bluuebunny/crossref_metadata_2025 huggingface dataset:
Supersonic surface acoustic waves on the 001 and 110 surfaces of cubic crystals
Authors: Every A. G.
Published: November 2015

Criteria are reported here for the existence of supersonic surface acoustic waves (SSAW) on the (001) and (110) surfaces of cubic crystals. These are the common crystal cuts for which SSAW have been observed experimentally using surface Brillouin scattering and other techniques. Two categories of SSAW are distinguished. Symmetry protected SSAW exist by virtue of being located in high symmetry crystallographic directions for which the coupling to the phase matched bulk wave, which would otherwise result in their attenuation, is suppressed by symmetry. Secluded SSAW occur in lower-symmetry directions, where the reason for the vanishing of their coupling to their phase matched bulk wave is less evident. The stability domain for the elastic constant ratios a=C11/C44 and b=C12/C44 is subdivided into a number of regions in which various symmetry protected and secluded SSAW exist. Some of the boundaries between these regions are expressible in analytical form, others have been established purely numerically.
Generation of a reference radiation pattern of string instruments using automatic excitation and acoustic centering
Authors: Shabtai Noam R. , Behler Gottfried , Vorländer Michael
Published: November 2015

Radiation patterns of musical instruments are important for the understanding of music perception in concert halls, and may be used to improve the plausibility of virtual acoustic systems. Many attempts have been performed to measure the spatial response of musical instruments using surrounding spherical microphone arrays with a limited number of microphones. This work presents a high-resolution spatial sampling of the radiation pattern of an electrically excited violin, and addresses technical problems that arise due to mechanical reasons of the excitation apparatus using acoustic centering.
How warming oceans unleashed an ice stream
Authors: Gramling Carolyn
Published: November 2015

Accelerating retreat of a Greenland glacier could raise sea level for decades to come.
Cancer research centers pool tumor genome data
Authors: Kaiser Jocelyn
Published: November 2015

DNA registry could lead to new treatments.
Baby's leukemia recedes after novel cell therapy
Authors: Couzin-Frankel Jennifer
Published: November 2015

Gene editing used to create “off-the-shelf” T cells.
Not guilty as charged
Authors: Hvistendahl Mara
Published: November 2015

Several cases have unraveled lately against Chinese-born scientists accused of sharing industrial secrets. Critics smell a witch-hunt.
Moveable feast
Authors: Lavelle Marianne
Published: November 2015

In the early 2000s, trawler crews working the Celtic Sea off Ireland noticed something unusual. Small, spiny, bright orange fish, called boarfish, began appearing in their nets in huge numbers. Previously, the intruders had been a minor nuisance; their sharp spines jammed equipment and damaged the soft flesh of more valuable species, such as cod and hake. Irritated crews tossed them overboard. As boarfish schools grew, however, the problem became an opportunity. Trawlers retooled to target the fish, which were turned into meal and oil. Boarfish went from trash to treasure, and they now generate more than $10 million annually for Irish fleets. Scientists aren't exactly sure what is causing the boarfish boom, but there is evidence that a warming ocean is playing a role.
Stakeholders in climate science: Beyond lip service?
Authors: Klenk Nicole L. , Meehan Katie , Pinel Sandra Lee , Mendez Fabian , Lima Pablo Torres , Kammen Daniel M.
Published: November 2015

Local knowledge coproduction must be rewarded
Evidence for primordial water in Earth’s deep mantle
Authors: Hallis Lydia J. , Huss Gary R. , Nagashima Kazuhide , Taylor G. Jeffrey , Halldórsson Sæmundur A. , Hilton David R. , Mottl Michael J. , Meech Karen J.
Published: November 2015

Shaking out water's dusty origin

Where did Earth's water come from? Lavas erupting on Baffin Island, Canada, tap a part of Earth's mantle isolated from convective mixing. Hallis
et al.
studied hydrogen isotopes in the lavas that help to “fingerprint” the origin of water from what could be a primordial reservoir. The isotope ratios for the Baffin Island basalt lavas suggest a pre-solar origin of water in Earth, probably delivered by adsorption onto dust grains.

Science
, this issue p.
795
Dynamics of CRISPR-Cas9 genome interrogation in living cells
Authors: Knight Spencer C. , Xie Liangqi , Deng Wulan , Guglielmi Benjamin , Witkowsky Lea B. , Bosanac Lana , Zhang Elisa T. , El Beheiry Mohamed , Masson Jean-Baptiste , Dahan Maxime , Liu Zhe , Doudna Jennifer A. , Tjian Robert
Published: November 2015

Genome editing with a Cas9 scalpel

The Cas9 nuclease forms the heart of the CRISPR-Cas genome editing system. Cas9 binds small guide RNAs that direct it to its target sites, where the nuclease either cleaves or binds to genomic DNA. Knight
et al.
used single-molecule imaging to track Cas9 in living cells. Cas9 searches the genome for its target sites using rapid threedimensional diffusion. It spends very little time binding to off-target sites, which explains the high accuracy of the CRISPRCas9 editing machine.

