bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular immunology profiles of monkeys following xenografting with the islets and heart of α‐1,3‐galactosyltransferase knockout pigs
Authors: Ock Sun A , Lee Jungkyu , Oh Keon Bong , Hwang Seongsoo , Yun Ik Jin , Ahn Curie , Chee Hyun Keun , Kim Hwajung , Park Jae Berm , Kim Sung Joo , Kim Youngim , Im Gi‐Sun , Park EungWoo
Published: August 2016

Effective immunosuppression strategies and genetically modified animals have been used to prevent hyperacute and acute xenograft rejection; however, the underlying mechanisms remain unknown. In this study, we evaluated the expression of a comprehensive set of immune system‐related genes (89 genes, including five housekeeping genes) in the blood of cynomolgus monkeys (~5 yr old) used as graft recipients, before and after the xenografting of the islets and heart from single and double α‐1,3‐galactosyltransferase (GalT) knockout (KO) pigs (<6 weeks old). The immunosuppressive regimen included administration of cobra venom factor, anti‐thymocyte globulin, rituximab, and anti‐CD154 monoclonal antibodies to recipients before and after grafting. Islets were xenografted into the portal vein in type 1 diabetic monkeys, and the heart was xenografted by heterotopic abdominal heart transplantation. Genes from recipient blood were analyzed using RT2 profiler PCR arrays and the web‐based RT2 profiler PCR array software v.3.5. Recipients treated with immunosuppressive agents without grafting showed significant downregulation of CCL5, CCR4, CCR6, CD4, CD40LG, CXCR3, FASLG, CXCR3, FOXP3, GATA3, IGNG, L10, IL23A, TRAF6, MAPK8, MIF, STAT4, TBX21, TLR3, TLR7, and TYK2 and upregulation of IFNGR1; thus, genes involved in protection against viral and bacterial infection were downregulated, confirming the risk of infection. Notably, C3‐level control resulted in xenograft failure within 2 days because of a 7‐ to 11‐fold increase in all xenotransplanted models. Islet grafting using single GalT‐KO pigs resulted in upregulation of CXCL10 and MX1, early inflammation, and acute rejection‐associated signals at 2 days after xenografting. We observed at least 5‐fold upregulation in recipients transplanted with islets grafts from single (MX1) or double (C3, CCR8, IL6, IL13, IRF6, CXCL10, and MX1) GalT‐KO pigs after 77 days; single GalT‐KO incurred early losses owing to immune attacks. Our results suggest that this novel, simple, non‐invasive, and time‐efficient procedure (requiring only 1.5 ml blood) for evaluating graft success, minimizing immune rejection, and blocking infection.
Human antibody recognition of xenogeneic antigens (NeuGc and Gal) on porcine heart valves: could genetically modified pig heart valves reduce structural valve deterioration?
Authors: Lee Whayoung , Long Cassandra , Ramsoondar Jagdeece , Ayares David , Cooper David K. C. , Manji Rizwan A. , Hara Hidetaka
Published: August 2016

Background

Glutaraldehyde‐fixed bioprosthetic heart valves (GBHVs) derived from wild‐type (WT, genetically unmodified) pigs are widely used clinically for heart valve replacement. There is evidence that their failure is related to an immune response. The use of valves from genetically engineered pigs that do not express specific pig antigens may prolong GBHV survival. Our aims were to determine (i) expression of Gal and NeuGc on heart (aortic and pulmonary) valves and pericardium of WT, α1,3‐galactosyltransferase gene knockout (GTKO) and GTKO/N‐glycolylneuraminic acid gene‐knockout (GTKO/NeuGcKO) pigs in comparison with three different commercially available GBHVs and (ii) to determine human antibody binding to these tissues.

Methods

Wild‐type, GTKO/CD46, and GTKO/CD46/NeuGcKO pig valves and pericardium were tested (i) fresh and (ii) after fixation with glutaraldehyde (0.02%, 0.2%, 2%). Sections of GBHVs, fresh and fixed valves, and pericardium were stained for Gal and NeuGc expression, and for human IgM and IgG antibody binding.

Results

Gal and NeuGc expression was high on all GBHVs and WT pig valves/pericardium, but was absent after antigen‐specific‐knockout. There was no difference in antigen expression or antibody binding among WT aortic, pulmonary valves, and pericardium as well as GBHVs. Glutaraldehyde fixation did not alter expression of Gal or NeuGc. After incubation with human serum, human IgM and IgG bound to all GBHVs and WT pig valves/pericardium. Valves from GTKO/CD46 pigs and, particularly, GTKO/CD46/NeuGcKO pigs (with/without glutaraldehyde fixation) showed less IgM and IgG binding.

