. Recent studies have uncovered a number of additional roles for FMRP besides RNA regulation. FMRP was shown to directly interact with, and modulate, a number of ion channel complexes. The sodium‐activated potassium (Slack) channel was the first ion channel shown to directly interact with FMRP; this interaction alters the single‐channel properties of the Slack channel. FMRP was also shown to interact with the auxiliary β4 subunit of the calcium‐activated potassium (BK) channel; this interaction increases calcium‐dependent activation of the BK channel. More recently, FMRP was shown to directly interact with the voltage‐gated calcium channel, Cav2.2, and reduce its trafficking to the plasma membrane. Studies performed on animal models of fragile X syndrome have revealed links between modifications of ion channel activity and changes in neuronal excitability, suggesting that these modifications could contribute to the phenotypes observed in patients with fragile X‐associated disorders.

image
Superconducting NbTiN thin films for superconducting radio frequency accelerator cavity applications
Authors: Burton Matthew C. , Beebe Melissa R. , Yang Kaida , Lukaszew Rosa A. , Valente-Feliciano Anne-Marie , Reece Charles
Published: February 2016

Current superconducting radio frequency technology, used in various particle accelerator facilities across the world, is reliant upon bulk niobium superconducting cavities. Due to technological advancements in the processing of bulk Nb cavities, the facilities have reached accelerating fields very close to a material-dependent limit, which is close to 50 MV/m for bulk Nb. One possible solution to improve upon this fundamental limitation was proposed a few years ago by Gurevich [Appl. Phys. Lett. 88, 012511 (2006)], consisting of the deposition of alternating thin layers of superconducting and insulating materials on the interior surface of the cavities. The use of type-II superconductors with Tc > TcNb and Hc > HcNb, (e.g., Nb3Sn, NbN, or NbTiN) could potentially greatly reduce the surface resistance (Rs) and enhance the accelerating field, if the onset of vortex penetration is increased above HcNb, thus enabling higher field gradients. Although Nb3Sn may prove superior, it is not clear that it can be grown as a suitable thin film for the proposed multilayer approach, since very high temperature is typically required for its growth, hindering achieving smooth interfaces and/or surfaces. On the other hand, since NbTiN has a smaller lower critical field (Hc1) and higher critical temperature (Tc) than Nb and increased conductivity compared to NbN, it is a promising candidate material for this new scheme. Here, the authors present experimental results correlating film microstructure with superconducting properties on NbTiN thin film coupon samples while also comparing films grown with targets of different stoichiometry. It is worth mentioning that the authors have achieved thin films with bulk-like lattice parameter and transition temperature while also achieving Hc1 values larger than bulk for films thinner than their London penetration depths.
Stress-dependent ultrasonic scattering in polycrystalline materials
Authors: Kube Christopher M. , Turner Joseph A.
Published: February 2016

Stress-dependent elastic moduli of polycrystalline materials are used in a statistically based model for the scattering of ultrasonic waves from randomly oriented grains that are members of a stressed polycrystal. The stress is assumed to be homogeneous and can be either residual or generated from external loads. The stress-dependent elastic properties are incorporated into the definition of the differential scattering cross-section, which defines how strongly an incident wave is scattered into various directions. Nine stress-dependent differential scattering cross-sections or scattering coefficients are defined to include all possibilities of incident and scattered waves, which can be either longitudinal or (two) transverse wave types. The evaluation of the scattering coefficients considers polycrystalline aluminum that is uniaxially stressed. An analysis of the influence of incident wave propagation direction, scattering direction, frequency, and grain size on the stress-dependency of the scattering coefficients follows. Scattering coefficients for aluminum indicate that ultrasonic scattering is much more sensitive to a uniaxial stress than ultrasonic phase velocities. By developing the stress-dependent scattering properties of polycrystals, the influence of acoustoelasticity on the amplitudes of waves propagating in stressed polycrystalline materials can be better understood. This work supports the ongoing development of a technique for monitoring and measuring stresses in metallic materials.
Structural basis for histone H2B deubiquitination by the SAGA DUB module
Authors: Morgan Michael T. , Haj-Yahya Mahmood , Ringel Alison E. , Bandi Prasanthi , Brik Ashraf , Wolberger Cynthia
Published: February 2016

The SAGA of removing nucleosomal ubiquitin

Covalent modifications of histones play a critical role in gene regulation. The addition of the small protein ubiquitin to histone H2B in nucleosomes is a mark of actively transcribed chromatin. Morgan
et al.
determined the crystal structure of a nucleosome bound by a module of the SAGA protein complex that removes ubiquitin from histone H2B (see the Perspective by Workman). The structure suggests that the deubiquitinating module can remove ubiquitin at multiple points during the transcription cycle.