Science
, this issue p.
823
Body-size reduction in vertebrates following the end-Devonian mass extinction
Authors: Sallan Lauren , Galimberti Andrew K.
Published: November 2015

The small will inherit the Earth…

Understanding how communities and ecosystems recovered from the previous five global extinction events sheds light on how extinctions shape broad patterns of biodiversity. Sallan
et al.
looked across vertebrate species during and after the Devonian extinction (see the Perspective by Wagner). Small-bodied species, with rapid reproductive rates, dominated post-extinction communities, despite the presence of many successful large-bodied species before the extinction. This pattern mimics, to some degree, current patterns of extinction, suggesting that we might expect similar loss of large-bodied species if we continue along our current path.

Science
, this issue p.
812
; see also p.
736
Climate change in the oceans: Human impacts and responses
Authors: Allison Edward H. , Bassett Hannah R.
Published: November 2015

Although it has far-reaching consequences for humanity, attention to climate change impacts on the ocean lags behind concern for impacts on the atmosphere and land. Understanding these impacts, as well as society’s diverse perspectives and multiscale responses to the changing oceans, requires a correspondingly diverse body of scholarship in the physical, biological, and social sciences and humanities. This can ensure that a plurality of values and viewpoints is reflected in the research that informs climate policy and may enable the concerns of maritime societies and economic sectors to be heard in key adaptation and mitigation discussions.
The Earth experiment
The Planet Remade: How Geoengineering Could Change the World
Oliver Morton
Princeton University Press, 2015. 438 pp.
Authors: Oelkers Eric
Published: November 2015

An investigation of the promise and peril of engineered solutions to climate change.
Flow cytometry strikes gold
Authors: Robinson J. Paul , Roederer Mario
Published: November 2015

Flow cytometry remains unparalleled as a high-throughput, high-content single-cell analysis technology
Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding
Authors: Johnston Christine , Corey Lawrence
Published: November 2015

Herpes simplex virus 2 (HSV-2) is a DNA virus that is efficiently transmitted through intimate genital tract contact and causes persistent infection that cannot be eliminated. HSV-2 may cause frequent, symptomatic self-limited genital ulcers, but in most persons infection is subclinical. However, recent studies have demonstrated that the virus is frequently shed from genital surfaces even in the absence of signs or symptoms of clinical disease and that the virus can be transmitted during these periods of shedding. Furthermore, HSV-2 shedding is detected throughout the genital tract and may be associated with genital tract inflammation, which likely contributes to increased risk of HIV acquisition. This review focuses on HSV diagnostics, as well as what we have learned about the importance of frequent genital HSV shedding for (i) HSV transmission and (ii) genital tract inflammation, as well as (iii) the impact of HSV-2 infection on HIV acquisition and transmission. We conclude with discussion of future areas of research to push the field forward.
Comparison of Three Whole-Cell Pertussis Vaccines in the Baboon Model of Pertussis
Authors: Warfel Jason M. , Zimmerman Lindsey I. , Merkel Tod J.
Published: November 2015

Pertussis is a highly contagious respiratory illness caused by the bacterial pathogen
Bordetella pertussis
. Pertussis rates in the United States have escalated since the 1990s and reached a 50-year high of 48,000 cases in 2012. While this pertussis resurgence is not completely understood, we previously showed that the current acellular pertussis vaccines do not prevent colonization or transmission following challenge. In contrast, a whole-cell pertussis vaccine accelerated the rate of clearance compared to rates in unvaccinated animals and animals treated with the acellular vaccine. In order to understand if these results are generalizable, we used our baboon model to compare immunity from whole-cell vaccines from three different manufacturers that are approved outside the United States. We found that, compared to clearance rates with no vaccine and with an acellular pertussis vaccine, immunization with any of the three whole-cell vaccines significantly accelerated the clearance of
B. pertussis
following challenge. Whole-cell vaccination also significantly reduced the total nasopharyngeal
B. pertussis
burden, suggesting that these vaccines reduce the opportunity for pertussis transmission. Meanwhile, there was no difference in either the duration or in
B. pertussis
burden between unvaccinated and acellular-pertussis-vaccinated animals, while previously infected animals were not colonized following reinfection. We also determined that transcription of the gene encoding interleukin-17 (IL-17) was increased in whole-cell-vaccinated and previously infected animals but not in acellular-pertussis-vaccinated animals following challenge. Together with our previous findings, these data are consistent with a role for Th17 responses in the clearance of
B. pertussis
infection.
Robust Real-Time Reverse Transcription-PCR for Detection of Foot-and-Mouth Disease Virus Neutralizing Carryover Contamination
Authors: Hwang Ji-Hyeon , Shin Yong-Keol , Park So-Yeon , Kim Jeesoo , Kim Su-Mi , Kim Byounghan , Park Jong-Hyeon , Lee Jong-Soo , Lee Kwang-Nyeong
Published: November 2015

During an outbreak of foot-and-mouth disease (FMD), real-time reverse transcription-PCR (rRT-PCR) is the most commonly used diagnostic method to detect viral RNA. However, while this assay is often conducted during the outbreak period, there is an inevitable risk of carryover contamination. This study shows that the carryover contamination can be prevented by the use of target-specific restriction endonuclease in that assay.
Comparison of Six Automated Treponema-Specific Antibody Assays
Authors: Park Borae G. , Yoon Jihoon G. , Rim John Hoon , Lee Anna , Kim Hyon-Suk
Published: November 2015