Conclusion

Compared to WT pigs, GTKO/CD46/NeuGcKO pigs would be preferable sources of GBHVs, because the absence of Gal/NeuGc expression reduces human antibody binding.
AN EASTERN ORTHODOX CRITIQUE OF THE SCIENCE–THEOLOGY DIALOGUE
Authors: Knight Christopher C.
Published: August 2016

On the basis of both philosophical arguments and the theological perspectives of Eastern Orthodox Christianity, a critique of two beliefs that are common within the mainstream science–theology dialogue is outlined. These relate to critical realism in understanding language usage and to naturalistic perspectives in relation to divine action. While the naturalistic perspectives on the history of the cosmos that are predominant within the dialogue are seen as generally acceptable from an Orthodox perspective, it is argued that they require theological expansion. This expansion suggests an understanding other than the “causal joint” model commonly adopted in relation to “special” divine action. This alternative model renders the distinction between “special” and “general” divine action redundant, and is based on what has been called a “teleological‐Christological” understanding of the cosmos, rooted in the fourth gospel's notion of the divine Logos. The relevance of this critique to scholars outside of the Orthodox community is urged.
SOME WAYS EMERGING ADULTS ARE SHAPING THE FUTURE OF RELIGION AND SCIENCE
Authors: Cootsona Greg
Published: August 2016

This article addresses how the field of religion and science will change in the coming decades by analyzing the attitudes of emerging adults (ages 18–30). I first present an overview of emerging adulthood to set the context for my analysis, especially highlighting the way in which emerging adults find themselves “in between” and in an “age of possibilities," free to explore a variety of options and thus often become “spiritual bricoleurs." Next, I expand on how a broadening pluralism in emerging adult culture changes both the conversation of “religion and science,” on one hand, and the locus for their interaction on the other. In the third section, I address the question of whether there exists a consensus view of how to relate religion and science. Paradoxically, though 18–30‐year‐olds perceive that there is conflict between science and religion, they personally endorse collaboration or independence. Finally, I draw conclusions for practitioners and theorists.
EARLY MODERN PROTESTANT VIRTUOSOS AND SCIENTISTS: SOME COMMENTS
Authors: von Greyerz Kaspar
Published: August 2016

The following essay is divided in three parts. First, while sharing in principle Harrison's hypothesis of an affinity between the sixteenth‐century Reformation and early modern science, it questions the connection between the latter and the Weberian “disenchantment of the world.” Second, it suggests a broader group of possible actors than that envisaged by Harrison in referring to virtuoso collectors and their cabinets of curiosities who are rather marginalized in Harrison's narrative. And third, it highlights (in agreement with Harrison) the physico‐theology of the second half of the seventeenth and the first half of the eighteenth century and beyond as an important temporary fusion of religion/theology and science at a time when the new science was still striving for social and religious respectability.
SECULARIZING DEMONS: FUNDAMENTALIST NAVIGATIONS IN RELIGION AND SECULARITY
Authors: O'Donnell S. Jonathon
Published: August 2016

Since the turn of the millennium, theologians and secular scholars of religion have increasingly begun exploring the relationship between transhumanism and religion. However, analyses of anti‐transhumanist apocalypticisms are still rare, and those that exist are situated mainly among broader explorations of religious and secular bioconservatism. This article addresses this lack of specificity by drawing analyses of transhumanism and religion into dialogue with explorations of contemporary demonology through a close study of the beliefs of the evangelical conspiracist Thomas Horn and the anti‐transhumanist milieu around him. Exploring the milieu's multifaceted demonology of the secular world in light of genealogies of religion and secularity, the article situates Horn's demonology as one attempt to negotiate these genealogies, using what Sean McCloud terms a “‘supernatural’ hermeneutics of suspicion” that sees spiritual forces as the structural base of reality. It argues that, while fringe, milieus like Horn's illuminate broader cultural tensions and genealogical relations surrounding the place of religion in a secular(izing) world.
APORETIC POSSIBILITIES IN CATHERINE KELLER'SCLOUD OF THE IMPOSSIBLE
Authors: White Carol Wayne
Published: August 2016

In stressing the beauty of ignorance, of not knowing in the usual manner, Catherine Keller'sCloud of the Impossibleevokes the death of a metaphysical (A)uthorial presence and the dissolution of closed systems of meaning. In this article, I view her text as part of a crisis of modernity that challenges dominant theological pathways, on which certain problematic views of the human have been constructed. In my reading, Keller'sCloudenriches humanistic thinking in the West and I explore the themes it shares with my own work in religious naturalism: there is no escape from the radical relationality and the irreducible materiality that structure human existence. I also emphasize that textual strategies are mere seductive, disembodied abstractions without acknowledging the force of materiality. Materiality matters; and I explore ways in which religious naturalism demonstrates how it does. In light of Keller's rich analysis, I focus on a “learned ignorance” that accompanies all of our limited interpretations emerging from the shifting, precarious positionalities as we rethink our relationality to each other and to all that it is.
WHY WE SHOULD CARE ABOUT EVOLUTION AND NATURAL HISTORY
Authors: Kjærgaard Peter C.
Published: August 2016

Historians play it safe. Complex issues are dissected while analytical distance keeps stakeholders at bay. But the relevance of historical research may be lost in caution and failure to engage with a wider audience. We can't afford that. We have too much to offer and too much at stake. We need to take the discussion of science and religion beyond our own professional circles. Peter Harrison's The Territories of Science and Religion gives us an opportunity to do so. We can use his book to understand why people consistently get the relation wrong. However, we need to take the next step ourselves, involve historians in the common academic goal, across disciplines, to make sense of the world around us and make that combined knowledge truly useful. Evolution and natural history might help to that effect.
Systemic availability and metabolism of colonic‐derived short‐chain fatty acids in healthy subjects: a stable isotope study
Authors: Boets Eef , Gomand Sara V. , Deroover Lise , Preston Tom , Vermeulen Karen , De Preter Vicky , Hamer Henrike M. , Van den Mooter Guy , De Vuyst Luc , Courtin Christophe M. , Annaert Pieter , Delcour Jan A. , Verbeke Kristin A.
Published: August 2016

Key points

The short‐chain fatty acids (SCFAs) are bacterial metabolites produced during the colonic fermentation of undigested carbohydrates, such as dietary fibre and prebiotics, and can mediate the interaction between the diet, the microbiota and the host.

