bluuebunny/crossref_metadata_2025 huggingface dataset:
The Anthroposcenic
Authors: Matless David
Published: January 2017

This paper presents the ‘Anthroposcenic’ as a geographical contribution to debates around the Anthropocene, deploying the insights of cultural and historical geography to ask how thinking through landscape and time might shape understanding. The paper begins by elaborating on the term ‘Anthroposcenic’, foregrounding the ways in which landscape becomes emblematic of environmental transformation, and reflects further on geological wordplay in science and the humanities. The role of historical enquiry in addressing the times of the Anthropocene is considered, in terms of the dating of a proposed Anthropocene epoch, and the resonance of past geological debate. The possibilities of the Anthroposcenic are then demonstrated through studies of eroding coastal landscapes, drawing on contemporary and historical material from the English coast. Landscape here becomes emblematic of the Anthropocene, and shows how processes of environmental change are articulated through different geographical scales. Coastal studies also show past landscape achieving present resonance, and thereby how the Anthroposcenic may encompass historical material anticipatory of current debate. The paper reflects too on the ways in which questions of inheritance may frame Anthroposcenic enquiry. A specific Anthroposcene serves to open and close the paper.
Tears of time: a Lefebvrian rhythmanalysis approach to explore the mobility experiences of young Eastern Europeans in Spain
Authors: Marcu Silvia
Published: January 2017

This paper explores the rhythm of temporary mobility experiences of young Eastern Europeans in Spain, after the European Union (EU) enlargement towards the East. Following Lefebvre's rhythmanalysis approach, and drawing on 60 in‐depth qualitative interviews, this paper investigates how rhythms are linked to youth mobility and how different interplays of rhythms are connected and disconnected in multiple ways. I argue that both the EU socio‐economic context and the personal and professional life‐course circumstances of young Eastern Europeans who practice mobility create different, uneven rhythms that influence their everyday lives and their perceptions of mobility. This paper highlights the issue of rhythmic change in temporary mobility, uncovering ‘arrhythmic’ mobility, reflected in the loss and insecurity in the lives of those who practice it; ‘polyrhythmic’ mobility, practised by people looking to study and/or work and expressed through uncertainty on the one hand and the possibility of establishing a certain rhythm in their lives on the other; and ‘eurhythmic’ mobility, used by those with a stable professional status in one of the EU countries, in this case, Spain. The conclusions provide a better comprehension of Lefebvre's thinking, offering insights for wider applications. They show the need to advance the theoretical and empirical understandings of rhythm in relation to mobility during the lifecourse.
Immunogenicity of hepatic differentiated human umbilical cord mesenchymal stem cells promoted by porcine decellularized liver scaffolds
Authors: Li Yi , Wu Qiong , Wang Yujia , Li Li , Chen Fei , Shi Yujun , Bu Hong , Bao Ji
Published: January 2017

Cell‐based approaches, including hepatocyte transplantation and tissue‐engineered livers, offer promising alternatives and are expected to help support patients with liver diseases until liver transplantation or recovery via regeneration of the damaged liver. However, the success of cell therapies remains dependent on how well the cells are accepted after transplantation and is directly related to their degree of immunogenicity. In this study, hepatic differentiation of human umbilical cord mesenchymal stem cells (hUC‐MSCs) was induced in the traditional monolayer (2D) culture and newly established three‐dimensional (3D) aggregation culture with the porcine decellularized liver scaffold (DLS) system (3D‐DLS). We investigated the immunogenicity of these hepatocyte‐like cells in vitro. We found that monolayer hepatic differentiated hUC‐MSCs expressed higher levels of human leukocyte antigen‐DR (HLA‐DR) (P<.05) and lost the ability to inhibit lymphocyte proliferation (P<.05), in association with a lower level of prostaglandin E2 (PGE2) (P<.05) and a higher level of interferon‐γ (IFN‐γ) (P<.05) secretion, compared to undifferentiated hUC‐MSCs. The hepatocyte‐like cells differentiated in the 3D‐DLS system did not show an elevation of MHC‐II (P>.05), or cause obvious lymphocytes proliferation, and demonstrated more PGE2 (P<.05) and less IFN‐γ (P<.05) secretion. Hepatocyte‐like cells in the 3D‐DLS system presented a lower immunogenic phenotype than the 2D culture in vitro. Hepatocyte‐like cells in 3D‐DLS system also performed a higher immunosuppressive capacity than 2D culture.
Refined global Gan–Gross–Prasad conjecture for Fourier–Jacobi periods on symplectic groups
Authors: Xue Hang
Published: January 2017

In this paper, we propose a conjectural identity between the Fourier–Jacobi periods on symplectic groups and the central value of certain Rankin–Selberg$L$-functions. This identity can be viewed as a refinement to the global Gan–Gross–Prasad conjecture for$\text{Sp}(2n)\times \text{Mp}(2m)$. To support this conjectural identity, we show that when$n=m$and$n=m\pm 1$, it can be deduced from the Ichino–Ikeda conjecture in some cases via theta correspondences. As a corollary, the conjectural identity holds when$n=m=1$or when$n=2$,$m=1$and the automorphic representation on the bigger group is endoscopic.
L’AFFAIRE DU DIFFÉREND TERRITORIAL ET MARITIME ENTRE LE NICARAGUA ET LA COLOMBIE: CERTAINES QUESTIONS CONCERNANT LA SOUVERAINETÉ TERRITORIALE ET LA DÉLIMITATION MARITIME
Authors: Gómez-Pulisich Facundo M.
Published: January 2017

