bluuebunny/crossref_metadata_2025 huggingface dataset:
The Implications of Poverty on the Cameroon Economic Emergence Vision 2035
Authors: Oumar Saidou Baba , Sama Molem Christopher
Published: April 2017

This paper examines the implications of poverty on the Cameroon economic emergence vision 2035. Both primary and secondary data were collected on selected indicators of economic emergence for the period 1990-2035 and analyzed with descriptive and inferential tools of data analysis. The results reveal that the performance of major socio-economic indicators of well-being is poor in Cameroon. In consonance with the situation, a global assessment of the economic performance of Cameroon shows little hope for the economic emergence of the country by the target date of 2035. In order for the goal of economic emergence of Cameroon to come true as planned, it is suggested that the problem of poverty should be solved first by appropriately targeting macro-economic variables through policies that focus on job creation, provision of basic needs and services of life to people.
La creación artística como desrealización. Novedad y virtualidad en el pensamiento estético de Ortega y Gasset
Authors: Gutiérrez-Pozo Antonio
Published: April 2017

Este artículo muestra cómo las vanguardias artísticas de principios del siglo XX representan para Ortega y Gasset una nueva sensibilidad: la tendencia a deshumanizar el arte. Este arte deshumanizado es una reacción contra el popular arte romántico y naturalista, por lo que se propone como nuevo arte impopular. Lo que define es el deshumanizar y su esencia es la desrealización, o sea, la destrucción de la realidad. Para Ortega el objeto estético es un objeto metafórico, a saber, una irrealidad o virtualidad; desrealizar implica la fuga de la realidad. El arte es un mundo incomunicado con la realidad porque es irrealidad. Pero precisamente porque es irrealidad, el arte puede aumentar el mundo.
El panóptico de Bentham y la instrumentalización de los derechos humanos
Authors: Beytía Reyes Pablo
Published: April 2017

Este artículo revisa los fundamentos del utilitarismo de Jeremy Bentham y las principales críticas a esta doctrina, profundizando en aquella que sostiene su incompatibilidad con el respeto irrestricto de los derechos humanos. Insertándose en esta problemática, analiza una paradigmática propuesta política del filósofo inglés: el panóptico, proyecto arquitectónico formulado por Bentham a finales del siglo XVIII con el fin de reformar el sistema penitenciario europeo. A partir del análisis del Panóptico –que se descubre como una aplicación coherente del utilitarismo benthamiano–, se postula que: a) esta doctrina fomenta un trato humanitario; b) los derechos humanos no quedan garantizados, sino condicionados al grado de beneficio colectivo que generen; c) este utilitarismo supone un cuestionamiento por la universalidad e irrevocabilidad de dichos preceptos.
Simpatía, resentimiento y perdón: un análisis del rol del resentimiento en la tms de Adam Smith
Authors: Rodríguez Baños Jeyver
Published: April 2017

El artículo analiza el papel del resentimiento en la Teoría de los sentimientos morales de Adam Smith y su conexión con el proceso de la simpatía mutua por medio del cual el “espectador imparcial” asume plenamente el resentimiento de la víctima, al considerar que su pasión se rige por los principios de la propiedad y la justicia. Se sostiene que el resentimiento no solo cumple un rol central en la teoría del castigo de Adam Smith, en la medida en que permite retribuir, disuadir y rehabilitar al victimario sino que, además, aporta a la discusión contemporánea sobre el perdón y la reconciliación, pues convoca la posibilidad de superar el resentimiento y restablecer las relaciones sociales entre el agresor y la víctima.
Steady-State Response of a Flexibly Mounted Stator Mechanical Face Seal Subject to Dynamic Forcing of a Flexible Rotor
Authors: Varney Philip , Green Itzhak
Published: April 2017

Mechanical face seals are constitutive components of much larger turbomachines and require consideration of the system dynamics for successful design. The dynamic interplay between the seal and rotor is intensified by recent trends toward reduced clearances, higher speeds, and more flexible rotors. Here, the “rotor” consists of the flexible shaft and the rotating seal seat. The objective here is to, for the first time, determine how the rotor affects the seal performance and vice versa. Thresholds can then be established beyond which the rotor influences the seal but not vice versa (i.e., the rotordynamics can be sent to the seal analysis as an exogenous input). To this end, a model of a flexibly mounted stator face seal is provided including the coupled dynamics of the flexible rotor. The model accounts for axial and angular deflections of the rotor and seal. Coupled rotordynamics are modeled using a lumped-parameter approach including static and dynamic rotor angular misalignments. For expediency, linearized expressions for fluid forces are used, and the resulting steady-state equations of motion are solved analytically to investigate how rotor inertia, speed, and angular misalignment influence the coupled seal dynamics. Importantly, results from the study reveal that in some operating regimes, neglecting the rotordynamics implies healthy seal operation when instead intermittent rub exists between the faces. This work also shows that when the rotor inertia is much larger than the seal inertia, the rotordynamics can be solved separately and used in the seal model as an external input.
Effect of a chamber orchestra on direct sound and early reflections for performers on stage: A boundary element method study
Authors: Panton Lilyan , Holloway Damien , Cabrera Densil
Published: April 2017

