bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of a dielectric phantom for high‐field magnetic resonance imaging applications
Authors: Duan Qi , Duyn Jeff H. , Gudino Natalia , de Zwart Jacco A. , van Gelderen Peter , Sodickson Daniel K. , Brown Ryan
Published: September 2014

Purpose:

In this work, a generic recipe for an inexpensive and nontoxic phantom was developed within a range of biologically relevant dielectric properties from 150 MHz to 4.5 GHz.

Methods:

The recipe includes deionized water as the solvent, NaCl to primarily control conductivity, sucrose to primarily control permittivity, agar–agar to gel the solution and reduce heat diffusivity, and benzoic acid to preserve the gel. Two hundred and seventeen samples were prepared to cover the feasible range of NaCl and sucrose concentrations. Their dielectric properties were measured using a commercial dielectric probe and were fitted to a 3D polynomial to generate a recipe describing the properties as a function of NaCl concentration, sucrose concentration, and frequency.

Results:

Results indicated that the intuitive linear and independent relationships between NaCl and conductivity and between sucrose and permittivity are not valid. A generic polynomial recipe was developed to characterize the complex relationship between the solutes and the resulting dielectric values and has been made publicly available as a web application. In representative mixtures developed to mimic brain and muscle tissue, less than 2% difference was observed between the predicted and measured conductivity and permittivity values.

Conclusions:

It is expected that the recipe will be useful for generating dielectric phantoms for general magnetic resonance imaging (MRI) coil development at high magnetic field strength, including coil safety evaluation as well as pulse sequence evaluation (including mapping, shimming, and selective excitation pulse design), and other non‐MRI applications which require biologically equivalent dielectric properties.
Denoising of B1+ field maps for noise‐robust image reconstruction in electrical properties tomography
Authors: Michel Eric , Hernandez Daniel , Cho Min Hyoung , Lee Soo Yeol
Published: September 2014

Purpose:

To validate the use of adaptive nonlinear filters in reconstructing conductivity and permittivity images from the noisy maps in electrical properties tomography (EPT).

Methods:

In EPT, electrical property images are computed by taking Laplacian of the maps. To mitigate the noise amplification in computing the Laplacian, the authors applied adaptive nonlinear denoising filters to the measured complex maps. After the denoising process, they computed the Laplacian by central differences. They performed EPT experiments on phantoms and a human brain at 3 T along with corresponding EPT simulations on finite‐difference time‐domain models. They evaluated the EPT images comparing them with the ones obtained by previous EPT reconstruction methods.

Results:

In both the EPT simulations and experiments, the nonlinear filtering greatly improved the EPT image quality when evaluated in terms of the mean and standard deviation of the electrical property values at the regions of interest. The proposed method also improved the overall similarity between the reconstructed conductivity images and the true shapes of the conductivity distribution.

Conclusions:

The nonlinear denoising enabled us to obtain better‐quality EPT images of the phantoms and the human brain at 3 T.
Motion management during IMAT treatment of mobile lung tumors—A comparison of MLC tracking and gated delivery
Authors: Falk Marianne , Pommer Tobias , Keall Paul , Korreman Stine , Persson Gitte , Poulsen Per , Munck af Rosenschöld Per
Published: September 2014

Purpose:

To compare real‐time dynamic multileaf collimator (MLC) tracking, respiratory amplitude and phase gating, and no compensation for intrafraction motion management during intensity modulated arc therapy (IMAT).

Methods:

Motion management with MLC tracking and gating was evaluated for four lung cancer patients. The IMAT plans were delivered to a dosimetric phantom mounted onto a 3D motion phantom performing patient‐specific lung tumor motion. The MLC tracking system was guided by an optical system that used stereoscopic infrared (IR) cameras and five spherical reflecting markers attached to the dosimetric phantom. The gated delivery used a duty cycle of 35% and collected position data using an IR camera and two reflecting markers attached to a marker block.

Results:

The average gamma index failure rate (2% and 2 mm criteria) was <0.01% with amplitude gating for all patients, and <0.1% with phase gating and <3.7% with MLC tracking for three of the four patients. One of the patients had an average failure rate of 15.1% with phase gating and 18.3% with MLC tracking. With no motion compensation, the average gamma index failure rate ranged from 7.1% to 46.9% for the different patients. Evaluation of the dosimetric error contributions showed that the gated delivery mainly had errors in target localization, while MLC tracking also had contributions from MLC leaf fitting and leaf adjustment. The average treatment time was about three times longer with gating compared to delivery with MLC tracking (that did not prolong the treatment time) or no motion compensation. For two of the patients, the different motion compensation techniques allowed for approximately the same margin reduction but for two of the patients, gating enabled a larger reduction of the margins than MLC tracking.