La presente contribución tiene como principal objetivo proponer un análisis detallado de ciertas cuestiones jurídicas tratadas por la Corte Internacional de Justicia (CIJ) en las dos principales sentencias concernientes al Diferendo territorial y marítimo entre Nicaragua y Colombia, emitidas el 13 de diciembre de 2007 y el 19 de noviembre de 2012 sobre las excepciones preliminares y el fondo, respectivamente. Estas dos decisiones revisten una importancia particular, debido principalmente al efecto que ellas tuvieron sobre el comportamiento adoptado por cada uno de los Estados partes en el litigio, una vez que la decisión sobre el fondo fue adoptada. El presente artículo está dividido en dos partes. En la primera parte, el recorrido seguido por el Tratado de 1928 y su Protocolo de 1930, en su condición de títulos jurídicos, atraerá nuestra atención. En efecto, en primer lugar, se trata la pertinencia del análisis sobre la validez de estos instrumentos, para luego concentrar la atención sobre la interpretación jurídica que la CIJ les ha dado. En la segunda parte, presentamos ciertas reflexiones sobre la delimitación marítima. Primero, serán examinados los argumentos presentados por la Corte para justificar su decisión de no tratar la segunda demanda presentada por Nicaragua. En segundo lugar, analizaremos tanto el método de delimitación marítima identificado como su aplicación.
High-k oxides by atomic layer deposition—Applications in biology and medicine
Authors: Godlewski Marek , Gierałtowska Sylwia , Wachnicki Łukasz , Pietuszka Rafał , Witkowski Bartłomiej S. , Słońska Anna , Gajewski Zdzisław , Godlewski Michał M.
Published: January 2017

Wide band gap oxides grown by atomic layer deposition (ALD) are intensively studied for applications as insulators (gate oxides in field effect transistors) and as resistance switching materials in electronic memories. For these applications, compositions of dielectric films (laminar structures of HfO2, TiO2, ZrO2, and Al2O3) can also be used. Our research shows that the same layers show antibacterial activity comparable to ZnO. For mentioned application, it is important that the ALD allows uniform coating of various materials, including temperature sensitive ones (e.g., perishable fabrics) and equipment and instruments (including implants) used in hospitals and in a food industry. Here, the authors present the antibacterial activity of ALD-deposited metal oxides, promising a range of potential applications in medicine, veterinary, broader health care, and food industry.
Rainfall regimes of the Green Sahara
Authors: Tierney Jessica E. , Pausata Francesco S. R. , deMenocal Peter B.
Published: January 2017

We estimate rainfall during the “Green Sahara” period.
Science suffers in cold war over polar base
Authors: Enserink Martin
Published: January 2017

Researchers frozen out as parties vie for control of research station.
Unique free electron laser laboratory opens in China
Authors: Normile Dennis
Published: January 2017

New device will probe smog and other gaseous phenomena.
Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy
Authors: Davoli Teresa , Uno Hajime , Wooten Eric C. , Elledge Stephen J.
Published: January 2017

Chromosomal chaos and tumor immunity

Cancer immunotherapy produces durable clinical responses in only a subset of patients. Identification of tumor characteristics that correlate with responses could lead to predictive biomarkers and shed light on causal mechanisms. Davoli
et al.
found that human tumors with extensive aneuploidy—i.e., that display a highly abnormal number of chromosomes and chromosomal segments—express fewer markers of the immune cells responsible for tumor destruction. In a retrospective analysis of clinical trial data, they found that melanoma patients with highly aneuploid tumors were less likely to benefit from immune checkpoint blockade therapy than patients whose tumors had a more normal karyotype. Thus, aneuploidy appears to enhance the ability of tumors to evade the immune system.

Science
, this issue p.
10.1126/science.aaf8399
Closing global achievement gaps in MOOCs
Authors: Kizilcec René F. , Saltarelli Andrew J. , Reich Justin , Cohen Geoffrey L.
Published: January 2017

Brief interventions address social identity threat at scale
Regional and global sea-surface temperatures during the last interglaciation
Authors: Hoffman Jeremy S. , Clark Peter U. , Parnell Andrew C. , He Feng
Published: January 2017

Sea surface temperatures of the past

Understanding how warm intervals affected sea level in the past is vital for projecting how human activities will affect it in the future. Hoffman
et al.
compiled estimates of sea surface temperatures during the last interglacial period, which lasted from about 129,000 to 116,000 years ago. The global mean annual values were ∼0.5°C warmer than they were 150 years ago and indistinguishable from the 1995–2014 mean. This is a sobering point, because sea levels during the last interglacial period were 6 to 9 m higher than they are now.

Science
, this issue p.
276
Born this way?
Testosterone Rex Myths of Sex, Science, and Society
Cordelia Fine
Norton, 2017. 266 pp.
Authors: Berenbaum Sheri
Published: January 2017

A spirited polemic takes aim at biological sex differences but misses opportunities to highlight relevant science
Beyond Schrödinger's cat
Furry Logic The Physics of Animal Life
Matin Durrani and Liz Kalaugher
Bloomsbury Sigma, 2017. 312 pp.
Authors: Kovac Mirko
Published: January 2017

A physics-focused tour of the animal kingdom offers inspiration for engineers and roboticists
Enzymes at work are enzymes in motion
Authors: Saleh Tamjeed , Kalodimos Charalampos G.
Published: January 2017