Early reflections are known to be important to musicians performing on stage, but acoustic measurements are usually made on empty stages. This work investigates how a chamber orchestra setup on stage affects early reflections from the stage enclosure. A boundary element method (BEM) model of a chamber orchestra is validated against full scale measurements with seated and standing subjects in an anechoic chamber and against auditorium measurements, demonstrating that the BEM simulation gives realistic results. Using the validated BEM model, an investigation of how a chamber orchestra attenuates and scatters both the direct sound and the first-order reflections is presented for two different sized “shoe-box” stage enclosures. The first-order reflections from the stage are investigated individually: at and above the 250 Hz band, horizontal reflections from stage walls are attenuated to varying degrees, while the ceiling reflection is relatively unaffected. Considering the overall effect of the chamber orchestra on the direct sound and first-order reflections, differences of 2–5 dB occur in the 1000 Hz octave band when the ceiling reflection is excluded (slightly reduced when including the unobstructed ceiling reflection). A tilted side wall case showed the orchestra has a reduced effect with a small elevation of the lateral reflections.
Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation
Authors: Schneider Craig S. , Xu Qingguo , Boylan Nicholas J. , Chisholm Jane , Tang Benjamin C. , Schuster Benjamin S. , Henning Andreas , Ensign Laura M. , Lee Ethan , Adstamongkonkul Pichet , Simons Brian W. , Wang Sho-Yu S. , Gong Xiaoqun , Yu Tao , Boyle Michael P. , Suk Jung Soo , Hanes Justin
Published: April 2017

Debunking the mucoadhesion myth: Nonsticky particles for enhanced pulmonary drug delivery.
The economic value of grassland species for carbon storage
Authors: Hungate Bruce A. , Barbier Edward B. , Ando Amy W. , Marks Samuel P. , Reich Peter B. , van Gestel Natasja , Tilman David , Knops Johannes M. H. , Hooper David U. , Butterfield Bradley J. , Cardinale Bradley J.
Published: April 2017

Biodiversity confers economic value by enhancing carbon storage in grasslands, an economic argument for biodiversity conservation.
Normal sleep requires the astrocyte brain-type fatty acid binding protein FABP7
Authors: Gerstner Jason R. , Perron Isaac J. , Riedy Samantha M. , Yoshikawa Takeo , Kadotani Hiroshi , Owada Yuji , Van Dongen Hans P. A. , Galante Raymond J. , Dickinson Kaitlin , Yin Jerry C. P. , Pack Allan I. , Frank Marcos G.
Published: April 2017

The astrocyte brain-type fatty acid binding protein FABP7 regulates sleep consolidation across phylogeny.
Unusual presidential race rattles French scientists
Authors: Pain Elisabeth
Published: April 2017

Their ideas about science are sketchy, but Marine Le Pen and Emmanuel Macron have vastly different world views.
Cell-like giant viruses found
Authors: Leslie Mitch
Published: April 2017

Pieced-together viral genomes contradict view that giant viruses represent a distinct branch of life.
Nigeria's invisible crisis
Authors: Roberts Leslie
Published: April 2017

Hunger amplifies infectious diseases for millions fleeing the violence of Boko Haram.
High-performance vitrimers from commodity thermoplastics through dioxaborolane metathesis
Authors: Röttger Max , Domenech Trystan , van der Weegen Rob , Breuillac Antoine , Nicolaÿ Renaud , Leibler Ludwik
Published: April 2017

A metathesis reaction yields a strategy to cross-link and enhance polymers without compromising easy processing and recycling.
Tungsten-182 heterogeneity in modern ocean island basalts
Authors: Mundl Andrea , Touboul Mathieu , Jackson Matthew G. , Day James M. D. , Kurz Mark D. , Lekic Vedran , Helz Rosalind T. , Walker Richard J.
Published: April 2017

A mantle story told with metal and gas

Differences in isotopic compositions of trace elements can help identify how regions of Earth's mantle have evolved over time. Mundl
et al.
identified several ancient domains that have been isolated from mantle homogenization and thus contain signatures of primordial material. Tungsten and helium isotope values indicate fractionation and isolation of these mantle domains just after Earth's formation. The findings help constrain ancient processes such as core formation, but also provide insight into unexplained structures in the lower mantle today.