Conclusions:

Both gating and MLC tracking reduced the effects of the target movements, although the gated delivery showed a better dosimetric accuracy and enabled a larger reduction of the margins in some cases. MLC tracking did not prolong the treatment time compared to delivery with no motion compensation while gating had a considerably longer delivery time. In a clinical setting, the optical monitoring of the patients breathing would have to be correlated to the internal movements of the tumor.
mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity
Authors: Cheng Shih-Chin , Quintin Jessica , Cramer Robert A. , Shepardson Kelly M. , Saeed Sadia , Kumar Vinod , Giamarellos-Bourboulis Evangelos J. , Martens Joost H. A. , Rao Nagesha Appukudige , Aghajanirefah Ali , Manjeri Ganesh R. , Li Yang , Ifrim Daniela C. , Arts Rob J. W. , van der Veer Brian M. J. W. , Deen Peter M. T. , Logie Colin , O’Neill Luke A. , Willems Peter , van de Veerdonk Frank L. , van der Meer Jos W. M. , Ng Aylwin , Joosten Leo A. B. , Wijmenga Cisca , Stunnenberg Hendrik G. , Xavier Ramnik J. , Netea Mihai G.
Published: September 2014

A BLUEPRINT of immune cell development

To determine the epigenetic mechanisms that direct blood cells to develop into the many components of our immune system, the BLUEPRINT consortium examined the regulation of DNA and RNA transcription to dissect the molecular traits that govern blood cell differentiation. By inducing immune responses, Saeed
et al.
document the epigenetic changes in the genome that underlie immune cell differentiation. Cheng
et al.
demonstrate that trained monocytes are highly dependent on the breakdown of sugars in the presence of oxygen, which allows cells to produce the energy needed to mount an immune response. Chen
et al.
examine RNA transcripts and find that specific cell lineages use RNA transcripts of different length and composition (isoforms) to form proteins. Together, the studies reveal how epigenetic effects can drive the development of blood cells involved in the immune system.

Science
, this issue
10.1126/science.1251086
,
10.1126/science.1250684
,
10.1126/science.1251033
Transcriptional diversity during lineage commitment of human blood progenitors
Authors: Chen Lu , Kostadima Myrto , Martens Joost H. A. , Canu Giovanni , Garcia Sara P. , Turro Ernest , Downes Kate , Macaulay Iain C. , Bielczyk-Maczynska Ewa , Coe Sophia , Farrow Samantha , Poudel Pawan , Burden Frances , Jansen Sjoert B. G. , Astle William J. , Attwood Antony , Bariana Tadbir , de Bono Bernard , Breschi Alessandra , Chambers John C. ,   BRIDGE Consortium, Choudry Fizzah A. , Clarke Laura , Coupland Paul , van der Ent Martijn , Erber Wendy N. , Jansen Joop H. , Favier Rémi , Fenech Matthew E. , Foad Nicola , Freson Kathleen , van Geet Chris , Gomez Keith , Guigo Roderic , Hampshire Daniel , Kelly Anne M. , Kerstens Hindrik H. D. , Kooner Jaspal S. , Laffan Michael , Lentaigne Claire , Labalette Charlotte , Martin Tiphaine , Meacham Stuart , Mumford Andrew , Nürnberg Sylvia T. , Palumbo Emilio , van der Reijden Bert A. , Richardson David , Sammut Stephen J. , Slodkowicz Greg , Tamuri Asif U. , Vasquez Louella , Voss Katrin , Watt Stephen , Westbury Sarah , Flicek Paul , Loos Remco , Goldman Nick , Bertone Paul , Read Randy J. , Richardson Sylvia , Cvejic Ana , Soranzo Nicole , Ouwehand Willem H. , Stunnenberg Hendrik G. , Frontini Mattia , Rendon Augusto
Published: September 2014

A BLUEPRINT of immune cell development

To determine the epigenetic mechanisms that direct blood cells to develop into the many components of our immune system, the BLUEPRINT consortium examined the regulation of DNA and RNA transcription to dissect the molecular traits that govern blood cell differentiation. By inducing immune responses, Saeed
et al.
document the epigenetic changes in the genome that underlie immune cell differentiation. Cheng
et al.
demonstrate that trained monocytes are highly dependent on the breakdown of sugars in the presence of oxygen, which allows cells to produce the energy needed to mount an immune response. Chen
et al.
examine RNA transcripts and find that specific cell lineages use RNA transcripts of different length and composition (isoforms) to form proteins. Together, the studies reveal how epigenetic effects can drive the development of blood cells involved in the immune system.

Science
, this issue
10.1126/science.1251086
,
10.1126/science.1250684
,
10.1126/science.1251033
Whose conservation?
Authors: Mace Georgina M.
Published: September 2014

Changes in the perception and goals of nature conservation require a solid scientific basis
Environmental filtering explains variation in plant diversity along resource gradients
Authors: Laliberté Etienne , Zemunik Graham , Turner Benjamin L.
Published: September 2014

How plant species diversity is shaped

Factors controlling plant species diversity have been teased apart in an ancient dune ecosystem in western Australia. Laliberté
et al.
surveyed plants in the ancient dune, where variation in soil properties is associated with changes in plant diversity. Local plant diversity was mostly determined by environmental filtering from the regional species pool. This process is driven by acidification during long-term soil formation. The findings challenge the prevailing view that resource competition controls local plant diversity.

Science
, this issue p.
1602
Early Levallois technology and the Lower to Middle Paleolithic transition in the Southern Caucasus
Authors: Adler D. S. , Wilkinson K. N. , Blockley S. , Mark D. F. , Pinhasi R. , Schmidt-Magee B. A. , Nahapetyan S. , Mallol C. , Berna F. , Glauberman P. J. , Raczynski-Henk Y. , Wales N. , Frahm E. , Jöris O. , MacLeod A. , Smith V. C. , Cullen V. L. , Gasparian B.
Published: September 2014

An early assemblage of obsidian artifacts

Levallois technology is the name for the stone knapping technique used to create tools thousands of years ago. The technique appeared in the archeological record across Eurasia 200 to 300 thousand years ago (ka) and appeared earlier in Africa. Adler
et al.
challenge the hypothesis that the technique's appearance in Eurasia was the result of the expansion of hominins from Africa. Levallois obsidian artifacts in the southern Caucasus, dated at 335 to 325 ka, are the oldest in Eurasia. This suggests that Levallois technology may have evolved independently in different hominin populations. Stone technology cannot thus be used as a reliable indicator of Paleolithic human population change and expansion.