Six different
Treponema
(TP)-specific immunoassays were compared to the fluorescent treponemal antibody absorption (FTA-ABS) test. A total of 615 samples were tested. The overall percent agreement, analytical sensitivity, and analytical specificity of each assay compared to the FTA-ABS test were as follows: Architect Syphilis TP, 99.2%, 96.8%, and 100%; Cobas Syphilis, 99.8%, 99.4%, and 100%; ADVIA Centaur Syphilis, 99.8%, 99.4%, and 100%; HISCL Anti-TP assay kit, 99.7%, 98.7%, and 100%; Immunoticles Auto3 TP, 99.0%, 97.5%, and 99.6%; Mediace TPLA, 98.0%, 98.1%, and 98.0%. All results that were discrepant between the TP-specific assays were associated with samples from noninfectious cases (11 immunoassay false positives and 7 from previous syphilis cases). Our study demonstrated that TP-specific immunoassays generally showed high sensitivities, specificities, and percentages of agreement compared to FTA-ABS, with rare cases of false-positive or false-negative results. Therefore, most TP-specific immunoassays are acceptable for use in screening for syphilis. However, it is important to perform a thorough review of a patient's clinical and treatment history for interpreting the results of syphilis serology.
Simultaneous Detection of Major Drug Resistance Mutations of HIV-1 Subtype B Viruses from Dried Blood Spot Specimens by Multiplex Allele-Specific Assay
Authors: Zhang Guoqing , Cai Fangping , de Rivera Ivette Lorenzana , Zhou Zhiyong , Zhang Jing , Nkengasong John , Gao Feng , Yang Chunfu
Published: November 2015

A multiplex allele-specific (MAS) assay has been developed for the detection of HIV-1 subtype C drug resistance mutations (DRMs). We have optimized the MAS assay to determine subtype B DRMs in dried blood spots (DBS) collected from patients on antiretroviral therapy. The new assay accurately detected DRMs, including low-abundance mutations that were often missed by Sanger sequencing.
HemaSpot, a Novel Blood Storage Device for HIV-1 Drug Resistance Testing
Authors: Brooks K. , DeLong A. , Balamane M. , Schreier L. , Orido M. , Chepkenja M. , Kemboi E. , D'Antuono M. , Chan P. A. , Emonyi W. , Diero L. , Coetzer M. , Kantor R.
Published: November 2015

HemaSpot, a novel dried-blood storage filter device, was used for HIV-1
pol
resistance testing in 30 fresh United States blood samples and 54 previously frozen Kenyan blood samples. Genotyping succeeded in 79% and 58% of samples, respectively, improved with shorter storage and higher viral load, and had good (86%) resistance mutation concordance to plasma.
Performance of a Novel Point-of-Care Molecular Assay for Detection of Influenza A and B Viruses and Respiratory Syncytial Virus (Enigma MiniLab) in Children with Acute Respiratory Infection
Authors: Douthwaite Sam T. , Walker Charlotte , Adams Elisabeth J. , Mak Catherine , Vecino Ortiz Andres , Martinez-Alier Nuria , Goldenberg Simon D.
Published: November 2015

The performance of the Enigma MiniLab assay for influenza A and B viruses and respiratory syncytial virus (RSV) was compared to a centralized laboratory respiratory virus panel. The positive and negative percent agreement for influenza A virus, influenza B virus, and RSV were 79.2% (95% confidence interval [95% CI], 57.8 to 92.9%) and 99.4% (95% CI, 98.4 to 99.9), 100% (95% CI, 47.8 to 100%) and 100% (95% CI, 99.3 to 100%), 98.5% (95% CI, 94.6 to 99.8%) and 94.5% (95% CI, 91.9 to 96.4%), respectively.
Viral Regulation of Cell Tropism in Human Cytomegalovirus
Authors: Li Gang , Kamil Jeremy P.
Published: November 2015

The viral glycoproteins that decorate enveloped viruses play crucial roles in cell entry and in large part dictate the spectrum of cell types that a virus can infect. The identification in human cytomegalovirus (HCMV) of a viral endoplasmic reticulum (ER)-resident glycoprotein that regulates the composition of alternative viral envelope glycoprotein complexes raises the intriguing possibility that certain viruses might actively regulate the tropism of progeny virions to improve their fitness or to navigate through the host.
A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2
Authors: Wang Kening , Goodman Kyle N. , Li Daniel Y. , Raffeld Mark , Chavez Mayra , Cohen Jeffrey I.
Published: November 2015

A recent phase 3 trial with soluble herpes simplex virus 2 (HSV-2) glycoprotein D (gD2t) in adjuvant failed to show protection against genital herpes. We postulated that live attenuated HSV-2 would provide more HSV antigens for induction of virus-specific antibodies and cellular immunity than would gD2t. We previously reported an HSV-2 mutant, HSV2-gD27, in which the nectin-1 binding domain of gD2 is altered so that the virus is impaired for infecting neural cells, but not epithelial cells,in vitroand is impaired for infecting dorsal root ganglia in mice (K. Wang, J. D. Kappel, C. Canders, W. F. Davila, D. Sayre, M. Chavez, L. Pesnicak, and J. I. Cohen, J Virol 86:12891–12902, 2012, doi:10.1128/JVI.01055-12). Here we report that the mutations in HSV2-gD27 were stable when the virus was passaged in cell culture and during acute infection of mice. HSV2-gD27 was attenuated in mice when it was inoculated onto the cornea, intramuscularly (i.m.), intravaginally, and intracranially. Vaccination of mice i.m. with HSV2-gD27 provided better inhibition of challenge virus replication in the vagina than when the virus was used to vaccinate mice intranasally or subcutaneously. Comparison of i.m. vaccinations with HSV2-gD27 versus gD2t in adjuvant showed that HSV2-gD27 induced larger reductions of challenge virus replication in the vagina and reduced latent viral loads in dorsal root ganglia but induced lower serum neutralizing antibody titers than those obtained with gD2t in adjuvant. Taken together, our data indicate that a live attenuated HSV-2 vaccine impaired for infection of neurons provides better protection from vaginal challenge with HSV-2 than that obtained with a subunit vaccine, despite inducing lower titers of HSV-2 neutralizing antibodies in the serum.