Science
, this issue p.
725
; see also p.
667
Spatial colocalization and functional link of purinosomes with mitochondria
Authors: French Jarrod B. , Jones Sara A. , Deng Huayun , Pedley Anthony M. , Kim Doory , Chan Chung Yu , Hu Haibei , Pugh Raymond J. , Zhao Hong , Zhang Youxin , Huang Tony Jun , Fang Ye , Zhuang Xiaowei , Benkovic Stephen J.
Published: February 2016

Spatial control of cellular enzymes

Purine is a building block of DNA and also a component of ATP that is used as an energy source in the cell. Enzymes involved in purine biosynthesis organize into dynamic bodies called purinosomes. French
et al.
found that purinosomes colocalize with mitochondria, organelles that generate ATP (see the Perspective by Ma and Jones). Dysregulation of mitochondria caused an increase in the number of purinosomes. This suggests a synergy, with the purinosomes supplying the purine required for ATP production and in turn using ATP in the biosynthetic pathway. A master regulator of cellular metabolism, mTOR, appears to mediate the association of purinosomes and mitochondria. This could make purine and ATP synthesis responsive to changes in the metabolic needs of the cell.

Science
, this issue p.
733
; see also p.
670
Retrotransposons as regulators of gene expression
Authors: Elbarbary Reyad A. , Lucas Bronwyn A. , Maquat Lynne E.
Published: February 2016

Parasitic DNAs help and hinder evolution

Transposable elements are parasitic DNAs that can duplicate themselves and jump around their host genomes. They can both disrupt gene function and drive genome evolution. Elbarbary
et al.
review the roles of two classes of transposable elements in gene regulation and disease: long interspersed elements (LINEs) and short interspersed elements (SINEs). Roughly a third of the human genome consists of LINEs and SINEs. They contribute to a broad range of important genome and gene regulatory features, while at the same time being responsible for number of human diseases.

Science
, this issue p.
10.1126/science.aac7247
Observation of the Dirac fluid and the breakdown of the Wiedemann-Franz law in graphene
Authors: Crossno Jesse , Shi Jing K. , Wang Ke , Liu Xiaomeng , Harzheim Achim , Lucas Andrew , Sachdev Subir , Kim Philip , Taniguchi Takashi , Watanabe Kenji , Ohki Thomas A. , Fong Kin Chung
Published: February 2016

Electrons that flow like a fluid

Electrons inside a conductor are often described as flowing in response to an electric field. This flow rarely resembles anything like the familiar flow of water through a pipe, but three groups describe counterexamples (see the Perspective by Zaanen). Moll
et al.
found that the viscosity of the electron fluid in thin wires of PdCoO
2
had a major effect on the flow, much like what happens in regular fluids. Bandurin
et al.
found evidence in graphene of electron whirlpools similar to those formed by viscous fluid flowing through a small opening. Finally, Crossno
et al.
observed a huge increase of thermal transport in graphene, a signature of so-called Dirac fluids.

Science
, this issue p.
1061
,
1055
,
1058
; see also p.
1026
The phenotypic legacy of admixture between modern humans and Neandertals
Authors: Simonti Corinne N. , Vernot Benjamin , Bastarache Lisa , Bottinger Erwin , Carrell David S. , Chisholm Rex L. , Crosslin David R. , Hebbring Scott J. , Jarvik Gail P. , Kullo Iftikhar J. , Li Rongling , Pathak Jyotishman , Ritchie Marylyn D. , Roden Dan M. , Verma Shefali S. , Tromp Gerard , Prato Jeffrey D. , Bush William S. , Akey Joshua M. , Denny Joshua C. , Capra John A.
Published: February 2016

The legacy of human-Neandertal interbreeding

Non-African humans are estimated to have inherited on average 1.5 to 4% of their genomes from Neandertals. However, how this genetic legacy affects human traits is unknown. Simonti
et al.
combined genotyping data with electronic health records. Individual Neandertal alleles were correlated with clinically relevant phenotypes in individuals of European descent. These archaic genetic variants were associated with medical conditions affecting the skin, the blood, and the risk of depression.