Science
, this issue p.
1609
The ancient heritage of water ice in the solar system
Authors: Cleeves L. Ilsedore , Bergin Edwin A. , Alexander Conel M. O’D. , Du Fujun , Graninger Dawn , Öberg Karin I. , Harries Tim J.
Published: September 2014

Nature or nurture for solar system ices?

We know that life's favorite molecule, water, exists throughout the solar system. What we don't know is whether present water levels reflect the chemical conditions of our parent nebula or whether they result from later reprocessing in the young system. The levels of deuterium and hydrogen in solar system water ice offer a tracer for chemical history, and Cleeves
et al.
model the processes at play. The analysis suggests that all nascent planetary systems may have the same water resources that we did.

Science
, this issue p.
1590
Water photolysis at 12.3% efficiency via perovskite photovoltaics and Earth-abundant catalysts
Authors: Luo Jingshan , Im Jeong-Hyeok , Mayer Matthew T. , Schreier Marcel , Nazeeruddin Mohammad Khaja , Park Nam-Gyu , Tilley S. David , Fan Hong Jin , Grätzel Michael
Published: September 2014

The power of a pair of perovskites

In the past several years, perovskite solar cells have emerged as a low-cost experimental alternative to more traditional silicon devices. Luo
et al.
now show that a pair of perovskite cells connected in series can power the electrochemical breakdown of water into hydrogen and oxygen efficiently (see the Perspective by Hamann). Hydrogen generation from water is being actively studied as a supplement in solar power generation to smooth out the fluctuations due to variations in sunlight.

Science
, this issue p.
1593
; see also p.
1566
Perovskites take lead in solar hydrogen race
Authors: Hamann Thomas
Published: September 2014

Earth-abundant materials show promise for solar hydrogen production

[Also see Report by

Luo
et al.

]
Culturing human cells: Optimizing growth conditions for immunotherapy
Authors: Cooper Laurence J. N. , Janas Michelle
Published: September 2014

Growing human cells in culture for research is one thing, but the isolation and culture of high-quality cells that will be re-injected back into the donor is quite another. Manipulation and expansion of cells in a clinical setting carries its own unique requirements and complications. Growth and survival needs to be optimized and quality control is paramount. Often only a single opportunity for successful treatment is possible, so chances of success need to be maximized in all respects, including high-yield isolation of good quality cells from patients, cell culture conditions, cell characterization, and reperfusion back into patients. During this webinar, we will broadly examine the process of immunotherapy as well as examine in more detail some of the most critical steps along the pathway to generating a therapeutic dose of modified cells.
Tenosynovitis Caused by a Novel Nontuberculous Mycobacterium Species Initially Misidentified as a Member of the Mycobacterium tuberculosis Complex
Authors: Simner Patricia J. , Hyle Emily P. , Buckwalter Seanne P. , Branda John A. , Brown-Elliott Barbara A. , Franklin Jameelah , Toney Nadege C. , de Man Tom J. B. , Wallace Richard J. , Vasireddy Ravikiran , Gandhi Rajesh T. , Wengenack Nancy L.
Published: September 2014

We present a case of tenosynovitis caused by a novel, slowly growing, nonchromogenic, nontuberculous mycobacterium (NTM). Originally misidentified as
Mycobacterium tuberculosis
complex, the NTM cross-reacts with the
M. tuberculosis
complex nucleic acid hybridization probe, a
M. tuberculosis
gamma interferon release assay, and is closely related to
M. tuberculosis
by 16S rRNA gene sequencing.
Suppressors of Cytokine Signaling 1 and 3 Are Upregulated in Brain Resident Cells in Response to Virus-Induced Inflammation of the Central Nervous System via at Least Two Distinctive Pathways
Authors: Steffensen Maria Abildgaard , Fenger Christina , Christensen Jeanette Erbo , Jørgensen Carina Krogsgaard , Bassi Maria Rosaria , Christensen Jan Pravsgaard , Finsen Bente , Thomsen Allan Randrup
Published: September 2014

Suppressors of cytokine signaling (SOCS) proteins are intracellular proteins that inhibit cytokine signaling in a variety of cell types. A number of viral infections have been associated with SOCS upregulation; however, not much is known about the mechanisms regulating SOCS expression during viral infection. In this study, we used two pathologically distinct intracerebral (i.c.) infection models to characterize temporal and spatial aspects of SOCS expression in the virus-infected central nervous system (CNS), and by employing various knockout mouse models, we sought to identify regulatory mechanisms that may underlie a virus induced upregulation of SOCS in the CNS. We found that i.c. infection with either lymphocytic choriomeningitis virus (LCMV) or yellow fever virus (YF) results in gradual upregulation of SOCS1/3 mRNA expression peaking at day 7 postinfection (p.i.). In the LCMV model, SOCS mRNA was expressed in brain resident cells, including astrocytes and some neurons, and for SOCS1 in particular this upregulation was almost entirely mediated by gamma interferon (IFN-γ) produced by infiltrating T cells. After infection with YF, we also found SOCS expression to be upregulated in brain resident cells with a peak on day 7 p.i., but in this model, the upregulation was only partially dependent on IFN-γ and T cells, indicating that at least one other mediator was involved in the upregulation of SOCS following YF infection. We conclude that virus-induced inflammation of the CNS is associated with upregulation of SOCS1/3 mRNA expression in brain resident cells and that at least two distinctive pathways can lead to this upregulation.