Science
, this issue p.
66
CRISPR-Cas: Adapting to change
Authors: Jackson Simon A. , McKenzie Rebecca E. , Fagerlund Robert D. , Kieper Sebastian N. , Fineran Peter C. , Brouns Stan J. J.
Published: April 2017

Variation in prokaryote adaptive immunity

To repel infection by phage and mobile genetic elements, prokaryotes have a form of adaptive immune response and memory invested in clustered regularly interspaced short palindromic repeats and associated proteins (CRISPR-Cas). This molecular machinery can recognize and remember foreign nucleic acids by capturing and retaining small nucleotide sequences. On subsequent encounters, the cognate CRISPR-Cas marshals enzymatic defenses to destroy infecting elements that contain the same sequences. Jackson
et al.
review the molecular mechanisms by which diverse CRISPR-Cas systems adapt and anticipate novel threats and evasive countermeasures from mobile genetic elements.

Science
, this issue p.
eaal5056
Unequivocal determination of complex molecular structures using anisotropic NMR measurements
Authors: Liu Yizhou , Saurí Josep , Mevers Emily , Peczuh Mark W. , Hiemstra Henk , Clardy Jon , Martin Gary E. , Williamson R. Thomas
Published: April 2017

Picking structures out of a lineup

Pharmaceutical research relies critically on determining the correct structures of numerous complex molecules. When well-ordered crystals are not available for x-ray analysis, nuclear magnetic resonance (NMR) spectroscopy is the most common structure-elucidation method. However, sometimes it is hard to distinguish isomers with similar spectra. Liu
et al.
showcase a protocol that combines computer modeling with anisotropic NMR data acquired using gel-aligned samples. Because of its uniform sensitivity to relative bond orientations across the whole molecular framework, the method overcomes common pitfalls that can lead to invalid structure assignments.

Science
, this issue p.
eaam5349
Long-range hot-carrier transport in hybrid perovskites visualized by ultrafast microscopy
Authors: Guo Zhi , Wan Yan , Yang Mengjin , Snaider Jordan , Zhu Kai , Huang Libai
Published: April 2017

Extraction of photoexcited charge carriers transported up to 600 nanometers in CH
3
NH
3
PbI
3
could boost solar cell efficiency.
Passing epigenetic silence to the next generation
Authors: De Sandip , Kassis Judith A.
Published: April 2017

Long-term epigenetic memory requires sequence-specific recruitment of enzymes
March for science
Authors: Berg Jeremy
Published: April 2017

In Frank Capra's seasonal classic
It's a Wonderful Life
, the main character, George Bailey, wishes he had never been born and is then transported to a version of his world where all traces of his existence have been removed. This world is much different—darker and less enlightened. Distressingly, the United States is now filled with echoes of George Bailey's nightmare. It seems that some people are dismissive of the beneficial effects of evidence-based approaches on our lives. Available evidence, even when quite substantial, is ignored or minimized. Non–evidence-based approaches are treated as equally likely as evidence-based ones to lead to factually correct, robust results. The federal budget proposal recently released by President Trump's administration includes draconian cuts for almost all research agencies. If implemented, these cuts will severely damage the U.S. scientific enterprise for years to come. Based on history, this path is likely to lead to decreased long-term technological innovation as well as poorly conceived public policy.
Decreased Vector Gene Expression from E2b Gene-Deleted Adenovirus Serotype 5 Vaccines Intensifies Proinflammatory Immune Responses
Authors: Quiroga Dionisia , Aldhamen Yasser A. , Godbehere Sarah , Harding Laura , Amalfitano Andrea
Published: April 2017