IMPORTANCEGenital herpes simplex is one of the most prevalent sexually transmitted diseases. Though HSV-2 disease is usually mild, it can be life threatening in neonates and immunocompromised persons. In addition, genital herpes increases the frequency of HIV infection and transmission. HSV-2 maintains a latent infection in sensory neurons and cannot be cleared with antiviral drugs. The virus frequently reactivates, resulting in virus shedding in the genital area, which serves as a source for transmission. A prophylactic vaccine is needed to prevent disease and to control the spread of the virus. Previous human trials of subunit vaccines have been unsuccessful. Here we report the results of vaccinating mice with a new type of live attenuated HSV-2 vaccine that is impaired for infection of neurons and provides better protection of mice than that obtained with a subunit vaccine. The strategy of altering the cell tropism of a virus is a new approach for a live attenuated vaccine.
The Cellular Protein Complex Associated with a Transforming Region of E1A Contains c-MYC
Authors: Vijayalingam S. , Subramanian T. , Zhao Ling-jun , Chinnadurai G.
Published: November 2015

The cell-transforming activity of human adenovirus 5 (hAd5) E1A is mediated by the N-terminal half of E1A, which interacts with three different major cellular protein complexes, p300/CBP, TRRAP/p400, and pRb family members. Among these protein interactions, the interaction of pRb family proteins with conserved region 2 (CR2) of E1A is known to promote cell proliferation by deregulating the activities of E2F family transcription factors. The functional consequences of interaction with the other two protein complexes in regulating the transforming activity of E1A are not well defined. Here, we report that the E1A N-terminal region also interacted with the cellular proto-oncoprotein c-MYC and the homolog of enhancer of yellow 2 (ENY2). Our results suggested that these proteins interacted with an essential E1A transforming domain spanning amino acid residues 26 to 35 which also interacted with TRRAP and p400. Small interfering RNA (siRNA)-mediated depletion of TRRAP reduced c-MYC interaction with E1A, while p400 depletion did not. In contrast, depletion of TRRAP enhanced ENY2 interaction with E1A, suggesting that ENY2 and TRRAP may interact with E1A in a competitive manner. The same E1A region additionally interacted with the constituents of a deubiquitinase complex consisting of USP22, ATXN7, and ATXN7L3 via TRRAP. Acute short hairpin RNA (shRNA)-mediated depletion of c-MYC reduced the E1A transforming activity, while depletion of ENY2 and MAX did not. These results suggested that the association of c-MYC with E1A may, at least partially, play a role in the E1A transformation activity, independently of MAX.

IMPORTANCE
The transforming region of adenovirus E1A consists of three short modules which complex with different cellular protein complexes. The mechanism by which one of the transforming modules, CR2, promotes cell proliferation, through inactivating the activities of the pRb family proteins, is better understood than the activities of the other domains. Our analysis of the E1A proteome revealed the presence of the proto-oncoprotein c-MYC and of ENY2. We mapped these interactions to a critical transforming module of E1A that was previously known to interact with the scaffolding molecule TRRAP and the E1A-binding protein p400. We showed that c-MYC interacted with E1A through TRRAP, while ENY2 interacted with it independently. The data reported here indicated that depletion of c-MYC in normal human cells reduced the transforming activity of E1A. Our result raises a novel paradigm in oncogenic transformation by a DNA viral oncogene, the E1A gene, that may exploit the activity of a cellular oncogene, the c-MYC gene, in addition to inactivation of the tumor suppressors, such as pRb.
The C Terminus of the Core β-Ladder Domain in Japanese Encephalitis Virus Nonstructural Protein 1 Is Flexible for Accommodation of Heterologous Epitope Fusion
Authors: Yen Li-Chen , Liao Jia-Teh , Lee Hwei-Jen , Chou Wei-Yuan , Chen Chun-Wei , Lin Yi-Ling , Liao Ching-Len
Published: November 2015

NS1 is the only nonstructural protein that enters the lumen of the endoplasmic reticulum (ER), where NS1 is glycosylated, forms a dimer, and is subsequently secreted during flavivirus replication as dimers or hexamers, which appear to be highly immunogenic to the infected host, as protective immunity can be elicited against homologous flavivirus infections. Here, by using a
trans
-complementation assay, we identified the C-terminal end of NS1 derived from Japanese encephalitis virus (JEV), which was more flexible than other regions in terms of housing foreign epitopes without a significant impact on virus replication. This mapped flexible region is located in the conserved tip of the core β-ladder domain of the multimeric NS1 structure and is also known to contain certain linear epitopes, readily triggering specific antibody responses from the host. Despite becoming attenuated, recombinant JEV with insertion of a neutralizing epitope derived from enterovirus 71 (EV71) into the C-terminal end of NS1 not only could be normally released from infected cells, but also induced dual protective immunity for the host to counteract lethal challenge with either JEV or EV71 in neonatal mice. These results indicated that the secreted multimeric NS1 of flaviviruses may serve as a natural protein carrier to render epitopes of interest more immunogenic in the C terminus of the core β-ladder domain.