IMPORTANCEIn the present report, we have studied the induction of SOCS1 and SOCS3 expression in the context of virus-induced CNS infection. We found that both a noncytolytic and a cytolytic virus induce marked upregulation of SOCS1 and -3 expression. Notably, the kinetics of the observed upregulation follows that of activity within proinflammatory signaling pathways and, interestingly, type II interferon (IFN), which is also a key inducer of inflammatory mediators, seems to be essential in initiating this counterinflammatory response. Another key observation is that not only cells of the immune system but also CNS resident cells are actively involved in both the pro- and the counterinflammatory immune circuits; thus, for example, astrocytes upregulate both C-X-C-motif chemokine 10 (CXCL10) and SOCS when exposed to type II IFNin vivo.
Structurally Similar Woodchuck and Human Hepadnavirus Core Proteins Have Distinctly Different Temperature Dependences of Assembly
Authors: Kukreja Alexander A. , Wang Joseph C.-Y. , Pierson Elizabeth , Keifer David Z. , Selzer Lisa , Tan Zhenning , Dragnea Bogdan , Jarrold Martin F. , Zlotnick Adam
Published: September 2014

Woodchuck hepatitis virus (WHV), a close relative of human hepatitis B virus (HBV), has been a key model for disease progression and clinical studies. Sequences of the assembly domain of WHV and HBV core proteins (wCp149 and hCp149, respectively) have 65% identity, suggesting similar assembly behaviors. We report a cryo-electron microscopy (cryo-EM) structure of the WHV capsid at nanometer resolution and characterization of wCp149 assembly. At this resolution, the T=4 capsid structures of WHV and HBV are practically identical. In contrast to their structural similarity, wCp149 demonstrates enhanced assembly kinetics and stronger dimer-dimer interactions than hCp149: at 23°C and at 100 mM ionic strength, the pseudocritical concentrations of assembly of wCp149 and hCp149 are 1.8 μM and 43.3 μM, respectively. Transmission electron microscopy reveals that wCp149 assembles into predominantly T=4 capsids with a sizeable population of larger, nonicosahedral structures. Charge detection mass spectrometry indicates that T=3 particles are extremely rare compared to the ∼5% observed in hCp149 reactions. Unlike hCp149, wCp149 capsid assembly is favorable over a temperature range of 4°C to 37°C; van't Hoff analyses relate the differences in temperature dependence to the high positive values for heat capacity, enthalpy, and entropy of wCp149 assembly. Because the final capsids are so similar, these findings suggest that free wCp149 and hCp149 undergo different structural transitions leading to assembly. The difference in the temperature dependence of wCp149 assembly may be related to the temperature range of its hibernating host.

IMPORTANCE
In this paper, we present a cryo-EM structure of a WHV capsid showing its similarity to HBV. We then observe that the assembly properties of the two homologous proteins are very different. Unlike human HBV, the capsid protein of WHV has evolved to function in a nonhomeostatic environment. These studies yield insight into the interplay between core protein self-assembly and the host environment, which may be particularly relevant to plant viruses and viruses with zoonotic cycles involving insect vectors.
The Exonuclease Domain of Lassa Virus Nucleoprotein Is Involved in Antigen-Presenting-Cell-Mediated NK Cell Responses
Authors: Russier Marion , Reynard Stéphanie , Carnec Xavier , Baize Sylvain
Published: September 2014

Lassa virus is an Old World
Arenavirus
which causes Lassa hemorrhagic fever in humans, mostly in West Africa. Lassa fever is an important public health problem, and a safe and effective vaccine is urgently needed. The infection causes immunosuppression, probably due to the absence of activation of antigen-presenting cells (dendritic cells and macrophages), low type I interferon (IFN) production, and deficient NK cell function. However, a recombinant Lassa virus carrying D389A and G392A substitutions in the nucleoprotein that abolish the exonuclease activity and IFN activation loses its inhibitory activity and induces strong type I IFN production by dendritic cells and macrophages. We show here that during infection by this mutant Lassa virus, antigen-presenting cells trigger efficient human NK cell responses
in vitro
, including production of IFN-γ and cytotoxicity. NK cell activation involves close contact with both antigen-presenting cells and soluble factors. We report that infected dendritic cells and macrophages express the NKG2D ligands major histocompatibility complex (MHC) class I-related chains A and B and that they may produce interleukin-12 (IL-12), IL-15, and IL-18, all involved in NK cell functions. NK cell degranulation is significantly increased in cocultures, suggesting that NK cells seem to kill infected dendritic cells and macrophages. This work confirms the inhibitory function of Lassa virus nucleoprotein. Importantly, we demonstrate for the first time that Lassa virus nucleoprotein is involved in the inhibition of antigen-presenting cell-mediated NK cell responses.