Protein motions and water both play key roles in enzyme catalysis
The Predominant CD4+Th1 Cytokine Elicited to Chlamydia trachomatis Infection in Women Is Tumor Necrosis Factor Alpha and Not Interferon Gamma
Authors: Jordan Stephen J. , Gupta Kanupriya , Ogendi Brian M. O. , Bakshi Rakesh K. , Kapil Richa , Press Christen G. , Sabbaj Steffanie , Lee Jeannette Y. , Geisler William M.
Published: January 2017

Chlamydia trachomatisinfection is the most prevalent bacterial sexually transmitted infection and can cause significant reproductive morbidity in women. There is insufficient knowledge ofC. trachomatis-specific immune responses in humans, which could be important in guiding vaccine development efforts. In contrast, murine models have clearly demonstrated the essential role of T helper type 1 (Th1) cells, especially interferon gamma (IFN-γ)-producing CD4+T cells, in protective immunity to chlamydia. To determine the frequency and magnitude of Th1 cytokine responses elicited toC. trachomatisinfection in humans, we stimulated peripheral blood mononuclear cells from 90 chlamydia-infected women withC. trachomatiselementary bodies, Pgp3, and major outer membrane protein and measured IFN-γ-, tumor necrosis factor alpha (TNF-α)-, and interleukin-2 (IL-2)-producing CD4+and CD8+T-cell responses using intracellular cytokine staining. The majority of chlamydia-infected women elicited CD4+TNF-α responses, with frequency and magnitude varying significantly depending on theC. trachomatisantigen used. CD4+IFN-γ and IL-2 responses occurred infrequently, as did production of any of the three cytokines by CD8+T cells. About one-third of TNF-α-producing CD4+T cells coproduced IFN-γ or IL-2. In summary, the predominant Th1 cytokine response elicited toC. trachomatisinfection in women was a CD4+TNF-α response, not CD4+IFN-γ, and a subset of the CD4+TNF-α-positive cells produced a second Th1 cytokine.
Preexisting Immunity, Not Frailty Phenotype, Predicts Influenza Postvaccination Titers among Older Veterans
Authors: Van Epps Puja , Tumpey Terrence , Pearce Melissa B. , Golding Hana , Higgins Patricia , Hornick Thomas , Burant Christopher , Wilson Brigid M. , Banks Richard , Gravenstein Stefan , Canaday David H.
Published: January 2017

Both preexisting immunity to influenza and age have been shown to be correlates of influenza vaccine responses. Frailty, an indicator of functional impairment in older adults, was also shown in one study to predict lower influenza vaccine responses among nonveterans. In the current study, we aimed to determine the associations between frailty, preexisting immunity, and immune responses to influenza vaccine among older veterans. We studied 117 subjects (age range, 62 to 95 years [median age, 81 years]), divided into three cohorts based on the Fried frailty test, i.e., nonfrail (NF) (
n
= 23 [median age, 68 years]), prefrail (
n
= 50 [median age, 80 years]), and frail (
n
= 44 [median age, 82 years]), during the 2010-2011 and 2011-2012 influenza seasons. Subjects received the seasonal trivalent inactivated influenza vaccine, and baseline and postvaccination samples were obtained. Anti-influenza humoral immunity, as measured by hemagglutination inhibition (HI) and microneutralization assays, was measured for influenza B, A(H1N1)pdm09, and A(H3N2) viruses. Postvaccination titers were not different between frail and NF subjects overall in this older subset of veterans. However, preexisting HI titers were strongly correlated with postvaccination titers among all functional status groups. When microneutralization titers were compared, the association between preexisting immunity and vaccine responses varied by frailty status, with the strongest correlation being observed for the NF group. In conclusion, preexisting immunity rather than frailty appeared to predict postvaccination titers in this older veteran cohort.
Avian and Human Seasonal Influenza Hemagglutinin Proteins Elicit CD4 T Cell Responses That Are Comparable in Epitope Abundance and Diversity
Authors: DiPiazza Anthony , Richards Katherine , Poulton Nicholas , Sant Andrea J.
Published: January 2017

Avian influenza viruses remain a significant concern due to their pandemic potential. Vaccine trials have suggested that humans respond poorly to avian influenza vaccines relative to seasonal vaccines. It is important to understand, first, if there is a general deficiency in the ability of avian hemagglutinin (HA) proteins to generate immune responses and, if so, what underlies this defect. This question is of particular interest because it has been suggested that in humans, the poor immunogenicity of H7 vaccines may be due to a paucity of CD4 T cell epitopes. Because of the generally high levels of cross-reactive CD4 T cells in humans, it is not possible to compare the inherent immunogenicities of avian and seasonal HA proteins in an unbiased manner. Here, we empirically examine the epitope diversity and abundance of CD4 T cells elicited by seasonal and avian HA proteins. HLA-DR1 and HLA-DR4 transgenic mice were vaccinated with purified HA proteins, and CD4 T cells to specific epitopes were identified and quantified. These studies revealed that the diversity and abundance of CD4 T cells specific for HA do not segregate on the basis of whether the HA was derived from human seasonal or avian influenza viruses. Therefore, we conclude that failure in responses to avian vaccines in humans is likely due to a lack of cross-reactive CD4 T cell memory perhaps coupled with competition with or suppression of naive, HA-specific CD4 T cells by memory CD4 T cells specific for more highly conserved proteins.
FIND Tuberculosis Strain Bank: a Resource for Researchers and Developers Working on Tests To Detect Mycobacterium tuberculosis and Related Drug Resistance
Authors: Tessema Belay , Nabeta Pamela , Valli Eloise , Albertini Audrey , Collantes Jimena , Lan Nguyen Huu , Romancenco Elena , Tukavdze Nestani , Denkinger Claudia M. , Dolinger David L.
Published: January 2017