IMPORTANCE
The positive-sense RNA genomes of mosquito-borne flaviviruses appear to be flexible in terms of accommodating extra insertions of short heterologous antigens into their virus genes. Here, we illustrate that the newly identified C terminus of the core β-ladder domain in NS1 could be readily inserted into entities such as EV71 epitopes, and the resulting NS1-epitope fusion proteins appeared to maintain normal virus replication, secretion ability, and multimeric formation from infected cells. Nonetheless, such an insertion attenuated the recombinant JEV in mice, despite having retained the brain replication ability observed in wild-type JEV. Mother dams immunized with recombinant JEV expressing EV71 epitope-NS1 fused proteins elicited neutralizing antibodies that protected the newborn mice against lethal EV71 challenge. Together, our results implied a potential application of JEV NS1 as a viral carrier protein to express a heterologous epitope to stimulate dual/multiple protective immunity concurrently against several pathogens.
Identification and Characterization of the Physiological Gene Targets of the Essential Lytic Replicative Epstein-Barr Virus SM Protein
Authors: Thompson Jacob , Verma Dinesh , Li DaJiang , Mosbruger Tim , Swaminathan Sankar
Published: November 2015

Epstein-Barr virus (EBV) SM protein is an essential lytic cycle protein with multiple posttranscriptional mechanisms of action. SM binds RNA and increases accumulation of specific EBV transcripts. Previous studies using microarrays and PCR have shown that SM-null mutants fail to accumulate several lytic cycle mRNAs and proteins at wild-type levels. However, the complete effect of SM on the EBV transcriptome has been incompletely characterized. Here we precisely identify the effects of SM on all EBV transcripts by high-throughput RNA sequencing, quantitative PCR (qPCR), and Northern blotting. The effect of SM on EBV mRNAs was highly skewed and was most evident on 13 late genes, demonstrating why SM is essential for infectious EBV production. EBV DNA replication was also partially impaired in SM mutants, suggesting additional roles for SM in EBV DNA replication. While it has been suggested that SM specificity is based on recognition of either RNA sequence motifs or other sequence properties, no such unifying property of SM-responsive targets was discernible. The binding affinity of mRNAs for SM also did not correlate with SM responsiveness. These data suggest that while target RNA binding by SM may be required for its effect, specific activation by SM is due to differences in inherent properties of individual transcripts. We therefore propose a new model for the mechanism of action and specificity of SM and its homologs in other herpesviruses: that they bind many RNAs but only enhance accumulation of those that are intrinsically unstable and poorly expressed.

IMPORTANCE
This study examines the mechanism of action of EBV SM protein, which is essential for EBV replication and infectious virus production. Since SM protein is not similar to any cellular protein and has homologs in all other human herpesviruses, it has potential importance as a therapeutic target. Here we establish which EBV RNAs are most highly upregulated by SM, allowing us to understand why it is essential for EBV replication. By comparing and characterizing these RNA transcripts, we conclude that the mechanism of specific activity is unlikely to be based simply on preferential recognition of a target motif. Rather, SM binding to its target RNA may be necessary but not sufficient for enhancing accumulation of the RNA. Preferential effects of SM on its most responsive RNA targets may depend on other inherent characteristics of these specific mRNAs that require SM for efficient expression, such as RNA stability.
Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types
Authors: Belzile Jean-Philippe , Sabalza Maite , Craig Megan , Clark Elizabeth , Morello Christopher S. , Spector Deborah H.
Published: November 2015

Human cytomegalovirus (HCMV) is the major viral cause of birth defects and a serious problem in immunocompromised individuals and has been associated with atherosclerosis. Previous studies have shown that the induction of autophagy can inhibit the replication of several different types of DNA and RNA viruses. The goal of the work presented here was to determine whether constitutive activation of autophagy would also block replication of HCMV. Most prior studies have used agents that induce autophagy via inhibition of the mTOR pathway. However, since HCMV infection alters the sensitivity of mTOR kinase-containing complexes to inhibitors, we sought an alternative method of inducing autophagy. We chose to use trehalose, a nontoxic naturally occurring disaccharide that is found in plants, insects, microorganisms, and invertebrates but not in mammals and that induces autophagy by an mTOR-independent mechanism. Given the many different cell targets of HCMV, we proceeded to determine whether trehalose would inhibit HCMV infection in human fibroblasts, aortic artery endothelial cells, and neural cells derived from human embryonic stem cells. We found that in all of these cell types, trehalose induces autophagy and inhibits HCMV gene expression and production of cell-free virus. Treatment of HCMV-infected neural cells with trehalose also inhibited production of cell-associated virus and partially blocked the reduction in neurite growth and cytomegaly. These results suggest that activation of autophagy by the natural sugar trehalose or other safe mTOR-independent agents might provide a novel therapeutic approach for treating HCMV disease.