We quantified the fraction of colonic administered SCFAs that could be recovered in the systemic circulation, the fraction that was excreted via the breath and urine, and the fraction that was used as a precursor for glucose, cholesterol and fatty acids.

This information is essential for understanding the molecular mechanisms by which SCFAs beneficially affect physiological functions such as glucose and lipid metabolism and immune function.

The short‐chain fatty acids (SCFAs), acetate, propionate and butyrate, are bacterial metabolites that mediate the interaction between the diet, the microbiota and the host. In the present study, the systemic availability of SCFAs and their incorporation into biologically relevant molecules was quantified. Known amounts of 13C‐labelled acetate, propionate and butyrate were introduced in the colon of 12 healthy subjects using colon delivery capsules and plasma levels of 13C‐SCFAs 13C‐glucose, 13C‐cholesterol and 13C‐fatty acids were measured. The butyrate‐producing capacity of the intestinal microbiota was also quantified. Systemic availability of colonic‐administered acetate, propionate and butyrate was 36%, 9% and 2%, respectively. Conversion of acetate into butyrate (24%) was the most prevalent interconversion by the colonic microbiota and was not related to the butyrate‐producing capacity in the faecal samples. Less than 1% of administered acetate was incorporated into cholesterol and <15% in fatty acids. On average, 6% of colonic propionate was incorporated into glucose. The SCFAs were mainly excreted via the lungs after oxidation to 13CO2, whereas less than 0.05% of the SCFAs were excreted into urine. These results will allow future evaluation and quantification of SCFA production from 13C‐labelled fibres in the human colon by measurement of 13C‐labelled SCFA concentrations in blood.
Effects of a near-field rigid sphere scatterer on the performance of linear microphone array beamformers
Authors: Hu Yuxiang , Zhou Haoran , Lu Jing , Qiu Xiaojun
Published: August 2016

Beamformers enable a microphone array to capture acoustic signals from a sound source with high signal to noise ratio in a noisy environment, and the linear microphone array is of particular importance, in practice, due to its simplicity and easy implementation. A linear microphone array sometimes is used near some scattering objects, which affect its beamforming performance. This paper develops a numerical model with a linear microphone array near a rigid sphere for both far-field plane wave and near-field sources. The effects of the scatterer on two typical beamformers, i.e., the delay-and-sum beamformer and the superdirective beamformer, are investigated by both simulations and experiments. It is found that the directivity factor of both beamformers improves due to the increased equivalent array aperture when the size of the array is no larger than that of the scatter. With the increase of the array size, the directivity factor tends to deteriorate at high frequencies because of the rising side-lobes. When the array size is significantly larger than that of the scatterer, the scattering has hardly any influence on the beamforming performance.
Identical band gaps in structurally re-entrant honeycombs
Authors: Zhu Zhu-Wei , Deng Zi-Chen
Published: August 2016

Structurally re-entrant honeycomb is a sort of artificial lattice material, characterized by star-like unit cells with re-entrant topology, as well as a high connectivity that the number of folded sheets jointing at each vertex is at least six. In-plane elastic wave propagation in this highly connected honeycomb is investigated through the application of the finite element method in conjunction with the Bloch's theorem. Attention is devoted to exploring the band characteristics of two lattice configurations with different star-like unit cells, defined as structurally square re-entrant honeycomb (SSRH) and structurally hexagonal re-entrant honeycomb (SHRH), respectively. Identical band gaps involving their locations and widths, interestingly, are present in the two considered configurations, attributed to the resonance of the sketch folded sheets, the basic component elements for SSRH and SHRH. In addition, the concept of heuristic models is implemented to elucidate the underlying physics of the identical gaps. The phenomenon of the identical bandgaps is not only beneficial for people to further explore the band characteristics of lattice materials, but also provides the structurally re-entrant honeycombs as potential host structures for the design of lattice-based metamaterials of interest for elastic wave control.
On the evaluation of effective density for plate- and membrane-type acoustic metamaterials without mass attached
Authors: Huang Tai-Yun , Shen Chen , Jing Yun
Published: August 2016

The effective densities of plate- and membrane-type acoustic metamaterials (AMMs) without mass attached are studied theoretically and numerically. Three models, including the analytic model (based on the plate flexural wave equation and the membrane wave equation), approximate model (under the low frequency approximation), and the finite element method (FEM) model, are first used to calculate the acoustic impedance of square and clamped plates or membranes. The effective density is then obtained using the resulting acoustic impedance and a lumped model. Pressure transmission coefficients of the AMMs are computed using the obtained densities. The effect of the loss from the plate is also taken into account. Results from different models are compared and good agreement is found, particularly between the analytic model and the FEM model. The approximate model is less accurate when the frequency of interest is above the first resonance frequency of the plate or membrane. The approximate model, however, provides simple formulae to predict the effective densities of plate- or membrane-type AMMs and is accurate for the negative density frequency region. The methods presented in this paper are useful in designing AMMs for manipulating acoustic waves.
Experimental test of nonlocal causality
Authors: Ringbauer Martin , Giarmatzi Christina , Chaves Rafael , Costa Fabio , White Andrew G. , Fedrizzi Alessandro
Published: August 2016