The spread of multidrug-resistant (MDR) tuberculosis (TB) and extensively drug-resistant (XDR) TB hampers global efforts in the fight against tuberculosis. To enhance the development and evaluation of diagnostic tests quickly and efficiently, well-characterized strains and samples from drug-resistant tuberculosis patients are necessary. In this project, the Foundation for Innovative New Diagnostics (FIND) has focused on the collection, characterization, and storage of such well-characterized reference materials and making them available to researchers and developers. The collection is being conducted at multiple centers in Southeast Asia, South America, Eastern Europe, and soon the sub-Saharan Africa regions. Strains are characterized for their phenotypic resistances and MICs to first-line drugs (FLDs) and second-line drugs (SLDs) using the automated MGIT 960 system following validated procedures and WHO criteria. Analysis of resistance-associated mutations is done by whole-genome sequencing (WGS) using the Illumina NextSeq system. Mycobacterial interspersed repetitive-unit–variable-number tandem-repeat analysis and WGS are used to determine strain lineages. All strains are maintained frozen at −80°C ± 10°C as distinct mother and daughter lots. All strains are extensively quality assured. The data presented here represent an analysis of the initial part of the collection. Currently, the bank contains 118 unique strains with extracted genomic DNA and matched sputum, serum, and plasma samples and will be expanded to a minimum of 1,000 unique strains over the next 3 years. Analysis of the current strains by phenotypic resistance testing shows 102 (86.4%), 10 (8.5%), and 6 (5.1%) MDR, XDR, and mono/poly resistant strains, respectively. Two of the strains are resistant to all 11 drugs that were phenotypically tested. WGS mutation analysis revealed FLD resistance-associated mutations in the
rpoB
,
katG
,
inhA
,
embB
,
embA
, and
pncA
genes; SLD resistance in the
gyrA
,
gyrB
,
rrs
,
eis
, and
tlyA
genes; and ethionamide resistance in the
ethA
genes. Most important lineages are represented in the bank, and further collections have been initiated to increase geographic and lineage diversity. The bank provides highly characterized and high-quality strains as a resource for researchers and developers in support of the development and evaluation of new diagnostics and drug resistance detection tools.
Determinants of Viral Oncogene E6-E7 mRNA Overexpression in a Population-Based Large Sample of Women Infected by High-Risk Human Papillomavirus Types
Authors: Giorgi Rossi Paolo , Bisanzi Simonetta , Allia Elena , Mongia Alessandra , Carozzi Francesca , Gillio-Tos Anna , De Marco Laura , Ronco Guglielmo , Gustinucci Daniela , Del Mistro Annarosa , Frayle Helena , Iossa Anna , Fantacci Giulia , Pompeo Giampaolo , Cesarini Elena , Bulletti Simonetta , Passamonti Basilio , Rizzi Martina , Penon Maria Gabriella , Barca Alessandra , Benevolo Maria
Published: January 2017

Cervical cancer screening by human papillomavirus (HPV) DNA testing with cytology triage is more effective than cytology testing. Compared to cytology, the HPV DNA test's higher sensitivity, which allows better protection with longer intervals, makes it necessary to triage the women with a positive result to compensate its lower specificity. We are conducting a large randomized clinical trial (New Technologies for Cervical Cancer 2 [NTCC2]) within organized population-based screening programs in Italy using HPV DNA as the primary screening test to evaluate, by the Aptima HPV assay (Hologic), the use of HPV E6-E7 mRNA in a triage test in comparison to cytology. By the end of June 2016, data were available for 35,877 of 38,535 enrolled women, 2,651 (7.4%) of whom were HPV DNA positive. Among the samples obtained, 2,453 samples were tested also by Aptima, and 1,649 (67.2%) gave a positive result. The proportion of mRNA positivity was slightly higher among samples tested for HPV DNA by the Cobas 4800 HPV assay (Roche) than by the Hybrid Capture 2 (HC2) assay (Qiagen). In our setting, the observed E6-E7 mRNA positivity rate, if used as a triage test, would bring a rate of immediate referral to colposcopy of about 4 to 5%. This value is higher than that observed with cytology triage for both immediate and delayed referrals to colposcopy. By showing only a very high sensitivity and thus allowing a longer interval for HPV DNA-positive/HPV mRNA-negative women, a triage by this test might be more efficient than by cytology.
Differences in Glycoprotein Complex Receptor Binding Site Accessibility Prompt Poor Cross-Reactivity of Neutralizing Antibodies between Closely Related Arenaviruses
Authors: Brouillette Rachel B. , Phillips Elisabeth K. , Ayithan Natarajan , Maury Wendy
Published: January 2017