IMPORTANCE
HCMV infects multiple cell types
in vivo
, establishes lifelong persistence in the host, and can cause serious health problems for fetuses and immunocompromised individuals. HCMV, like all other persistent pathogens, has to finely tune its interplay with the host cellular machinery to replicate efficiently and evade detection by the immune system. In this study, we investigated whether modulation of autophagy, a host pathway necessary for the recycling of nutrients and removal of protein aggregates, misfolded proteins, and pathogens, could be used to target HCMV. We found that autophagy could be significantly increased by treatment with the nontoxic, natural disaccharide trehalose. Importantly, trehalose had a profound inhibitory effect on viral gene expression and strongly impaired viral spread. These data constitute a proof-of-concept for the use of natural products targeting host pathways rather than the virus itself, thus reducing the risk of the development of resistance to treatment.
Upper ureteric transitional cell carcinoma, extending to the renal pelvis, presenting as duodenal obstruction
Authors: Stroman Luke Andrew , Sharma Naomi , Sullivan Mark
Published: November 2015

A 61-year-old man presented with weight loss, dysphagia and vomiting. A barium swallow revealed a duodenal obstruction at D3. CT of the abdomen and pelvis showed a left upper ureteric tumour extending to the renal pelvis compressing the duodenum and causing left-sided hydronephrosis. Cystoscopy and left-sided ureteroscopy proved difficult and were unable to visualise or biopsy the mass, but a left ureteric stent was placed. Laparoscopic biopsy of the mass was completed and histology revealed transitional cell carcinoma. The patient went on to receive palliative chemotherapy, which relieved the small bowel obstruction, and the patient was able to eat solid food 8 weeks later. This case highlights a previously unreported cause of duodenal obstruction.
A healthy patient with bilateral frozen hips preceding bilateral frozen shoulders: a cautionary tale
Authors: Miller Abigail R , Arnot Dean , Wake Melissa
Published: November 2015

Adhesive capsulitis of the shoulder (frozen shoulder) is a common disease characterised by spontaneous onset of pain and restriction of movement, followed by ‘thawing’, with complete or near-complete resolution. Adhesive capsulitis of the hip has been reported in around a dozen patients. This report describes an otherwise-healthy middle-aged woman with apparent sequential resolving adhesive capsulitis of all four ball-and-socket joints over a 9-year period, initially affecting each hip and then each shoulder sequentially. The likely hip diagnosis became clear only retrospectively with development of the second frozen shoulder, 5 years after the first pain. All joints subsequently resolved within the expected timeframe and the patient remains healthy, other than having mild hypertension. This case illustrates that, when hip precedes shoulder involvement, there is the potential for the frozen hip to receive alternate diagnoses for which invasive open hip surgery could unnecessarily be recommended.
DPG-plus syndrome: new report of a rare entity
Authors: Azurara Laura , Marçal Mónica , Vieira Filipa , Tuna Madalena Lopo
Published: November 2015

Pituitary gland duplication is a particularly rare finding. Different theories have been proposed to explain its pathogenesis, however, this phenomenon is not yet totally understood. Recently, duplication of the pituitary gland (DPG)-plus syndrome has been described, associating DPG with other blastogenic defects. We present the clinical and imaging findings of a newborn girl with DPG, associated with multiple other midline anomalies, including a nasopharyngeal teratoma, palate cleft deformity, bifid nasal bridge, tongue and uvula, hypoplasia of thebasis pontisand corpus callosum, duplication of the basilar artery and hypothalamic hamartoma. We describe our patient's multidisciplinary team approach and emphasise the importance of reporting upcoming cases, in order to give more insight into the understanding of this complex entity.
Metastatic choriocarcinoma induced separate simultaneous intracerebral haemorrhages: a very rare occurrence and its novel association with Klinefelter syndrome
Authors: Joret Maximilian Olavi , Starke Robert M , Scotter John , Heppner Peter
Published: November 2015

Non-traumatic separate simultaneous intracerebral haemorrhages (SSIHs) are rare. Relevant aetiologies are diverse and their diagnosis challenging. We report a unique case of SSIH in an 18-year-old male with a background of previously undiagnosed testicular choriocarcinoma and Klinefelter syndrome. The patient was admitted to Auckland City Hospital with headaches, drowsiness and vomiting. A CT scan revealed SSIH in a background of tumorous lesions. His β human chorionic gonadotropin titre was elevated at 355 000 IU/L. The SSIH and the associated tumorous lesions were acutely surgically resected and the patient started on bleomycin, etoposide and cisplatin combination chemotherapy with excellent results. In this article, we underline choriocarcinoma as a rare aetiology of SSIH and present an example of the clinical presentation, investigation and management of this very rare pathological entity.
Going for growth: improvement in the infrastructural and management support for clinical academic research
Authors: Fowler Davis Sally
Published: November 2015

Our objective was to implement a directorate research strategy to improve and grow clinical academic capacity and capability and ensure that the organisational systems and processes enabled clinical staff and managers to increase grant capture, undertake clinically relevant research, including the adoption of NIHR portfolio sites and established a culture in which research was an accepted part of professional practice.