Causation at a distance does not explain quantum correlations.
In-airway molecular flow sensing: A new technology for continuous, noninvasive monitoring of oxygen consumption in critical care
Authors: Ciaffoni Luca , O’Neill David P. , Couper John H. , Ritchie Grant A. D. , Hancock Gus , Robbins Peter A.
Published: August 2016

Laser absorption spectroscopy of respired gas offers new opportunities for monitoring critically ill patients.
A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease
Authors: Freer Rosie , Sormanni Pietro , Vecchi Giulia , Ciryam Prajwal , Dobson Christopher M. , Vendruscolo Michele
Published: August 2016

A tissue vulnerability map based on Aβ and tau homeostasis in healthy brains predicts the staging of Alzheimer’s disease.
Founder's death unsettles Egypt's science city
Authors: Service Robert F.
Published: August 2016

Nobel Prize-winning chemist Ahmed Zewail was key to fundraising and recruitment
NIH plans to fund human-animal chimera research
Authors: Kaiser Jocelyn
Published: August 2016

Agency would subject experiments—such as growing human organs in pigs—to extra ethical review
Oil in the forest
Authors: Fraser Barbara
Published: August 2016

A rash of spills in the Amazon has scientists and villagers scrambling to understand oil's effects on the ecosystem
Local modulation of human brain responses by circadian rhythmicity and sleep debt
Authors: Muto Vincenzo , Jaspar Mathieu , Meyer Christelle , Kussé Caroline , Chellappa Sarah L. , Degueldre Christian , Balteau Evelyne , Shaffii-Le Bourdiec Anahita , Luxen André , Middleton Benita , Archer Simon N. , Phillips Christophe , Collette Fabienne , Vandewalle Gilles , Dijk Derk-Jan , Maquet Pierre
Published: August 2016

Circadian rhythms and sleep deprivation

Sleep deprivation, such as that experienced because of shift work, jet lag, sleep disorders, and aging, leads to deterioration of many aspects of health. Cognition deteriorates rapidly and substantially when we stay awake through the night. To investigate the time course of brain responses during sleep loss, Muto
et al.
scanned volunteers repeatedly during an extended period of wakefulness (see the Perspective by Czeisler) in which circadian and homeostatic drives differentially affected local brain regions.

Science
, this issue p.
687
; see also p.
648
Comment on “Mutation rate and genotype variation of Ebola virus from Mali case sequences”
Authors: Rambaut Andrew , Dudas Gytis , Max de Carvalho Luiz , Park Daniel J. , Yozwiak Nathan L. , Holmes Edward C. , Andersen Kristian G.
Published: August 2016

Hoenen
et al
. (Reports, 3 April 2015, p. 117; published online 26 March) suggested that the Ebola virus Makona responsible for the West African epidemic evolved more slowly than previously reported. We show that this was based on corrupted data. An erratum provided a rate compatible with the initial and later, more precise, estimates but did not correctly state the nature of the error.
Spt4 selectively regulates the expression of
C9orf72
sense and antisense mutant transcripts
Authors: Kramer Nicholas J. , Carlomagno Yari , Zhang Yong-Jie , Almeida Sandra , Cook Casey N. , Gendron Tania F. , Prudencio Mercedes , Van Blitterswijk Marka , Belzil Veronique , Couthouis Julien , Paul Joseph West , Goodman Lindsey D. , Daughrity Lillian , Chew Jeannie , Garrett Aliesha , Pregent Luc , Jansen-West Karen , Tabassian Lilia J. , Rademakers Rosa , Boylan Kevin , Graff-Radford Neill R. , Josephs Keith A. , Parisi Joseph E. , Knopman David S. , Petersen Ronald C. , Boeve Bradley F. , Deng Ning , Feng Yanan , Cheng Tzu-Hao , Dickson Dennis W. , Cohen Stanley N. , Bonini Nancy M. , Link Christopher D. , Gao Fen-Biao , Petrucelli Leonard , Gitler Aaron D.
Published: August 2016

Targeting three defects with one strategy

The neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia are most commonly caused by a mutation in the
C9orf72
gene. The mutation is an expanded hexanucleotide repeat in a noncoding region. The expanded repeat produces sense and antisense RNA transcripts, which accumulate in patient cells and appear to sequester RNA-binding proteins. The sense and antisense transcripts are also translated into dipeptide repeat proteins, which are aggregation-prone and accumulate in the brain and spinal cord. Last, loss of function from reduced expression of
C9orf72
in neurons and glia could contribute to the disease. Kramer
et al.
targeted both sense and antisense repeats by blocking a single gene called
SPT4
, which mitigated degeneration in human cells by reducing all three types of pathologies.

Science
, this issue p.
708
Highly stretchable, transparent ionic touch panel
Authors: Kim Chong-Chan , Lee Hyun-Hee , Oh Kyu Hwan , Sun Jeong-Yun
Published: August 2016

Soft and still responsive

Transparent touch screens, from large-panel interactive information maps to advanced cell phones, have become a part of daily life. However, such devices all use hard materials. Kim
et al.
have developed a soft touch panel based on polyacrylamide hydrogels (cross-linked polymers swollen with water) that are highly transparent and contain trapped LiCl to enhance conductivity. The hydrogels are soft and can be stretched extensively while still maintaining touch sensitivity.