The glycoprotein complex (GPC) of arenaviruses, composed of stable signal peptide, GP1, and GP2, is the only antigen correlated with antibody-mediated neutralization. However, despite strong cross-reactivity of convalescent antisera between related arenavirus species, weak or no cross-neutralization occurs. Two closely related clade B viruses, Machupo virus (MACV) and Junín virus (JUNV), have nearly identical overall GPC architecture and share a host receptor, transferrin receptor 1 (TfR1). Given structural and functional similarities of the GP1 receptor binding site (RBS) of these viruses and the recent demonstration that the RBS is an important target for neutralizing antibodies, it is not clear how these viruses avoid cross-neutralization. To address this, MACV/JUNV chimeric GPCs were assessed for interaction with a group of α-JUNV GPC monoclonal antibodies (MAbs) and mouse antisera against JUNV or MACV GPC. All six MAbs targeted GP1, with those that neutralized JUNV GPC-pseudovirions competing with each other for RBS binding. However, these MAbs were unable to bind to a chimeric GPC composed of JUNV GP1 containing a small disulfide bonded loop (loop 10) unique to MACV GPC, suggesting that this loop may block MAbs interaction with the GP1 RBS. Consistent with this loop causing interference, mouse anti-JUNV GPC antisera that solely neutralized pseudovirions bearing autologous GP1 provided enhanced neutralization of MACV GPC when this loop was removed. Our studies provide evidence that loop 10, which is unique to MACV GP1, is an important impediment to binding of neutralizing antibodies and contributes to the poor cross-neutralization of α-JUNV antisera against MACV.

IMPORTANCE
Multiple New World arenaviruses can cause severe disease in humans, and some geographic overlap exists among these viruses. A vaccine that protects against a broad range of New World arenaviruses is desirable for purposes of simplicity, cost, and broad protection against multiple National Institute of Allergy and Infectious Disease-assigned category A priority pathogens. In this study, we sought to better understand how closely related arenaviruses elude cross-species neutralization by investigating the structural bases of antibody binding and avoidance. In our studies, we found that neutralizing antibodies against two New World arenaviruses, Machupo virus (MACV) and Junín virus (JUNV), bound to the envelope glycoprotein 1 (GP1) with JUNV monoclonal antibodies targeting the receptor binding site (RBS). We further show that altered structures surrounding the RBS pocket in MACV GP1 impede access of JUNV-elicited antibodies.
Sex-Dependent Intestinal Replication of an Enteric Virus
Authors: Robinson Christopher M. , Wang Yao , Pfeiffer Julie K.
Published: January 2017

Coxsackievirus is an enteric virus that initiates infection in the gastrointestinal tract before disseminating to peripheral tissues to cause disease, but intestinal factors that influence viral replication are understudied. Furthermore, a sex bias for severe sequelae from coxsackievirus infections has been observed in humans. While mouse models mimicking human pathogenesis have been well characterized, many of these experiments use intraperitoneal injection of coxsackievirus to infect mice, bypassing the intestine. In light of recent studies identifying intestinal factors, such as the microbiota, that alter enteric viral replication, we sought to investigate coxsackievirus replication within the intestine. Here, we orally infected mice with coxsackievirus B3 (CVB3) and found that CVB3 replication in the intestine is sex dependent. CVB3 replicated efficiently in the intestine of male mice but not female mice. Additionally, we found that the type I interferon response and sex hormones can alter both viral replication and lethality. Overall, these data suggest that sex and the immune response play a vital role in CVB3 replication in the intestine and should be considered in light of the sex bias observed in human disease.

IMPORTANCESex bias in severe sequelae from enteric viral infections has been observed. Since viruses have evolved to achieve optimal levels of fitness in their environmental niches, it is imperative to study viruses at the site of initial replication. Here, we used an oral inoculation system for CVB3, which follows the natural route of infection in the gastrointestinal tract. We found that sex can influence the replication of CVB3 in the intestine. Additionally, the type I interferon response and sex hormones alter both CVB3 intestinal replication and lethality. Overall this work highlights the fact that sex should be considered in investigations of enteric viral replication and pathogenesis.
The Envelope Gene of Transmitted HIV-1 Resists a Late Interferon Gamma-Induced Block
Authors: Rihn Suzannah J. , Foster Toshana L. , Busnadiego Idoia , Aziz Muhamad Afiq , Hughes Joseph , Neil Stuart J. D. , Wilson Sam J.
Published: January 2017

Type I interferon (IFN) signaling engenders an antiviral state that likely plays an important role in constraining HIV-1 transmission and contributes to defining subsequent AIDS pathogenesis. Type II IFN (IFN-γ) also induces an antiviral state but is often primarily considered to be an immunomodulatory cytokine. We report that IFN-γ stimulation can induce an antiviral state that can be both distinct from that of type I interferon and can potently inhibit HIV-1 in primary CD4+T cells and a number of human cell lines. Strikingly, we find that transmitted/founder (TF) HIV-1 viruses can resist a late block that is induced by type II IFN, and the use of chimeric IFN-γ-sensitive/resistant viruses indicates that interferon resistance maps to theenvgene. Simultaneously,in vitroevolution also revealed that just a single amino acid substitution in the envelope can confer substantial resistance to IFN-mediated inhibition. Thus, theenvgene of transmitted HIV-1 confers resistance to a late block that is phenotypically distinct from blocks previously described to be resisted byenvand is therefore mediated by unknown IFN-γ-stimulated factor(s) in human CD4+T cells and cell lines. This important unidentified block could play a key role in constraining HIV-1 transmission.