Science
, this issue p.
737
Using decoys to expand the recognition specificity of a plant disease resistance protein
Authors: Kim Sang Hee , Qi Dong , Ashfield Tom , Helm Matthew , Innes Roger W.
Published: February 2016

Improving plant disease responses

Disease resistance in plants depends on genes that allow them to recognize when they are infected by a pathogen so that they can mount a timely defense response. Unfortunately, pathogens can often overcome endogenous disease resistance genes by evolving new virulence strategies that escape detection. Kim
et al.
modified the pathogen recognition systems in the model plant
Arabidopsis thaliana
to widen its reach. The approach should enable the development of crops with more durable disease resistance and hence reduce pesticide use and increase crop yields.

Science
, this issue p.
684
Asymmetric copper-catalyzed C-N cross-couplings induced by visible light
Authors: Kainz Quirin M. , Matier Carson D. , Bartoszewicz Agnieszka , Zultanski Susan L. , Peters Jonas C. , Fu Gregory C.
Published: February 2016

Copper's light touch forges C-N bonds

Organic photochemistry has traditionally relied on excitation in the ultraviolet, where carbon-based compounds tend to absorb. Over the past decade, the field has undergone a renaissance as compounds that absorb visible light have proven to be versatile catalysts for organic reactions. For the most part, however, these catalysts have contained rare metals such as ruthenium or iridium. Kainz
et al.
now report a blue light-driven C-N bond-forming reaction catalyzed by Earth-abundant copper (see the Perspective by Greaney). Through coordination to a chiral ligand, the copper center couples alkyl chlorides to indoles and carbazoles with a high degree of enantioselectivity.

Science
, this issue p.
681
; see also p.
666
Copper catalysis in a blue light
Authors: Greaney Michael F.
Published: February 2016

Visible light, copper, and a phosphine ligand combine for C-N bond formation at fully substituted chiral centers

[Also see Report by

Kainz
et al.

]
Complete Coding Sequences of Three Toscana Virus Strains Isolated from Sandflies in France
Authors: Baklouti Amal , Leparc Goffard Isabelle , Piorkowski Geraldine , Coutard Bruno , Papageorgiou Nicolas , De Lamballerie Xavier , Charrel Rémi N.
Published: February 2016

Toscana virus (TOSV) is an arthropod-borne virus belonging to the sandfly fever Naples virus species within the genus
Phlebovirus
. We report here the complete coding sequences of three TOSV strains belonging to lineage B and isolated from sandflies trapped in the Southeast of France between 2009 and 2013.
Direct Visualization of Ebola Virus Fusion Triggering in the Endocytic Pathway
Authors: Spence Jennifer S. , Krause Tyler B. , Mittler Eva , Jangra Rohit K. , Chandran Kartik
Published: February 2016

Ebola virus (EBOV) makes extensive and intricate use of host factors in the cellular endosomal/lysosomal pathway to release its genome into the cytoplasm and initiate infection. Following viral internalization into endosomes, host cysteine proteases cleave the EBOV fusion glycoprotein (GP) to unmask the binding site for its intracellular receptor, the cholesterol transporter Niemann-Pick C1 (NPC1). GP-NPC1 interaction is required for viral entry. Despite these and other recent discoveries, late events in EBOV entry following GP-NPC1 binding and culminating in GP-catalyzed fusion between viral and cellular lipid bilayers remain enigmatic. A mechanistic understanding of EBOV membrane fusion has been hampered by the failure of previous efforts to reconstitute fusion
in vitro
or at the cell surface. This report describes an assay to monitor initial steps directly in EBOV membrane fusion—triggering of GP and virus-cell lipid mixing—by single virions in live cells. Fusogenic triggering of GP occurs predominantly in Rab7-positive (Rab7
+
) endosomes, absolutely requires interaction between proteolytically primed GP and NPC1, and is blocked by key GP-specific neutralizing antibodies with therapeutic potential. Unexpectedly, cysteine protease inhibitors do not inhibit lipid mixing by virions bearing precleaved GP, even though they completely block cytoplasmic entry by these viruses, as shown previously. These results point to distinct cellular requirements for different steps in EBOV membrane fusion and suggest a model in which host cysteine proteases are dispensable for GP fusion triggering after NPC1 binding but are required for the formation of fusion pores that permit genome delivery.