Science
, this issue p.
682
Balancing economic and ecological goals
Authors: Frank Eyal G. , Schlenker Wolfram
Published: August 2016

What are the trade-offs between economic development and ecosystem conservation?
Making sense of the exoplanet zoo
Authors: Oppenheimer Rebecca
Published: August 2016

The diversity of substellar objects may call for a rethinking of our labeling conventions
Atmospheric radical chemistry revisited
Authors: Vaida Veronica
Published: August 2016

Sunlight may directly drive previously unknown organic reactions at environmental surfaces
One target for amyotrophic lateral sclerosis therapy?
Authors: Mizielinska Sarah , Isaacs Adrian M.
Published: August 2016

Targeting a single protein reduces both toxic repeat RNAs and proteins
Malnutrition Is Associated with Protection from Rotavirus Diarrhea: Evidence from a Longitudinal Birth Cohort Study in Bangladesh
Authors: Verkerke Hans , Sobuz Shihab , Ma Jennie Z. , Petri Sarah E. , Reichman Dan , Qadri Firdausi , Rahman Mustafizur , Haque Rashidul , Petri William A.
Published: August 2016

Rotavirus is a leading cause of dehydrating diarrhea and death among infants and children globally, particularly in communities of the developing world. While numerous studies have described the complex relationships among infectious diarrhea, growth faltering, and poverty, the impact of nutritional status on susceptibility to rotavirus diarrhea is not well understood. In a longitudinal study conducted over the first 3 years of life among 626 slum-dwelling infants enrolled at birth in Dhaka, Bangladesh, we observed that common measures of healthy growth and development were positively associated with a risk of symptomatic rotavirus infection. This finding runs counter to the idea that improving childhood nutrition will implicitly decrease the incidence of symptomatic infection by enteric pathogens. As childhood nutrition improves worldwide, rotavirus infection may remain a public health challenge, making universal vaccination of even greater importance.
Evaluation of Hologic Aptima HIV-1 Quant Dx Assay on the Panther System on HIV Subtypes
Authors: Manak Mark M. , Hack Holly R. , Nair Sangeetha V. , Worlock Andrew , Malia Jennifer A. , Peel Sheila A. , Jagodzinski Linda L.
Published: August 2016

Quantitation of the HIV-1 viral load in plasma is the current standard of care for clinical monitoring of HIV-infected individuals undergoing antiretroviral therapy. This study evaluated the analytical and clinical performances of the Aptima HIV-1 Quant Dx assay (Hologic, San Diego, CA) for monitoring viral load by using 277 well-characterized subtype samples, including 171 cultured virus isolates and 106 plasma samples from 35 countries, representing all major HIV subtypes, recombinants, and circulating recombinant forms (CRFs) currently in circulation worldwide. Linearity of the Aptima assay was tested on each of 6 major HIV-1 subtypes (A, B, C, D, CRF01_AE, and CRF02_AG) and demonstrated an
R
2
value of ≥0.996. The performance of the Aptima assay was also compared to those of the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 v.2 (CAP/CTM) and Abbott m2000 RealTime HIV-1 (RealTime) assays on all subtype samples. The Aptima assay values averaged 0.21 log higher than the CAP/CTM values and 0.30 log higher than the RealTime values, and the values were >0.4 log higher than CAP/CTM values for subtypes F and G and than RealTime values for subtypes C, F, and G and CRF02_AG. Two samples demonstrated results with >1-log differences from RealTime results. When the data were adjusted by the average difference, 94.9% and 87.0% of Aptima results fell within 0.5 log of the CAP/CTM and RealTime results, respectively. The linearity and accuracy of the Aptima assay in correctly quantitating all major HIV-1 subtypes, coupled with the completely automated format and high throughput of the Panther system, make this system well suited for reliable measurement of viral load in the clinical laboratory.
Activation of the Chicken Anemia Virus Apoptin Protein by Chk1/2 Phosphorylation Is Required for Apoptotic Activity and Efficient Viral Replication
Authors: Kucharski Thomas J. , Ng Timothy F. , Sharon David M. , Navid-Azarbaijani Pedram , Tavassoli Mahvash , Teodoro Jose G.
Published: August 2016

Chicken anemia virus (CAV) is a single-stranded circular DNA virus that carries 3 genes, the most studied of which is the gene encoding VP3, also known as apoptin. This protein has been demonstrated to specifically kill transformed cells while leaving normal cells unharmed in a manner that is independent of p53 status. Although the mechanistic basis for this differential activity is unclear, it is evident that the subcellular localization of the protein is important for the difference. In normal cells, apoptin exists in filamentous networks in the cytoplasm, whereas in transformed cells, apoptin is present in the nucleus and appears as distinct foci. We have previously demonstrated that DNA damage signaling through the ataxia telangiectasia mutated (ATM) pathway induces the translocation of apoptin from the cytoplasm to the nucleus, where it induces apoptosis. We found that apoptin contains four checkpoint kinase consensus sites and that mutation of either threonine 56 or 61 to alanine restricts apoptin to the cytoplasm. Furthermore, treatment of tumor cells expressing apoptin with inhibitors of checkpoint kinase 1 (Chk1) and Chk2 causes apoptin to localize to the cytoplasm. Importantly, silencing of Chk2 rescues cancer cells from the cytotoxic effects of apoptin. Finally, treatment of virus-producing cells with Chk inhibitor protects them from virus-mediated toxicity and reduces the titer of progeny virus. Taken together, our results indicate that apoptin is a sensor of DNA damage signaling through the ATM-Chk2 pathway, which induces it to migrate to the nucleus during viral replication.