Recombinant adenovirus serotype 5 (Ad5) vectors are promising vaccine candidates due to their intrinsic immunogenicity and potent transgene expression; however, widespread preexisting Ad5 immunity has been considered a developmental impediment to the use of traditional, or conventional, E1 and E3 gene-deleted Ad5 (Ad5[E1−]) vaccines. Even in the presence of anti-Ad5 immunity, recent murine and human studies have confirmed E2b gene-deleted Ad5 (Ad5[E1−,E2b−]) vaccines to be highly efficacious inducers of transgene-specific memory responses and significantly less toxic options than Ad5[E1−] vaccines. While these findings have been substantially confirmed, the molecular mechanisms underlying the different reactions to these vaccine platforms are unknown. Using cultures of human peripheral blood mononuclear cells (hPBMCs) derived from multiple human donors, we found that Ad5[E1−,E2b−] vaccines trigger higher levels of hPBMC proinflammatory cytokine secretion than Ad5[E1−] vaccines. Interestingly, these responses were generated regardless of the donors' preexisting anti-Ad5 humoral and cell-mediated immune response status.In vitrohPBMC infection with the Ad5[E1−,E2b−] vaccine also provoked greater Th1-dominant gene responses yet smaller amounts of Ad-derived gene expression than Ad5[E1−] vaccines. These results suggest that Ad5[E1−,E2b−] vaccines, in contrast to Ad5[E1−] vaccines, do not promote activities that suppress innate immune signaling, thereby allowing for improved vaccine efficacy and a superior safety profile independently of previous Ad5 immunity.
Filamentous Structures Induced by a Phytoreovirus Mediate Viral Release from Salivary Glands in Its Insect Vector
Authors: Mao Qianzhuo , Liao Zhenfeng , Li Jiajia , Liu Yuyan , Wu Wei , Chen Hongyan , Chen Qian , Jia Dongsheng , Wei Taiyun
Published: April 2017

Numerous viral pathogens are persistently transmitted by insect vectors and cause agricultural or health problems. These viruses circulate in the vector body, enter the salivary gland, and then are released into the apical plasmalemma-lined cavities, where saliva is stored. The cavity plasmalemma of vector salivary glands thus represents the last membrane barrier for viral transmission. Here, we report a novel mechanism used by a persistent virus to overcome this essential barrier. We observed that the infection by rice gall dwarf virus (RGDV), a species of the genus
Phytoreovirus
in the family
Reoviridae
, induced the formation of virus-associated filaments constructed by viral nonstructural protein Pns11 within the salivary glands of its leafhopper vector,
Recilia dorsalis
. Such filaments attached to actin-based apical plasmalemma and induced an exocytosis-like process for viral release into vector salivary gland cavities, through a direct interaction of Pns11 of RGDV and actin of
R. dorsalis
. Failure of virus-induced filaments assembly by RNA interference with synthesized double-stranded RNA targeting the Pns11 gene inhibited the dissemination of RGDV into salivary cavities, preventing viral transmission by
R. dorsalis
. For the first time, we show that a virus can exploit virus-induced inclusion as a vehicle to pass through the apical plasmalemma into vector salivary gland cavities, thus overcoming the last membrane barrier for viral transmission by insect vectors.

IMPORTANCE
Understanding how persistent viruses overcome multiple tissue and membrane barriers within the insect vectors until final transmission is the key for viral disease control. The apical plasmalemma of the cavities where saliva is stored in the salivary glands is the last barrier for viral transmission by insect vectors; however, the mechanism is still poorly understood. Here we show that a virus has evolved to exploit virus-induced filaments to perform an exocytosis-like process that enables viral passage through the apical plasmalemma into salivary cavities. This mechanism could be extensively exploited by other persistent viruses to overcome salivary gland release barriers in insect vectors, opening new perspectives for viral control.
Cell Attachment Domains of the Porcine Epidemic Diarrhea Virus Spike Protein Are Key Targets of Neutralizing Antibodies
Authors: Li Chunhua , Li Wentao , Lucio de Esesarte Eduardo , Guo Hongbo , van den Elzen Paul , Aarts Eduard , van den Born Erwin , Rottier Peter J. M. , Bosch Berend-Jan
Published: April 2017

Porcine epidemic diarrhea virus (PEDV) causes enteric disease in pigs, resulting in significant economic losses to the swine industry worldwide. Current vaccination approaches against this emerging coronavirus are only partially effective, though natural infection protects pigs against reinfection and provides lactogenic immunity to suckling piglets. The viral spike (S) glycoprotein, responsible for receptor binding and cell entry, is the major target for neutralizing antibodies. However, knowledge of antibody epitopes, their nature and location in the spike structure, and the mechanisms by which the antibodies interfere with infection is scarce. Here we describe the generation and characterization of 10 neutralizing and nonneutralizing mouse monoclonal antibodies raised against the S1 receptor binding subunit of the S protein. By expression of different S1 protein fragments, six antibody epitope classes distributed over the five structural domains of the S1 subunit were identified. Characterization of antibodies for cross-reactivity and cross-neutralization revealed antigenic differences among PEDV strains. The epitopes of potent neutralizing antibodies segregated into two epitope classes and mapped within the N-terminal sialic acid binding domain and in the more C-terminal receptor binding domain. Antibody neutralization escape mutants displayed single amino acid substitutions that impaired antibody binding and neutralization and defined the locations of the epitopes. Our observations picture the antibody epitope landscape of the PEDV S1 subunit and reveal that its cell attachment domains are key targets of neutralizing antibodies.