IMPORTANCEThe human immune system can hinder invading pathogens through interferon (IFN) signaling. One consequence of this signaling is that cells enter an antiviral state, increasing the levels of hundreds of defenses that can inhibit the replication and spread of viruses. The majority of HIV-1 infections result from a single virus particle (the transmitted/founder) that makes it past these defenses and colonizes the host. Thus, the founder virus is hypothesized to be a relatively interferon-resistant entity. Here, we show that certain HIV-1 envelope genes have the unanticipated ability to resist specific human defenses mediated by different types of interferons. Strikingly, the envelope gene from a founder HIV-1 virus is far better at evading these defenses than the corresponding gene from a common HIV-1 lab strain. Thus, these defenses could play a role in constraining the transmission of HIV-1 and may select for transmitted viruses that are resistant to this IFN-mediated inhibition.
Intestinal Mononuclear Phagocytes in Health and Disease
Authors: Sanders Theodore J. , Yrlid Ulf , Maloy Kevin J.
Published: January 2017

The intestine is the tissue of the body with the highest constitutive exposure to foreign antigen and is also a common entry portal for many local and systemic pathogens. Therefore, the local immune system has the unenviable task of balancing efficient responses to dangerous pathogens with tolerance toward beneficial microbiota and food antigens. As in most tissues, the decision between tolerance and immunity is critically governed by the activity of local myeloid cells. However, the unique challenges posed by the intestinal environment have necessitated the development of several specialized mononuclear phagocyte populations with distinct phenotypic and functional characteristics that have vital roles in maintaining barrier function and immune homeostasis in the intestine. Intestinal mononuclear phagocyte populations, comprising dendritic cells and macrophages, are crucial for raising appropriate active immune responses against ingested pathogens. Recent technical advances, including microsurgical approaches allowing collection of cells migrating in intestinal lymph, intravital microscopy, and novel gene-targeting approaches, have led to clearer distinctions between mononuclear phagocyte populations in intestinal tissue. In this review, we present an overview of the various subpopulations of intestinal mononuclear phagocytes and discuss their phenotypic and functional characteristics. We also outline their roles in host protection from infection and their regulatory functions in maintaining immune tolerance toward beneficial intestinal antigens.
Myeloid Cells in Asthma
Authors: Lambrecht Bart N. , Persson Emma K. , Hammad Hamida
Published: January 2017

Asthma is a heterogeneous chronic inflammatory disorder of the airways, and not surprisingly, many myeloid cells play a crucial role in pathogenesis. Antigen-presenting dendritic cells are the first to recognize the allergens, pollutants, and viruses that are implicated in asthma pathogenesis, and subsequently initiate the adaptive immune response by migrating to lymph nodes. Eosinophils are the hallmark of type 2 inflammation, releasing toxic compounds in the airways and contributing to airway remodeling. Mast cells and basophils control both the early- and late-phase allergic response and contribute to alterations in smooth muscle reactivity. Finally, relatively little is known about neutrophils and macrophages in this disease. Although many of these myeloid cells respond well to treatment with inhaled steroids, there is now an increasing armamentarium of targeted biologicals that can specifically eliminate only one myeloid cell population, like eosinophils. It is only with those new tools that we will be able to fully understand the role of myeloid cells in chronic asthma in humans.
Paradoxical insomnia in a patient taking zopiclone
Authors: Abba-Aji Adam , Bardoloi Prajjita
Published: January 2017

We present a case of a man aged 20 years who was diagnosed with a major depressive disorder and was started on escitalopram and zopiclone. The patient had a significant response to escitalopram except that he developed severe insomnia which dramatically resolved following discontinuation of zopiclone. The patient was recommenced on low dose of zopiclone and unfortunately redeveloped moderate insomnia. The patient was thoroughly investigated and zopiclone was determined to have paradoxically caused the insomnia.
Prevalence, impact and cost of multimorbidity in a cohort of people with chronic pain in Ireland: a study protocol
Authors: Slattery Brian W , O'Connor Laura , Haugh Stephanie , Dwyer Christopher P , O'Higgins Siobhan , Caes Line , Egan Jonathan , McGuire Brian E
Published: January 2017

Introduction

Multimorbidity (MM) refers to the coexistence of two or more chronic conditions within one person, where no one condition is considered primary. As populations age and healthcare provision improves, MM is becoming increasingly common and poses a challenge to the single morbidity approach to illness management, usually adopted by healthcare systems. Indeed, recent research has shown that 66.2% of the people in primary care in Ireland are living with MM. Healthcare usage and cost is significantly associated with MM, and additional chronic conditions lead to exponential increases in service usage and financial costs, and decreases in physical and mental well-being. Certain conditions, for example, chronic pain, are highly correlated with MM. This study aims to assess the extent, profile, impact and cost of MM among Irish adults with chronic pain.

Methods and analysis

Using cluster sampling, participants aged 18 years and over will be recruited from Irish pain clinics and provided an information package and questionnaire asking them to participate in our study at three time points, 1 year apart. The questionnaire will include our specially developed checklist to assess the prevalence and impact of MM, along with validated measures of quality of life, pain, depression and anxiety, and illness perception. Economic data will also be collected, including direct and indirect costs.

Ethics and dissemination

Ethical approval has been granted by the Research Ethics Committee of the National University of Ireland, Galway. Dissemination of results will be via journal articles and conference presentations.
Prevalence and clinical impact of recreational drug consumption in people living with HIV on treatment: a cross-sectional study
Authors: Garin Noe , Zurita Beatriz , Velasco Cesar , Feliu Anna , Gutierrez Mar , Masip Montserrat , Mangues M Antonia
Published: January 2017

Objectives

Drug interactions, poor adherence to medication and high-risk sexual behaviour may occur in individuals with HIV using recreational drugs. Thus, we aimed to assess the prevalence of recreational drugs use and to explore its clinical impact in HIV patients on treatment.