IMPORTANCE
The chicken anemia virus (CAV) protein apoptin is known to induce tumor cell-specific death when expressed. Therefore, understanding its regulation and mechanism of action could provide new insights into tumor cell biology. We have determined that checkpoint kinase 1 and 2 signaling is important for apoptin regulation and is a likely feature of both tumor cells and host cells producing virus progeny. Inhibition of checkpoint signaling prevents apoptin toxicity in tumor cells and attenuates CAV replication, suggesting it may be a future target for antiviral therapy.
Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis
Authors: Ismail Ashrafali M. , Lee Ji Sun , Dyer David W. , Seto Donald , Rajaiya Jaya , Chodosh James
Published: August 2016

Human adenoviruses (HAdVs) contain seven species (HAdV-A to -G), each associated with specific disease conditions. Among these, HAdV-D includes those viruses associated with epidemic keratoconjunctivitis (EKC), a severe ocular surface infection. The reasons for corneal tropism for some but not all HAdV-Ds are not known. The fiber protein is a major capsid protein; its C-terminal “knob” mediates binding with host cell receptors to facilitate subsequent viral entry. In a comprehensive phylogenetic analysis of HAdV-D capsid genes, fiber knob gene sequences of HAdV-D types associated with EKC formed a unique clade. By proteotyping analysis, EKC virus-associated fiber knobs were uniquely shared. Comparative structural modeling showed no distinct variations in fiber knobs of EKC types but did show variation among HAdV-Ds in a region overlapping with the known CD46 binding site in HAdV-B. We also found signature amino acid positions that distinguish EKC from non-EKC types, and byin vitrostudies we showed that corneal epithelial cell tropism can be predicted by the presence of a lysine or alanine at residue 240. This same amino acid residue in EKC viruses shows evidence for positive selection, suggesting that evolutionary pressure enhances fitness in corneal infection, and may be a molecular determinant in EKC pathogenesis.

IMPORTANCEViruses adapt various survival strategies to gain entry into target host cells. Human adenovirus (HAdV) types are associated with distinct disease conditions, yet evidence for connections between genotype and cellular tropism is generally lacking. Here, we provide a structural and evolutionary basis for the association between specific genotypes within HAdV species D and epidemic keratoconjunctivitis, a severe ocular surface infection. We find that HAdV-D fiber genes of major EKC pathogens, specifically the fiber knob gene region, share a distinct phylogenetic clade. Deeper analysis of the fiber gene revealed that evolutionary pressure at crucial amino acid sites has a significant impact on its structural conformation, which is likely important in host cell binding and entry. Specific amino acids in hot spot residues provide a link to ocular cell tropism and possibly to corneal pathogenesis.
Japanese Macaque Rhadinovirus Encodes a Viral MicroRNA Mimic of the miR-17 Family
Authors: Skalsky Rebecca L. , Barr Sarah A. , Jeffery Andrew J. , Blair Tiffany , Estep Ryan , Wong Scott W.
Published: August 2016

Japanese macaque (JM) rhadinovirus (JMRV) is a novel, gamma-2 herpesvirus that was recently isolated from JM with inflammatory demyelinating encephalomyelitis (JME). JME is a spontaneous and chronic disease with clinical characteristics and immunohistopathology comparable to those of multiple sclerosis in humans. Little is known about the molecular biology of JMRV. Here, we sought to identify and characterize the small RNAs expressed during lytic JMRV infection using deep sequencing. Fifteen novel viral microRNAs (miRNAs) were identified in JMRV-infected fibroblasts, all of which were readily detectable by 24 h postinfection and accumulated to high levels by 72 h. Sequence comparisons to human Kaposi's sarcoma-associated herpesvirus (KSHV) miRNAs revealed several viral miRNA homologs. To functionally characterize JMRV miRNAs, we screened for their effects on nuclear factor kappa B (NF-κB) signaling in the presence of two proinflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β). Multiple JMRV miRNAs suppressed cytokine-induced NF-κB activation. One of these miRNAs, miR-J8, has seed sequence homology to members of the cellular miR-17/20/106 and miR-373 families, which are key players in cell cycle regulation as well as inflammation. Using reporters, we show that miR-J8 can target 3′ untranslated regions (UTRs) with miR-17-5p or miR-20a cognate sites. Our studies implicate JMRV miRNAs in the suppression of innate antiviral immune responses, which is an emerging feature of many viral miRNAs.

IMPORTANCE
Gammaherpesviruses are associated with multiple diseases linked to immunosuppression and inflammation, including AIDS-related cancers and autoimmune diseases. JMRV is a recently identified herpesvirus that has been linked to JME, an inflammatory demyelinating disease in Japanese macaques that mimics multiple sclerosis. There are few large-animal models for gammaherpesvirus-associated pathogenesis. Here, we provide the first experimental evidence of JMRV miRNAs
in vitro
and demonstrate that one of these viral miRNAs can mimic the activity of the cellular miR-17/20/106 family. Our work provides unique insight into the roles of viral miRNAs during rhadinovirus infection and provides an important step toward understanding viral miRNA function in a nonhuman primate model system.
Long and Short Isoforms of the Human Cytomegalovirus UL138 Protein Silence IE Transcription and Promote Latency
Authors: Lee Song Hee , Caviness Katie , Albright Emily R. , Lee Jeong-Hee , Gelbmann Christopher B. , Rak Mike , Goodrum Felicia , Kalejta Robert F.
Published: August 2016