An initial evaluation of senior and middle manager attitudes and understanding of the research infrastructure and benefits of research identified that the directorate had a deeply segmented view of research and only a partial view of how research could benefit patients and improve their services. A significant number of staff claimed to be research active but this activity was not contributing to the service knowledge or being translated into grant capture, leading to income that could be used to invest in patient facing research. Few managers had appreciated the challenge of implementing the research strategy or the potential of enabling research active staff to generate clinical academic careers.

A quality improvement methodology was adopted, based on four equally important elements [1]; involving people (staff and patients) in research, developing people's research knowledge and skills, promoting an understanding of the complex systems and processes associated with research, and using an organisational research strategy with leadership to drive change. This improvement method suggests an equal and proportional range of activity to engage staff, amend and adapt processes and systems, carry out organisational change and "make it a habit". The improvement measures were selected by a number of managers who acted as "research champions" and shared these with all staff across the directorate; the focus was on delivering sustained improvements in performance targets agreed with the organisation. The interventions were introduced to assist managers in each professional group to champion research and undertake the organisational change that would be needed.

The two cycles of improvement over 14 months were used to achieve "academic status" within the organisation, to include clinical staff in the delivery of the research strategy and to create a clinical academic infrastructure that incorporated a well organised public and patient involvement (PPI) panel. Additional measures included the level of participation of clinical academic staff in grant capture and the level of income from research to sustain the growth in activity.
Chemotherapy-induced nausea and vomiting: an overview and comparison of three consensus guidelines
Authors: Tageja Nishant , Groninger Hunter
Published: November 2015

Chemotherapy-induced nausea and vomiting (CINV) remains one of the most debilitating toxicities associated with cancer treatment. In recent decades, significant strides have been made in our understanding of the pathophysiology of CINV, making way to more effective targeted pharmacotherapies, especially 5-hydroxytryptamine3 receptor antagonists and neurokinin-1 (NK-1) receptor antagonists. As much as 70%–80% of CINV can be prevented with appropriate administration of available antiemetics. Nevertheless, fear of CINV still may diminish cancer treatment adherence. To assimilate and summarise the rapidly growing body of clinical research literature on CINV, three professional organisations—the Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology, the American Society of Clinical Oncology and the National Comprehensive Cancer Network—have created CINV management guidelines. While these respective guidelines are developed from similar consensus processes using similar clinical research literature, their results demonstrate several key differences in recommended strategies. This article aims to provide an overview of CINV pathophysiology, compare and contrast three expert guidelines and offer considerations for future clinical and research challenges.
Ten‐minute chat
Authors: Matthews Pete
Published: November 2015

Pete Matthews works in mixed practice at Galedin Veterinary in the Scottish Borders. He has been a member of the Tweed Valley Mountain Rescue Team for eight years and last year took on the role of team leader for a three‐year term.
The Lusternik–Fet theorem for autonomous Tonelli Hamiltonian systems on twisted cotangent bundles
Authors: Asselle Luca , Benedetti Gabriele
Published: November 2015

Let [Formula: see text] be a closed manifold and consider the Hamiltonian flow associated to an autonomous Tonelli Hamiltonian [Formula: see text] and a twisted symplectic form. In this paper we study the existence of contractible periodic orbits for such a flow. Our main result asserts that if [Formula: see text] is not aspherical, then contractible periodic orbits exist for almost all energies above the maximum critical value of [Formula: see text].
Activation of aryl hydrocarbon receptor mediates suppression of hypoxia-inducible factor-dependent erythropoietin expression by indoxyl sulfate
Authors: Asai Hirobumi , Hirata Junya , Hirano Ayumi , Hirai Kazuya , Seki Sayaka , Watanabe-Akanuma Mie
Published: November 2015

Indoxyl sulfate (IS) is a representative uremic toxin that accumulates in the blood of patients with chronic kidney disease (CKD). In addition to the involvement in the progression of CKD, a recent report indicates that IS suppresses hypoxia-inducible factor (HIF)-dependent erythropoietin (EPO) production, suggesting that IS may also contribute to the progression of renal anemia. In this report, we provide evidence that aryl hydrocarbon receptor (AhR) mediates IS-induced suppression of HIF activation and subsequent EPO production. In HepG2 cells, IS at concentrations similar to the blood levels in CKD patients suppressed hypoxia- or cobalt chloride-induced EPO mRNA expression and transcriptional activation of HIF. IS also induced AhR activation, and AhR blockade resulted in abolishment of IS-induced suppression of HIF activation. The HIF transcription factor is a heterodimeric complex composed of HIF-α subunits (HIF-1α and HIF-2α) and AhR nuclear translocator (ARNT). IS suppressed nuclear accumulation of the HIF-α-ARNT complex accompanied by an increase of the AhR-ARNT complex in the nucleus, implying the involvement of interactions among AhR, HIF-α, and ARNT in the suppression mechanism. In rats, oral administration of indole, a metabolic precursor of IS, inhibited bleeding-induced elevation of renal EPO mRNA expression and plasma EPO concentration and strongly induced AhR activation in the liver and renal cortex tissues. Collectively, this study is the first to elucidate the detailed mechanism by which AhR plays an indispensable role in the suppression of HIF activation by IS. Hence, IS-induced activation of AhR may be a potential therapeutic target for treating renal anemia.
Central ghrelin increases food foraging/hoarding that is blocked by GHSR antagonism and attenuates hypothalamic paraventricular nucleus neuronal activation
Authors: Thomas Michael A. , Ryu Vitaly , Bartness Timothy J.
Published: November 2015