Methods

Observational, cross sectional, study conducted in a 700 bed university hospital, Barcelona, Spain. A total of 208 adults living with HIV on treatment were included. A questionnaire was administered by clinical pharmacists, including evaluation of sociodemographic variables, past 12-month drug consumption, adherence to antiretrovirals (Simplified Medication Adherence Questionnaire) and high-risk sexual behaviour (condomless sex/multiple partners). Additional data were obtained from clinical records. Recreational drug-antiretroviral interactions were checked in reference databases. Prevalence was calculated for 5% precision and 95% CI. Crude and adjusted binary logistic regressions were performed to identify associations between recreational drug use and adherence problems, and between recreational drug use and high-risk sexual behaviour.

Results

From the overall sample, 92 participants (44.2%) consumed recreational drugs over the past 1 year. Of these, 44 (48.8%) had used different types of recreational drugs in this period. We detected 11 recreational substances, including sildenafil and nitrites. The most consumed drugs were: cannabis (68.5%), cocaine (45.5%), nitrites (31.5%), sildenafil (28.3) and ecstasy (19.6%). Relevant interactions occurred in 46 (50%) of the individuals consuming drugs. Recreational drug consumption was found to be related to adherence problems with antiretrovirals (OR: 2.51 (95% CI 1.32 to 4.77) p=0.005) and high-risk sexual behaviour (OR: 2.81 (95% CI 1.47 to 5.39) p=0.002).

Conclusions

Recreational drugs are frequently used by HIV patients on treatment. Classical drugs and new substances consumed in sexual context are usual. Recreational drug consumption interferes with several clinical outcomes, including potentially relevant interactions between drugs and antiretrovirals, adherence problems and high-risk sexual behaviour. Thus, there is the urgent need of implementing patient-centred care involving recreational drug consumption.
Clinical implications ofDNMT3Amutations in a Southeast Asian cohort of acute myeloid leukaemia patients
Authors: Tan Marcus , Ng Isaac K S , Chen Zhaojin , Ban Kenneth , Ng Christopher , Chiu Lily , Seah Elaine , Lin Mingxuan , Tai Bee Choo , Yan Benedict , Ng Chin Hin , Chng Wee-Joo
Published: January 2017

Aims

In recent years, genomic technologies have enabled the identification of mutations in acute myeloid leukaemia (AML).DNMT3Ais a recurrently mutated epigenetic modifier gene in AML. To date, the prognostic significance ofDNMT3Amutations has not been studied in a Southeast Asian AML population. We sought to investigate the clinical implications ofDNMT3Amutations in a Southeast Asian cohort of AML patients.

Methods

DNMT3Amutations were identified using a targeted next-generation sequencing panel in 157 AML patients. We studied the molecular and clinical features of patients withDNMT3Amutations and assessed the prognostic impact ofDNMT3Amutations.

Results

DNMT3Amutations were found in 33 of 157 (21.0%) AML patients. 114 patients were included for statistical analysis. Pretreatment data revealed that patients withDNMT3Amutations were older (≥60 years old), had a higher white blood cell count at diagnosis, had more adverse cytogenetic risk profiles and were more often associated withNPM1mutations compared with patients with wild-typeDNMT3A. Survival analysis showed that DNMT3A mutations were associated with poorer clinical outcomes. This was especially when associated with NPM1 and FLT3-ITD mutations (AMLNPM1/FLT3/DNMT3A), which are common. The AMLNPM1/FLT3/DNMT3Asubtype was an independent predictor for poorer overall survival (OS). Other independent risk factors for poorer OS include advanced age at diagnosis and adverse cytogenetic risk stratification.

Conclusions

DNMT3Amutations are associated with an unfavourable clinical outcome in our Southeast Asian AML patient cohort. In particular, AMLNPM1/FLT3/DNMT3Apatients had the poorest prognosis.
Cost minimisation analysis of thermometry in two different hospital systems
Authors: Hayes Kenneth , Shepard Amanda , Cesarec August , Likić Robert
Published: January 2017

Introduction

Temperature monitoring can be accomplished by various methods, including oral (OT), rectal (RT), axillary (AT), tympanic membrane (TMT) and temporal artery (TAT) thermometry, with varying amounts of cost incurred by healthcare systems.

Methods

The potential thermometry cost savings in two hospital systems—University Hospital Centre Zagreb (UHCZ), which uses TMT (device Covidien Genius 2) and University of Michigan Hospitals (UMH), which relies on OT, RT and AT (device Welch Allyn suretemp plus 692)—were analysed to evaluate institution-wide TAT (device Exergen TAT-5000) implementation. Two scenarios were developed: scenario 1, comparing costs for a period of 1, 3 and 5 years; scenario 2, calculation of the number of measurements per device for TAT to be cost-effective.

Results

At UHCZ, use of TAT would bring budget savings regardless of the number of devices per bed and the number of years observed. Savings would range from US$0.08 million (one device per bed, impact for 1 year) to US$1.8 million (one device per 10 beds, impact for 5 years). At UMH, use of TAT would lead to budget savings if one device per 10 beds were acquired, but only over a period of 3 or 5 years. Other TAT scenarios were associated with budget costs at UMH even after a period of 5 years.