IMPORTANCE
The pathogenesis and immune responses induced by Lassa virus are poorly known. Recently, an exonuclease domain contained in the viral nucleoprotein has been shown to be able to inhibit the type I IFN response by avoiding the recognition of viral RNA by cell sensors. Here, we studied the responses of NK cells to dendritic cells and macrophages infected with a recombinant Lassa virus in which the exonuclease functions have been abolished and demonstrated that NK cells are strongly activated and presented effective functions. These results show that the strategy developed by Lassa virus to evade innate immunity is also effective on NK cells, explaining the weak NK cell activation observed with the wild-type virus. By providing a better understanding of the interactions between Lassa virus and the host immune system, these results are important for the field of arenavirus biology and may be useful for a vaccine approach against Lassa fever.
Variation of the Specificity of the Human Antibody Responses after Tick-Borne Encephalitis Virus Infection and Vaccination
Authors: Jarmer Johanna , Zlatkovic Jürgen , Tsouchnikas Georgios , Vratskikh Oksana , Strauß Judith , Aberle Judith H. , Chmelik Vaclav , Kundi Michael , Stiasny Karin , Heinz Franz X.
Published: September 2014

Tick-borne encephalitis (TBE) virus is an important human-pathogenic flavivirus endemic in large parts of Europe and Central and Eastern Asia. Neutralizing antibodies specific for the viral envelope protein E are believed to mediate long-lasting protection after natural infection and vaccination. To study the specificity and individual variation of human antibody responses, we developed immunoassays with recombinant antigens representing viral surface protein domains and domain combinations. These allowed us to dissect and quantify antibody populations of different fine specificities in sera of TBE patients and vaccinees. Postinfection and postvaccination sera both displayed strong individual variation of antibody titers as well as the relative proportions of antibodies to different domains of E, indicating that the immunodominance patterns observed were strongly influenced by individual-specific factors. The contributions of these antibody populations to virus neutralization were quantified by serum depletion analyses and revealed a significantly biased pattern. Antibodies to domain III, in contrast to what was found in mouse immunization studies with TBE and other flaviviruses, did not play any role in the human neutralizing antibody response, which was dominated by antibodies to domains I and II. Importantly, most of the neutralizing activity could be depleted from sera by a dimeric soluble form of the E protein, which is the building block of the icosahedral herringbone-like shell of flaviviruses, suggesting that antibodies to more complex quaternary epitopes involving residues from adjacent dimers play only a minor role in the total response to natural infection and vaccination in humans.

IMPORTANCE
Tick-borne encephalitis (TBE) virus is a close relative of yellow fever, dengue, Japanese encephalitis, and West Nile viruses and distributed in large parts of Europe and Central and Eastern Asia. Antibodies to the viral envelope protein E prevent viral attachment and entry into cells and thus mediate virus neutralization and protection from disease. However, the fine specificity and individual variation of neutralizing antibody responses are currently not known. We have therefore developed new
in vitro
assays for dissecting the antibody populations present in blood serum and determining their contribution to virus neutralization. In our analysis of human postinfection and postvaccination sera, we found an extensive variation of the antibody populations present in sera, indicating substantial influences of individual-specific factors that control the specificity of the antibody response. Our study provides new insights into the immune response to an important human pathogen that is of relevance for the design of novel vaccines.
Chlorovirus Skp1-Binding Ankyrin Repeat Protein Interplay and Mimicry of Cellular Ubiquitin Ligase Machinery
Authors: Noel Eric A. , Kang Ming , Adamec Jiri , Van Etten James L. , Oyler George A.
Published: September 2014

The ubiquitin-proteasome system is targeted by many viruses that have evolved strategies to redirect host ubiquitination machinery. Members of the genus
Chlorovirus
are proposed to share an ancestral lineage with a broader group of related viruses, nucleo-cytoplasmic large DNA viruses (NCLDV). Chloroviruses encode an Skp1 homolog and ankyrin repeat (ANK) proteins. Several chlorovirus-encoded ANK repeats contain C-terminal domains characteristic of cellular F-boxes or related NCLDV chordopox PRANC (pox protein repeats of ankyrin at C-terminal) domains. These observations suggested that this unique combination of Skp1 and ANK repeat proteins might form complexes analogous to the cellular Skp1-Cul1-F-box (SCF) ubiquitin ligase complex. We identified two ANK proteins from the prototypic chlorovirus
Paramecium bursaria
chlorella virus-1 (PBCV-1) that functioned as binding partners for the virus-encoded Skp1, proteins A682L and A607R. These ANK proteins had a C-terminal Skp1 interactional motif that functioned similarly to cellular F-box domains. A C-terminal motif of ANK protein A682L binds Skp1 proteins from widely divergent species. Yeast two-hybrid analyses using serial domain deletion constructs confirmed the C-terminal localization of the Skp1 interactional motif in PBCV-1 A682L. ANK protein A607R represents an ANK family with one member present in all 41 sequenced chloroviruses. A comprehensive phylogenetic analysis of these related ANK and viral Skp1 proteins suggested partnered function tailored to the host alga or common ancestral heritage. Here, we show protein-protein interaction between corresponding family clusters of virus-encoded ANK and Skp1 proteins from three chlorovirus types. Collectively, our results indicate that chloroviruses have evolved complementing Skp1 and ANK proteins that mimic cellular SCF-associated proteins.