The stomach-derived “hunger hormone” ghrelin increases in the circulation in direct response to time since the last meal, increasing preprandially and falling immediately following food consumption. We found previously that peripheral injection of ghrelin potently stimulates food foraging (FF), food hoarding (FH), and food intake (FI) in Siberian hamsters. It remains, however, largely unknown if central ghrelin stimulation is necessary/sufficient to increase these behaviors regardless of peripheral stimulation of the ghrelin receptor [growth hormone secretagogue receptor (GHSR)]. We injected three doses (0.01, 0.1, and 1.0 μg) of ghrelin into the third ventricle (3V) of Siberian hamsters and measured changes in FF, FH, and FI. To test the effects of 3V ghrelin receptor blockade, we used the potent GHSR antagonist JMV2959 to block these behaviors in response to food deprivation or a peripheral ghrelin challenge. Finally, we examined neuronal activation in the arcuate nucleus and paraventricular hypothalamic nucleus in response to peripheral ghrelin administration and 3V GHSR antagonism. Third ventricular ghrelin injection significantly increased FI through 24 h and FH through day 4. Pretreatment with 3V JMV2959 successfully blocked peripheral ghrelin-induced increases in FF, FH, and FI at all time points and food deprivation-induced increases in FF, FH, and FI up to 4 h. c-Fos immunoreactivity was significantly reduced in the paraventricular hypothalamic nucleus, but not in the arcuate nucleus, following pretreatment with intraperitoneal JMV2959 and ghrelin. Collectively, these data suggest that central GHSR activation is both necessary and sufficient to increase appetitive and consummatory behaviors in Siberian hamsters.
No reserve in isokinetic cycling power at intolerance during ramp incremental exercise in endurance-trained men
Authors: Ferguson Carrie , Wylde Lindsey A. , Benson Alan P. , Cannon Daniel T. , Rossiter Harry B.
Published: November 2015

During whole body exercise in health, maximal oxygen uptake (V̇o2max) is typically attained at or immediately before the limit of tolerance (LoT). At the V̇o2max and LoT of incremental exercise, a fundamental, but unresolved, question is whether maximal evocable power can be increased above the task requirement, i.e., whether there is a “power reserve” at the LoT. Using an instantaneous switch from cadence-independent (hyperbolic) to isokinetic cycle ergometry, we determined maximal evocable power at the limit of ramp-incremental exercise. We hypothesized that in endurance-trained men at LoT, maximal (4 s) isokinetic power would not differ from the power required by the task. Baseline isokinetic power at 80 rpm (Piso; measured at the pedals) and summed integrated EMG from five leg muscles (ΣiEMG) were measured in 12 endurance-trained men (V̇o2max = 4.2 ± 1.0 l/min). Participants then completed a ramp incremental exercise test (20-25 W/min), with instantaneous measurement of Piso and ΣiEMG at the LoT. Piso decreased from 788 ± 103 W at baseline to 391 ± 72 W at LoT, which was not different from the required ramp-incremental flywheel power (352 ± 58 W; P > 0.05). At LoT, the relative reduction in Piso was greater than the relative reduction in the isokinetic ΣiEMG (50 ± 9 vs. 63 ± 10% of baseline; P < 0.05). During maximal ramp incremental exercise in endurance-trained men, maximum voluntary power is not different from the power required by the task and is consequent to both central and peripheral limitations in evocable power. The absence of a power reserve suggests both the perceptual and physiological limits of maximum voluntary power production are not widely dissociated at LoT in this population.
Two-stage muscle activity responses in decisions about leg movement adjustments during trip recovery
Authors: Potocanac Zrinka , Pijnappels Mirjam , Verschueren Sabine , van Dieën Jaap , Duysens Jacques
Published: November 2015

Studies on neural decision making mostly investigated fast corrective adjustments of arm movements. However, fast leg movement corrections deserve attention as well, since they are often required to avoid falling after balance perturbations. The present study aimed at elucidating the mechanisms behind fast corrections of tripping responses by analyzing the concomitant leg muscle activity changes. This was investigated in seven young adults who were tripped in between normal walking trials and took a recovery step by elevating the tripped leg over the obstacle. In some trials, a forbidden landing zone (FZ) was presented behind the obstacle, at the subjects' preferred foot landing position, forcing a step correction. Muscle activity of the tripped leg gastrocnemius medialis (iGM), tibialis anterior (iTA), rectus femoris (iRF), and biceps femoris (iBF) muscles was compared between normal trips presented before any FZ appearance, trips with a FZ, and normal trips presented in between trips with a FZ (“catch” trials). When faced with a real or expected (catch trials) FZ, subjects shortened their recovery steps. The underlying changes in muscle activity consisted of two stages. The first stage involved reduced iGM activity, occurring at a latency shorter than voluntary reaction, followed by reduced iTA and increased iBF and iGM activities occurring at longer latencies. The fast response was not related to step shortening, but longer latency responses clearly were functional. We suggest that the initial response possibly acts as a “pause,” allowing the nervous system to integrate the necessary information and prepare the subsequent, functional movement adjustment.