Conclusions

Sensitivity analyses showed that the price of current consumables had the highest impact on the model in both hospital settings, with TAT up to 10 times cheaper in that regard over TMT at UHCZ, potentially leading to considerable budget savings within a year of hospital-wide implementation.
Effects of high-protein intake on bone turnover in long-term bed rest in women
Authors: Heer Martina , Baecker Natalie , Frings-Meuthen Petra , Graf Sonja , Zwart Sara R. , Biolo Gianni , Smith Scott M.
Published: January 2017

Bed rest (BR) causes bone loss, even in otherwise healthy subjects. Several studies suggest that ambulatory subjects may benefit from high-protein intake to stimulate protein synthesis and to maintain muscle mass. However, increasing protein intake above the recommended daily intake without adequate calcium and potassium intake may increase bone resorption. We hypothesized that a regimen of high-protein intake (HiPROT), applied in an isocaloric manner during BR, with calcium and potassium intake meeting recommended values, would prevent any effect of BR on bone turnover. After a 20-day ambulatory adaptation to a controlled environment, 16 women participated in a 60-day, 6° head-down-tilt (HDT) BR and were assigned randomly to 1 of 2 groups. Control (CON) subjects (n = 8) received 1 g/(kg body mass·day)−1 dietary protein. HiPROT subjects (n = 8) received 1.45 g protein/(kg body mass·day)−1 plus an additional 0.72 g branched-chain amino acids per day during BR. All subjects received an individually tailored diet (before HDTBR: 1888 ± 98 kcal/day; during HDTBR: 1604 ± 125 kcal/day; after HDTBR: 1900 ± 262 kcal/day), with the CON group’s diet being higher in fat and carbohydrate intake. High-protein intake exacerbated the BR-induced increase in bone resorption marker C-telopeptide (>30%) (p < 0.001) by the end of BR. Bone formation markers were unaffected by BR and high-protein intake. We conclude that high-protein intake in BR might increase bone loss. Further long-duration studies are mandatory to show how the positive effect of protein on muscle mass can be maintained without the risk of reducing bone mineral density.
Predator–prey interactions influenced by a dynamic river plume
Authors: Phillips Elizabeth M. , Horne John K. , Zamon Jeannette E.
Published: January 2017

Marine predator–prey interactions are often influenced by oceanographic processes that aggregate prey. We examined density distributions of seabirds and prey fish associated with the Columbia River plume to determine whether variation in plume size (i.e., volume or surface area) or location influences predator–prey interactions. Common murre (Uria aalge), sooty shearwater (Ardenna grisea), and forage fish, including northern anchovy (Engraulis mordax) and juvenile salmon (Oncorhynchus spp.), occurred disproportionately in plume waters relative to adjacent marine waters. Water clarity, an indicator of plume-influenced waters, was a significant predictor of seabird and prey densities throughout the survey area. Murres occurred within 20 km of the plume center of gravity, whereas shearwaters occurred ∼100 km north of the plume center of gravity, concurrent with the highest densities of prey fish. Global indices of collocation were relatively low between murres and prey compared with the high values between shearwaters and prey. Seabird densities were negatively correlated with plume size, suggesting that seabirds concentrate in the plume to maximize foraging effort. We conclude that variation in Columbia River plume size and location influences predator distributions, which increases predation pressure on prey, including threatened salmonid species.
Larval fish dispersal along an estuarine–ocean gradient
Authors: Ramos S. , Paris C.B. , Angélico M.M.
Published: January 2017

The present study investigated the larval fish dispersal along an estuarine–ocean gradient to explore connectivity between ocean and estuaries. During spring 2009, a combined ocean–estuarine survey was conducted along the Lima estuarine salinity gradient and in two transects off the adjacent coast (northwestern Iberian Peninsula), until the 100 m isobaths. Salinity, total particulate matter, particulate organic matter, total dissolved carbon, and dissolved organic carbon reached higher values at the ocean, and chlorophyll a and nutrients increased at the estuary. From the total 56 taxa identified, 14 were present along the gradient, including estuarine species (ES), marine stragglers (MS), and migrants (MM). Canonical correspondence analysis showed that species were separated along the gradient according to their ecological functional classification. MM associated with high salinity were separated from ES correlated with lower salinities and high chlorophyll a concentrations of inner estuary. Flounder (Platichthys flesus) showed a typical spatial gradient of MM, with abundance increasing from the ocean towards inner estuary. The dispersal of larvae along the Lima estuarine–ocean gradient was indicative of connectivity between habitats, emphasizing the need to consider this feature in management plans, mainly for species exploited by commercial fisheries.
Fast Computation of Domain Boundary Conditions Using Splines in Penalized VIC Method
Authors: Lee Seung-Jae , Suh Jung-Chun
Published: January 2017

In the vortex-in-cell method combined with the penalization method, fluid particles are traced by continuously updating their positions and strengths from the grid solution. To evaluate particle velocity, the velocity field is computed by solving a Poisson equation for the vector potential, namely [Formula: see text], where [Formula: see text], and its computation can be greatly accelerated by the use of a fast Poisson solver. While this method offers an efficient way to simulate unsteady viscous flows, the computation of the boundary values when solving the Poisson equation can become a computation time bottleneck. Although adopting the fast multipole method can lead to saving further computation time, its disadvantage is that it requires complicated hierarchical data structures such as a quad-tree and oct-tree. In this paper, we introduce and assess an approximation method for specifying domain boundary values using splines. Using the proposed spline approximation method we achieve significant savings in both computation time and memory consumption.
Determinantal variety and normal embedding
Authors: Katz K. , Katz M. , Kerner D. , Liokumovich Y.
Published: January 2017

The space [Formula: see text] of matrices of positive determinant inherits an extrinsic metric space structure from [Formula: see text]. On the other hand, taking the infimum of the lengths of all paths connecting a pair of points in [Formula: see text] gives an intrinsic metric. We prove bi-Lipschitz equivalence between intrinsic and extrinsic metrics on [Formula: see text], exploiting the conical structure of the stratification of the space of [Formula: see text] matrices by rank.