IMPORTANCE
Viruses have evolved ways to direct ubiquitination events in order to create environments conducive to their replication. As reported in the manuscript, the large chloroviruses encode several components involved in the SCF ubiquitin ligase complex including a viral Skp1 homolog. Studies on how chloroviruses manipulate their host algal ubiquitination system will provide insights toward viral protein mimicry, substrate recognition, and key interactive domains controlling selective protein degradation. These findings may also further understanding of the evolution of other large DNA viruses, like poxviruses, that are reported to share the same monophyly lineage as chloroviruses.
Activation of the RIG-I Pathway during Influenza Vaccination Enhances the Germinal Center Reaction, Promotes T Follicular Helper Cell Induction, and Provides a Dose-Sparing Effect and Protective Immunity
Authors: Kulkarni Raveendra R. , Rasheed Mohammed Ata Ur , Bhaumik Siddhartha Kumar , Ranjan Priya , Cao Weiping , Davis Carl , Marisetti Krishna , Thomas Sunil , Gangappa Shivaprakash , Sambhara Suryaprakash , Murali-Krishna Kaja
Published: September 2014

Pattern recognition receptors (PRR) sense certain molecular patterns uniquely expressed by pathogens. Retinoic-acid-inducible gene I (RIG-I) is a cytosolic PRR that senses viral nucleic acids and induces innate immune activation and secretion of type I interferons (IFNs). Here, using influenza vaccine antigens, we investigated the consequences of activating the RIG-I pathway for antigen-specific adaptive immune responses. We found that mice immunized with influenza vaccine antigens coadministered with 5′ppp-double-stranded RNA (dsRNA), a RIG-I ligand, developed robust levels of hemagglutination-inhibiting antibodies, enhanced germinal center reaction, and T follicular helper cell responses. In addition, RIG-I activation enhanced antibody affinity maturation and plasma cell responses in the draining lymph nodes, spleen, and bone marrow and conferred protective immunity against virus challenge. Importantly, activation of the RIG-I pathway was able to reduce the antigen requirement by 10- to 100-fold in inducing optimal influenza-specific cellular and humoral responses, including protective immunity. The effects induced by 5′ppp-dsRNA were significantly dependent on type I IFN and IPS-1 (an adapter protein downstream of the RIG-I pathway) signaling but were independent of the MyD88- and TLR3-mediated pathways. Our results show that activation of the RIG-I-like receptor pathway programs the innate immunity to achieve qualitatively and quantitatively enhanced protective cellular adaptive immune responses even at low antigen doses, and this indicates the potential utility of RIG-I ligands as molecular adjuvants for viral vaccines.

IMPORTANCE
The recently discovered RNA helicase family of RIG-I-like receptors (RLRs) is a critical component of host defense mechanisms responsible for detecting viruses and triggering innate antiviral cytokines that help control viral replication and dissemination. In this study, we show that the RLR pathway can be effectively exploited to enhance adaptive immunity and protective immune memory against viral infection. Our results show that activation of the RIG-I pathway along with influenza vaccination programs the innate immunity to induce qualitatively and quantitatively superior protective adaptive immunity against pandemic influenza viruses. More importantly, RIG-I activation at the time of vaccination allows induction of robust adaptive responses even at low vaccine antigen doses. These results highlight the potential utility of exploiting the RIG-I pathway to enhance viral-vaccine-specific immunity and have broader implications for designing better vaccines in general.
B Cell Response to Herpesvirus Infection of the Olfactory Neuroepithelium
Authors: Tan Cindy S. E. , Stevenson Philip G.
Published: September 2014

Viruses commonly infect the respiratory tract. Analyses of host defense have focused on the lungs and the respiratory epithelium. Spontaneously inhaled murid herpesvirus 4 (MuHV-4) and herpes simplex virus 1 (HSV-1) instead infect the olfactory epithelium, where neuronal cilia are exposed to environmental antigens and provide a route across the epithelial mucus. We used MuHV-4 to define how B cells respond to virus replication in this less well-characterized site. Olfactory infection elicited generally weaker acute responses than lung infection, particularly in the spleen, reflecting slower viral replication and spread. Few virus-specific antibody-forming cells (AFCs) were found in the nasal-associated lymphoid tissue (NALT), a prominent response site for respiratory epithelial infection. Instead, they appeared first in the superficial cervical lymph nodes. The focus of the AFC response then moved to the spleen, matching the geography of virus dissemination. Little virus-specific IgA response was detected until later in the bone marrow. Neuroepithelial HSV-1 infection also elicited no significant AFC response in the NALT and a weak IgA response. Thus, olfactory herpesvirus infection differed immunologically from an infection of the adjacent respiratory epithelium. Poor IgA induction may help herpesviruses to transmit via long-term mucosal shedding.

IMPORTANCEHerpesviruses are widespread, persistent pathogens against which vaccines have had limited success. We need to understand better how they interact with host immunity. MuHV-4 and HSV-1 inhaled by alert mice infect the olfactory neuroepithelium, suggesting that this is a natural entry route. Its immunology is almost completely unknown. The antibody response to neuroepithelial herpesvirus infection started in the cervical lymph nodes, and unlike respiratory influenza virus infection, did not significantly involve the nasal-associated lymphoid tissue. MuHV-4 and HSV-1 infections also elicited little virus-specific IgA. Therefore, vaccine-induced IgA might provide a defense that herpesviruses are ill-equipped to meet.
Latency-Associated Viral Interleukin-10 (IL-10) Encoded by Human Cytomegalovirus Modulates Cellular IL-10 and CCL8 Secretion during Latent Infection through Changes in the Cellular MicroRNA hsa-miR-92a
Authors: Poole Emma , Avdic Selmir , Hodkinson Jemima , Jackson Sarah , Wills Mark , Slobedman Barry , Sinclair John
Published: September 2014