IMPORTANCE
Ebola virus (EBOV) causes outbreaks of highly lethal disease for which no approved vaccines or treatments exist. Recent work has elucidated key molecular features of the complex EBOV entry process, including stepwise interactions with multiple host factors. However, there is a critical gap in our understanding of events that surround the final membrane fusion step which persists due to the paucity of direct and extensive investigation of EBOV fusion. Here, we report a real-time assay for EBOV glycoprotein fusion triggering and use it to define its cellular location and requirements. We also uncover an unexpected requirement for host proteases at a step after fusion triggering that may reflect their role in formation of fusion pores for genome delivery.
Adiposity and response to an obesity prevention intervention in Pakistani and Bangladeshi primary school boys and girls: a secondary analysis using the BEACHeS feasibility study
Authors: Cezard Geneviève , Bansal Narinder , Bhopal Raj , Pallan Miranda , Gill Paramjit , Barrett Timothy , Adab Peymane
Published: February 2016

Objectives

As a secondary analysis of the BEACHeS study, we hypothesised there would be sex differences in Pakistani and Bangladeshi school children when examining adiposity and their response to an obesity intervention.

Design

The Birmingham healthy Eating and Active lifestyle for CHildren Study (BEACHeS) was designed as a Phase II feasibility study of a complex intervention.

Setting

8 primary schools with predominantly South Asian children in Birmingham, UK

Participants

1090 pupils (aged 5–7 years old) from school year 1 and 2 were allocated at school level to receive an intervention. A total of 574 were enrolled in the study with consent. We focused on the 466 children of Pakistani and Bangladeshi origin (50.6% boys).

Intervention

Delivered between 2007 and 2009, the 1-year obesity prevention intervention targeted school and family-based dietary and physical activities.

Primary and secondary outcome measures and analysis

Adiposity measures including skinfold thickness were compared by sex at baseline and follow-up. Gains in adiposity measures were compared between control and intervention arms in boys and in girls. Measures were compared using two-sample t tests and Wilcoxon-Mann-Whitney rank sum tests according to normality distribution.

Results

At baseline, girls had larger skinfold measures at all sites compared to boys although body mass index (BMI) was similar (eg, median subscapular skinfold 6.6 mm vs 5.7 mm; p<0.001). At follow-up, girls in the intervention group gained less weight and adiposity compared to respective controls (p<0.05 for weight, BMI, waist circumference, central and thigh skinfold) with a median total skinfold gain of 7.0 mm in the control group compared to 0.3 mm in the intervention group.

Conclusions

Our secondary analysis suggests differences in adiposity in Pakistani and Bangladeshi girls and boys and in the effect of the intervention reducing adiposity in girls. These preliminary findings indicate that including sex differences should be examined in future trials.

Trial registration number

ISRCTN51016370; Post-results.
Association of ACE gene D polymorphism with left ventricular hypertrophy in patients with diastolic heart failure: a case–control study
Authors: Bahramali Ehsan , Rajabi Mona , Jamshidi Javad , Mousavi Seyyed Mohammad , Zarghami Mehrdad , Manafi Alireza , Firouzabadi Negar
Published: February 2016

Objectives

To explore the association between ACE gene insertion/deletion (I/D) polymorphism with left ventricular hypertrophy (LVH) in patients with hypertension who have developed heart failure with preserved ejection fraction (HFpEF). Being a major contributor to the development of diastolic heart dysfunction, the renin angiotensin aldosterone system and its genetic variations are thought to induce LVH in hypertensive hearts apart from haemodynamic factors.

Design

Case control study.

Setting

An Iranian referral university hospital.

Participants

176 patients with hypertension and a diagnosis of HFpEF on presence of symptoms of heart failure plus Doppler echocardiographic documentation of left ventricular (LV) diastolic dysfunction and/or elevated NT-proBNP levels. Those with significant coronary, valvular, pericardial and structural heart diseases were excluded as well as patients with atrial fibrillation, renal failure and pulmonary causes of dyspnoea. They were divided into two cohorts of 88 cases with and 88 controls without LVH, after determination of LV mass index, using two-dimensional and M-mode echocardiography. The I/D polymorphism of theACEgene was determined using the PCR method.