The UL133–138 locus present in clinical strains of human cytomegalovirus (HCMV) encodes proteins required for latency and reactivation in CD34
+
hematopoietic progenitor cells and virion maturation in endothelial cells. The encoded proteins form multiple homo- and hetero-interactions and localize within secretory membranes. One of these genes, UL136 gene, is expressed as at least five different protein isoforms with overlapping and unique functions. Here we show that another gene from this locus, the UL138 gene, also generates more than one protein isoform. A long form of UL138 (pUL138-L) initiates translation from codon 1, possesses an amino-terminal signal sequence, and is a type one integral membrane protein. Here we identify a short protein isoform (pUL138-S) initiating from codon 16 that displays a subcellular localization similar to that of pUL138-L. Reporter, short-term transcription, and long-term virus production assays revealed that both pUL138-L and pUL138-S are able to suppress major immediate early (IE) gene transcription and the generation of infectious virions in cells in which HCMV latency is studied. The long form appears to be more potent at silencing IE transcription shortly after infection, while the short form seems more potent at restricting progeny virion production at later times, indicating that both isoforms of UL138 likely cooperate to promote HCMV latency.

IMPORTANCE
Latency allows herpesviruses to persist for the lives of their hosts in the face of effective immune control measures for productively infected cells. Controlling latent reservoirs is an attractive antiviral approach complicated by knowledge deficits for how latently infected cells are established, maintained, and reactivated. This is especially true for betaherpesviruses. The functional consequences of HCMV UL138 protein expression during latency include repression of viral IE1 transcription and suppression of virus replication. Here we show that short and long isoforms of UL138 exist and can themselves support latency but may do so in temporally distinct manners. Understanding the complexity of gene expression and its impact on latency is important for considering potential antivirals targeting latent reservoirs.
Recognising early meningitis: a missed opportunity to diagnose meningitis
Authors: Ponnampalam Anusha , de Sousa Paula , Carroll Will
Published: August 2016

There are ∼250 cases of neonatal bacterial meningitis each year in the UK. Clinical evaluation of signs and symptoms of meningitis is challenging, particularly, during the neonatal period. Although uncommon, it is recognised that bacterial meningitis can be present in a child with an apparently normal cerebrospinal fluid (CSF) initially.We report the case of a newborn baby girl who was admitted with concerns regarding 2 dusky episodes. She underwent blood tests, a lumbar puncture and was started on intravenous antibiotics. With negative cultures, normal blood results and following a significant clinical improvement, antibiotics were discontinued after 48 hours and the baby was discharged home. She re-presented to the children's emergency department 7 hours later with a history of an apnoeic episode. A second CSF sample was suggestive of bacterial meningitis. We will discuss the published literature and the potential drawbacks of lumbar punctures and ways to diagnose meningitis early.
Case of coccidioidomycosis in Ireland
Authors: Duggan Patrick Thomas , Deegan Alexander P , McDonnell Timothy J
Published: August 2016

Coccidioidal infection is a well-recognised cause of pulmonary disease in certain parts of the south-western USA, Central and South America; however, it is rarely encountered elsewhere in the world. We describe the case of a previously healthy man presenting to a Dublin hospital with fever, dry cough and chest pain, following a visit to the western USA. Despite treatment with broad-spectrum antimicrobials, the patient developed progressive bilateral pulmonary infiltrates and a large pleural effusion. After extensive investigations including CT, bronchoscopy and pleural fluid analysis, a diagnosis of pulmonary coccidioidomycosis was made. Following the initiation of appropriate antifungal therapy, the patient made a full recovery. This case was of interest due to the rarity of the disease outside its areas of endemicity and the unusual findings associated with its diagnosis.
Future marginalisation and mortality in young Swedish men with non-psychotic psychiatric disorders and the resilience effect of cognitive ability: a prospective, population-based study
Authors: Löve J , Hensing G , Söderberg M , Torén K , Waern M , Åberg M
Published: August 2016

Objective

Large-scale studies examining future trajectories of marginalisation and health in adolescents with mental illness are scarce. The aim of this study was to examine if non-psychotic psychiatric disorders (NPDs) were associated with future indicators of marginalisation and mortality. We also aimed to determine whether these associations might be mediated by education level and attenuated by high cognitive ability.

Design

This is a prospective cohort study with baseline data from the Swedish Conscription register.

Setting

The study was carried out in Sweden from 1969 to 2005.

Participants

All of the participants were 18-year-old men at mandatory conscription in Sweden between 1969 and 2005 (n=1 609 690).

Measures

NPDs were clinically diagnosed at conscription. Cognitive ability was measured by a standardised IQ test at conscription. National register data covered information on welfare support, long-term unemployment, disability pension (DP) and mortality over a period of 1–36 years.

Results

NPD at the age of 18 years was a predictor of future welfare support, OR 3.73 (95% CI 3.65 to 3.80); long-term unemployment, OR 1.97 (95% CI 1.94 to 2.01); DP, HR 2.95 (95% CI 2.89 to 3.02); and mortality, HR 2.45 (2.33–2.52). The adjusted models suggested that these associations were not confounded by fathers’ educational level, cognitive ability had only a minor attenuating effect on most associations and the mediating effect of own educational level was small.

Conclusions

The present study underlines a higher prevalence of future adversities in young men experiencing NPDs at the age of 18 years. It also indicates that higher cognitive ability may work as a potential resilience factor against future marginalisation and mortality.
Study of seven single-nucleotide polymorphisms identified in East Asians for association with obesity in a Taiwanese population
Authors: Huang Wei-Hsin , Hwang Lee-Ching , Chan Hsin-Lung , Lin Hsiang-Yu , Lin Yung-Hsiang
Published: August 2016

Objective

This study aimed to examine single-nucleotide polymorphisms (SNPs) of seven previously reported obesity genes in East Asians and to analyse their associations and synergistic effects on obesity in the Taiwanese population.