The UL111A gene of human cytomegalovirus encodes a viral homologue of the cellular immunomodulatory cytokine interleukin 10 (cIL-10), which, due to alternative splicing, results in expression of two isoforms designated LAcmvIL-10 (expressed during both lytic and latent infection) and cmvIL-10 (identified only during lytic infection). We have analyzed the functions of LAcmvIL-10 during latent infection of primary myeloid progenitor cells and found that LAcmvIL-10 is responsible, at least in part, for the known increase in secretion of cellular IL-10 and CCL8 in the secretomes of latently infected cells. This latency-associated increase in CCL8 expression results from a concomitant LAcmvIL-10-mediated suppression of the expression of the cellular microRNA (miRNA) hsa-miR-92a, which targets CCL8 directly. Taking the data together, we show that the previously observed downregulation of hsa-miR-92a and upregulation of CCL8 during HCMV latent infection of myeloid cells are intimately linked via the latency-associated expression of LAcmvIL-10.

IMPORTANCEHCMV latency causes significant morbidity and mortality in immunocompromised individuals, yet HCMV is carried silently (latently) in 50 to 90% of the population. Understanding how HCMV maintains infection for the lifetime of an infected individual is critical for the treatment of immunocompromised individuals suffering with disease as a result of HCMV. In this study, we analyze one of the proteins that are expressed during the “latent” phase of HCMV, LAcmvIL-10, and find that the expression of the gene modulates the microenvironment of the infected cell, leading to evasion of the immune system.
Recurrent pulmonary embolus despite adequate anticoagulation: the case for routine cancer screening, prompted by an uncommon cause
Authors: Bendel Daniel , Loong Chee Yee
Published: September 2014

A middle-aged patient presented with dyspnoea, haemoptysis and weight loss following a recent admission for pulmonary embolus, diagnosed on CT pulmonary angiogram (CTPA). The patient was anticoagulated with warfarin to a therapeutic range 2–3. There was no relevant medical history. On examination, the pulse was 105 bpm and blood pressure was 70/50 mm Hg. Oxygen saturation was 94% on air. Repeat CTPA revealed extension of the clot burden, now a saddle embolus occluding pulmonary outflow. The patient underwent emergency surgical embolectomy, and histology of the excised clot revealed the underlying cause—a malignant, high-grade sarcoma of the pulmonary vasculature. The target international normalised ratio was increased to 3–4. Postoperatively, the patient developed a large malignant pericardial effusion which required urgent percutaneous drainage. The patient eventually underwent targeted chemotherapy, which extended patient survival. The patient passed away a year later from progressive right-sided heart failure as a result of cor pulmonale.
Diagnostic and management dilemma of a pancreas–kidney transplant recipient with aplastic anaemia
Authors: Viecelli Andrea , Hessamodini Hannah , Augustson Bradley , Lim Wai Hon
Published: September 2014

We report a case of a 57-year-old woman with type I diabetes who had received a simultaneous pancreas–kidney (SPK) transplant maintained on tacrolimus, mycophenolic acid (MPA) and prednisolone. Her renal allograft failed 6 years post-transplant but she continued to have a normal functioning pancreatic allograft. Over the course of 5 years, she developed progressive bone marrow failure with repeat bone marrow aspirates demonstrating an evolution from erythroid hypoplasia to hypocellular marrow and eventual aplastic anaemia despite discontinuation of MPA and reduction of tacrolimus. She was transfusion-dependent and had frequent admissions for sepsis. Despite treatment with antithymocyte globulin and cyclosporine for aplastic anaemia, she developed fatal invasive pulmonary aspergillosis within 3 weeks of treatment. Even though the cause of aplastic anaemia is likely multifactorial, this case highlights the difficulty in balancing the need for versus the risk of ongoing immunosuppression in a SPK transplant recipient who continues to have normal pancreatic graft function.
Open reduction and percutaneous fixation of a rare hamstring avulsion fracture
Authors: Watts Chad D , Hartzler Robert U , Cross William W
Published: September 2014

Surgical treatment has been advocated for ischial tuberosity avulsion fractures in athletes. This article presents the case of an elite rower with a large avulsion fracture involving the entire inferior obturator ring with a novel technique for open reduction using a limited Kocher-Langenbeck approach and percutaneous fixation using posterior column lag screws. The fracture healed anatomically, and at 1 year follow-up the patient had full range of motion, normal gait and had returned to high-level sporting activities.
Serum α-hydroxybutyrate (α-HB) predicts elevated 1 h glucose levels and early-phase β-cell dysfunction during OGTT
Authors: Varvel Stephen A , Pottala James V , Thiselton Dawn L , Caffrey Rebecca , Dall Tara , Sasinowski Maciek , McConnell Joseph P , Warnick G Russell , Voros Szilard , Graham Timothy E
Published: September 2014

Objective

Serum α-hydroxybutyrate (α-HB) is elevated in insulin resistance and diabetes. We tested the hypothesis that the α-HB level predicts abnormal 1 h glucose levels and β-cell dysfunction inferred from plasma insulin kinetics during a 75 g oral glucose tolerance test (OGTT).

Research design and methods

This cross-sectional study included 217 patients at increased risk for diabetes. 75 g OGTTs were performed with multiple postload glucose and insulin measurements over a 30–120 min period. OGTT responses were analyzed by repeated measures analysis of variance (ANOVA). Multivariable logistic regression was used to predict 1 h glucose ≥155 mg/dL with α-HB added to traditional risk factors.