Results

The D allele was significantly more prevalent among cases with compared with controls without LVH (p=0.0007). Genotype distributions also differed significantly under additive (p=0.005, OR=0.53, 95% CI 0.34 to 0.84) and recessive (p=0.001, OR=0.29, 95% CI 0.13 to 0.66) models.

Conclusions

In patients with hypertension who develop HFpEF, the D allele of theACEgene is probably associated with the development of LVH. With the detrimental effects of LVH on the heart's diastolic properties, this can signify the role of genetic contributors to the development of HFpEF in patients with hypertension and may serve as a future risk predictor for the disease.
Utilisation of helicopter emergency medical services in the early medical response to major incidents: a systematic literature review
Authors: Johnsen Anne Siri , Fattah Sabina , Sollid Stephen J M , Rehn Marius
Published: February 2016

Objective

This systematic review identifies, describes and appraises the literature describing the utilisation of helicopter emergency medical services (HEMS) in the early medical response to major incidents.

Setting

Early prehospital phase of a major incident.

Design

Systematic literature review performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Web of Science, PsycINFO, Scopus, Cinahl, Bibsys Ask, Norart, Svemed and UpToDate were searched using phrases that combined HEMS and ‘major incidents’ to identify when and how HEMS was utilised. The identified studies were subjected to data extraction and appraisal.

Results

The database search identified 4948 articles. Based on the title and abstract, the full text of 96 articles was obtained; of these, 37 articles were included in the review, and an additional five were identified by searching the reference lists of the 37 articles. HEMS was used to transport medical and rescue personnel to the incident and to transport patients to the hospital, especially when the infrastructure was damaged. Insufficient air traffic control, weather conditions, inadequate landing sites and failing communication were described as challenging in some incidents.

Conclusions

HEMS was used mainly for patient treatment and to transport patients, personnel and equipment in the early medical management of major incidents, but the optimal utilisation of this specialised resource remains unclear. This review identified operational areas with improvement potential. A lack of systematic indexing, heterogeneous data reporting and weak methodological design, complicated the identification and comparison of incidents, and more systematic reporting is needed.

Trial registration number

CRD42013004473.
Drinking patterns of adolescents who develop alcohol use disorders: results from the Victorian Adolescent Health Cohort Study
Authors: Olsson Craig A , Romaniuk Helena , Salinger Jodi , Staiger Petra K , Bonomo Yvonne , Hulbert Carol , Patton George C
Published: February 2016

Objective

We identify drinking styles that place teens at greatest risk of later alcohol use disorders (AUD).

Design

Population-based cohort study.

Setting

Victoria, Australia.

Participants

A representative sample of 1943 adolescents living in Victoria in 1992.

Outcome measures

Teen drinking was assessed at 6 monthly intervals (5 waves) between mean ages 14.9 and 17.4 years and summarised across waves as none, one, or two or more waves of: (1)frequent drinking(3+ days in the past week), (2)loss of control over drinking(difficulty stopping, amnesia), (3)binge drinking(5+ standard drinks in a day) and (4)heavy binge drinking(20+ and 11+ standard drinks in a day for males and females, respectively). Young Adult Alcohol Use Disorder (AUD) was assessed at 3 yearly intervals (3 waves) across the 20s (mean ages 20.7 through 29.1 years).

Results

We show that patterns of teen drinking characterised by loss of control increase risk for AUD across young adulthood:loss of control over drinking(one wave OR 1.4, 95% CI 1.1 to 1.8; two or more waves OR 1.9, CI 1.4 to 2.7);binge drinking(one wave OR 1.7, CI 1.3 to 2.3; two or more waves OR 2.0, CI 1.5 to 2.6), andheavy binge drinking(one wave OR 2.0, CI 1.4 to 2.8; two or more waves OR 2.3, CI 1.6 to 3.4). This is not so for frequent drinking, which was unrelated to later AUD. Although drinking was more common in males, there was no evidence of sex differences in risk relationships.

Conclusions

Our results extend previous work by showing that patterns of drinking that represent loss of control over alcohol consumption (however expressed) are important targets for intervention. In addition to current policies that may reduce overall consumption, emphasising prevention of more extreme teenage bouts of alcohol consumption appears warranted.
Challenges of a PhD
Authors: Hill Myfanwy
Published: February 2016

While Myfanwy Hill's PhD studies pose an ‘enjoyable challenge’, she has found that learning to manage her time and studies requires a new level of self discipline