Design

Cross-sectional study.

Setting

One medical centre in northern Taiwan.

Participants

A total of 323 non-obese and 264 obese participants were recruited. The threshold for obesity in this study was a body mass index of ≥27 kg/m2, as defined by the Ministry of Health and Welfare in Taiwan. The study was performed with the approval of the institutional review board of MacKay Memorial Hospital, Taipei, Taiwan (application number 12MMHIS106).

Outcome measures

We analysed the genotype distributions of seven SNPs localising to thePPARγ2, GNB3, SDC3, ADRB2, FTO, PPARγ and ESR1genes in obese and non-obese groups and then paired obesity-related SNPs to determine if they have synergistic effects on obesity.

Results

Analysis of the genotype distributions in obese and non-obese groups revealed only a significant positive correlation between an SNP in rs2282440-syndecan 3 (SDC3) and obesity in the Taiwanese population (p=0.006). In addition, the T/T genotype ofSDC3was significantly associated with a larger waist and hip circumference, higher body fat percentage and lower high-density lipoprotein cholesterol. Moreover, the combination of the rs2282440-SDC3T/T genotype with the rs1801282-peroxisome proliferator-activated receptor-gamma2 gene (PPARγ2) G carrier genotype was strongly associated with obesity (OR=6.77).

Conclusions

We found that the rs2282440-SDC3T/T genotype is associated with obesity in the Taiwanese population. Furthermore, there is a synergistic effect of the high-risk alleles of theSDC3andPPARγ2genes on the obese phenotype in the Taiwanese population.

Trial registration number

12MMHIS106; Results.
Fistulous-type vein of Galen malformation phantom model for endovascular training and research
Authors: Meila Dan , Melber Katharina , Grieb Dominik , Jacobs Collin , Lanfermann Heinrich , Brassel Friedhelm
Published: August 2016

Introduction

Vein of Galen malformation (VGM), a high-flow intracranial arteriovenous shunt, is among the most severe neurovascular diseases in childhood. In many cases untreated children die or survive only severely disabled. Endovascular embolization is the preferred treatment.

Objective

To develop a simple fistulous-type VGM phantom model for teaching and training of different endovascular treatment methods and to investigate new treatment options and devices.

Methods

An experimental in vitro pulsatile phantom model was developed imitating a high-flow fistulous-type VGM, which is typical, especially in the neonatal phase. Pressure measurements at different arterial sites were performed before and after closure of the VGM. Closure of the VGM was achieved by coiling using a combined microcatheter-based transvenous and transarterial approach called ‘kissing microcatheter technique’.

Results

The behaviour of the phantom model in vitro under fluoroscopy and under angiographic runs was extremely similar to that in in vivo conditions in children. The results showed that intra-arterial pressures changed and increased statistically significantly at all measurement sites after embolization, as in human arteriovenous malformation. We also demonstrated different and complementary visualizations of hemodynamics and angioarchitecture by antegrade and retrograde microcatheter injections.

Conclusions

Our phantom model behaves like a typical fistulous-type VGM and can be used in vitro for teaching and training and for further research. It offers a new and better understanding of hemodynamics and angioarchitecture in the endovascular management of VGM.
Critical thinking or common sense?
Authors: Adams Vicki
Published: August 2016

Vicki Adams grew up in Vancouver, Canada, and graduated with a degree in animal science from the University of British Columbia before being accepted into vet school in Saskatchewan. Her animal science background has given her the population perspective that is so important in epidemiology and she now runs her own consulting company, Vet Epi
Therapeutic effects of antibiotic drug mefloquine against cervical cancer through impairing mitochondrial function and inhibiting mTOR pathway
Authors: Li Hui , Jiao Shun , Li Xin , Banu Hasina , Hamal Shreejana , Wang Xianrong
Published: August 2016

Targeting mitochondria is an attractive strategy for cancer therapy due to the essential roles of mitochondria in cancer cell energy metabolism. In this study, we show that mefloquine, an antibiotic drug, effectively targets cervical cancer cells through impairing mitochondrial function. Mefloquine dose-dependently induces apoptosis and inhibits proliferation and anchorage-independent colony formation of multiple cervical cancer cell lines. Mefloquine alone inhibits cervical tumor growth in vivo and its combination with paclitaxel is synergistic in inhibiting tumor growth. Mechanistically, mefloquine inhibits mitochondrial function via inhibiting mitochondrial respiration, decreasing membrane potential, increasing ROS generation, and decreasing ATP level. We further show that mefloquine suppresses activation of mTOR signaling pathway in HeLa cells. However, the inhibitory effects of mefloquine on survival, colony formation, and ATP are abolished in mitochondrial respiration-deficient HeLa ρ0 cells, demonstrating that mefloquine acts on cervical cancer cells via targeting mitochondrial respiration. Inhibition of mTOR signaling pathway by mefloquine was also reversed in HeLa ρ0 cells, suggesting deactivation of mTOR pathway as a consequence of mitochondria function disruption. Our work suggests that mefloquine is a potential candidate for cervical cancer treatment. Our work also highlights the therapeutic value of anti-mitochondria and establishes the association of mitochondrial function and the activation of mTOR signaling pathway in cervical cancer cells.