Results

Mean±SD age was 51±15 years (44% male, 25% with impaired glucose tolerance). Fasting glucose and insulin levels, but not age or body mass index (BMI), were significantly higher in the second/third α-HB tertiles (>3.9 µg/mL) than in the first tertile. Patients in the second/third α-HB tertiles exhibited a higher glucose area under the receiver operating characteristics curve (AUC) and reduced initial slope of insulin response during OGTT. The AUC for predicting 1 h glucose ≥155 mg/dL was 0.82 for a base model that included age, gender, BMI, fasting glucose, glycated hemoglobin (HbA1c), and insulin, and increased to 0.86 with α-HB added (p=0.015), with a net reclassification index of 52% (p<0.0001).

Conclusions

Fasting serum α-HB levels predicted elevated 1 h glucose during OGTT, potentially due to impaired insulin secretion kinetics. This association persisted even in patients with an otherwise normal insulin–glucose homeostasis. Measuring serum α-HB could thus provide a rapid, inexpensive screening tool for detecting early subclinical hyperglycemia, β-cell dysfunction, and increased risk for diabetes.
Does anaphylaxis masquerade as asthma in children?
Authors: Sargant N , Erlewyn-Lajeunesse M , Benger J
Published: September 2014

Anaphylaxis in children presents most frequently with respiratory features, and concern exists about the potential for diagnostic confusion with acute asthma. 84 cases of asthma requiring intensive care were identified. 11 cases met exclusion criteria, which left 73 cases for analysis using established anaphylaxis diagnostic criteria. 13/73 children (17.8%) were found to have sufficient clinical features for a diagnosis of anaphylaxis to be entertained, with 3/73 cases (4.1%) considered highly likely to be anaphylaxis. This study highlights the potential for diagnostic confusion and demonstrates the need to consider anaphylaxis in all children presenting with severe asthma.
An identification of the Dirac operator with the parity operator
Authors: Sperança Llohann D.
Published: September 2014

In this paper, we provide a new derivation of the Dirac equation which promptly generalizes to higher spins. We apply this idea to spin-half Elko dark matter.
MASCOT: Multi-Criteria Analytical SCOring Tool for ArcGIS Desktop
Authors: Lacroix Pierre , Santiago Helder , Ray Nicolas
Published: September 2014

Multicriteria Analytical SCOring Tool (MASCOT) is a decision-support tool based on spatial analysis that can score items (points, lines, and polygons) as a function of their Euclidian distance to other data (points, lines, polygons, rasters). MASCOT is integrated with ArcGIS 9.3.1 and makes it possible to achieve a complete workflow that may include data preparation and grouping of factors by theme, weighting, scoring, post-processing and decision-making. To achieve the weighting process, the Analytic Hierarchy Process (AHP) has been integrated. MASCOT was originally developed for the demining community, with the purpose of prioritizing clearance of mine hazards as a function of their distance to a set of predefined and measurable factors. We show here an example based on mine action data, but MASCOT is not limited to this community and many other application fields will benefit from it.
Hybrid Computation Model for Intelligent System Design by Synergism of Modified EFC with Neural Network
Authors: Srivastava Vivek , Tripathi Bipin K. , Pathak Vinay K.
Published: September 2014

In recent past, it has been seen in many applications that synergism of computational intelligence techniques outperforms over an individual technique. This paper proposes a new hybrid computation model which is a novel synergism of modified evolutionary fuzzy clustering with associated neural networks. It consists of two modules: fuzzy distribution and neural classifier. In first module, mean patterns are distributed into the number of clusters based on the modified evolutionary fuzzy clustering, which leads the basis for network structure selection and learning in associated neural classifier. In second module, training and subsequent generalization is performed by the associated neural networks. The number of associated networks required in the second module will be same as the number of clusters generated in the first module. Whereas, each network contains as many output neurons as the maximum number of members assigned to each cluster. The proposed hybrid model is evaluated over wide spectrum of benchmark problems and real life biometric recognition problems even in presence of real environmental constraints such as noise and occlusion. The results indicate the efficacy of proposed method over related techniques and endeavor promising outcomes for biometric applications with noise and occlusion.
Nanohybrid Nanoparticles Based on Chitosan/Functionalized Carbon Nanotubes as Anti-HIV Nanocarrier
Authors: Afshari R. , Mazinani S. , Abdouss M.
Published: September 2014

Carbon nanotube-natural biopolymer nanovectors have important potential applications in delivery system for drugs and biomolecules. In this work, the use of multi-walled carbon nanotubes (MWCNT) as nanoreservoirs for drug loading and controlled release is demonstrated. We synthesized different carbon nanotube-based drug delivery systems including acid and amide-functionalized MWCNT; chitosan (CS) covalently grafted to functionalized MWCNT and MWCNT-CS nanoparticles (NPs) using an ionotropic gelation method as a sustained-release systems for delivery of Tenofovir (hydrophilic anti-retroviral drug). The prepared NPs as different drug delivery systems were characterized by Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA) and scanning electron microscopy (SEM). As it is shown, in vitro drug release studies indicated that the cumulative release rate of Tenofovir from MWCNT–CS NPs shows the best result and it reaches the maximum value (90%) after about 120 h. Moreover, comparing to ungrafted CNTs, MWCNT–CS shows high dispersability and long-term stability in aqueous medium which approves the effective solubilization of MWCNT followed by grafting with CS.