IMPORTANCEPorcine epidemic diarrhea virus (PEDV), an emerging porcine coronavirus, causes an economically important enteric disease in pigs. Effective PEDV vaccines for disease control are currently lacking. The spike (S) glycoprotein on the virion surface is the key player in virus cell entry and, therefore, the main target of neutralizing antibodies. To understand the antigenic landscape of the PEDV spike protein, we developed monoclonal antibodies against the spike protein's S1 receptor binding region and characterized their epitopes, neutralizing activity, and cross-reactivity toward multiple PEDV strains. Epitopes of antibodies segregated into six epitope classes dispersed over the multidomain S1 structure. Monoclonal antibodies revealed antigenic variability in B-cell epitopes between PEDV strains. The epitopes of neutralizing antibodies mapped to two distinct domains in S1 that are involved in binding to carbohydrate and proteinaceous cell surface molecules, respectively, indicating the importance of these cell attachment sites on the PEDV spike protein in eliciting a protective humoral immune response.
Reverse Transcription Mechanically Initiates HIV-1 Capsid Disassembly
Authors: Rankovic Sanela , Varadarajan Janani , Ramalho Ruben , Aiken Christopher , Rousso Itay
Published: April 2017

The HIV-1 core consists of the viral genomic RNA and several viral proteins encased within a conical capsid. After cell entry, the core disassembles in a process termed uncoating. Although HIV-1 uncoating has been linked to reverse transcription of the viral genome in target cells, the mechanism by which uncoating is initiated is unknown. Using time-lapse atomic force microscopy, we analyzed the morphology and physical properties of isolated HIV-1 cores during the course of reverse transcription
in vitro
. We found that, during an early stage of reverse transcription the pressure inside the capsid increases, reaching a maximum after 7 h. High-resolution mechanical mapping reveals the formation of a stiff coiled filamentous structure underneath the capsid surface. Subsequently, this coiled structure disappears, the stiffness of the capsid drops precipitously to a value below that of a pre-reverse transcription core, and the capsid undergoes partial or complete rupture near the narrow end of the conical structure. We propose that the transcription of the relatively flexible single-stranded RNA into a more rigid filamentous structure elevates the pressure within the core, which triggers the initiation of capsid disassembly.

IMPORTANCE
For successful infection, the HIV-1 genome, which is in the form of a single-stranded RNA enclosed inside a capsid shell, must be reverse transcribed into double-stranded DNA and released from the capsid (in a process known as uncoating) before it can be integrated into the target cell genome. The mechanism that triggers uncoating is a pivotal question of long standing. By using atomic force microscopy, we found that during reverse transcription the pressure inside the capsid increases until the internal stress exceeds the strength of the capsid structure and the capsid breaks open. The application of AFM technologies to study purified HIV-1 cores represents a new experimental platform for elucidating additional aspects of capsid disassembly and HIV-1 uncoating.
Understanding the Mechanism of the Broad-Spectrum Antiviral Activity of Favipiravir (T-705): Key Role of the F1 Motif of the Viral Polymerase
Authors: Abdelnabi Rana , Morais Ana Theresa Silveira de , Leyssen Pieter , Imbert Isabelle , Beaucourt Stéphanie , Blanc Hervé , Froeyen Mathy , Vignuzzi Marco , Canard Bruno , Neyts Johan , Delang Leen
Published: April 2017

Favipiravir (T-705) is a broad-spectrum antiviral agent that has been approved in Japan for the treatment of influenza virus infections. T-705 also inhibits the replication of various RNA viruses, including chikungunya virus (CHIKV). We demonstrated earlier that the K291R mutation in the F1 motif of the RNA-dependent RNA polymerase (RdRp) of CHIKV is responsible for low-level resistance to T-705. Interestingly, this lysine is highly conserved in the RdRp of positive-sense single-stranded RNA (+ssRNA) viruses. To obtain insights into the unique broad-spectrum antiviral activity of T-705, we explored the role of this lysine using another +ssRNA virus, namely, coxsackievirus B3 (CVB3). Introduction of the corresponding K-to-R substitution in the CVB3 RdRp (K159R) resulted in a nonviable virus. Replication competence of the K159R variant was restored by spontaneous acquisition of an A239G substitution in the RdRp. A mutagenesis analysis at position K159 identified the K159M variant as the only other viable variant which had also acquired the A239G substitution. The K159 substitutions markedly decreased the processivity of the purified viral RdRp, which was restored by the introduction of the A239G mutation. The K159R A239G and K159M A239G variants proved, surprisingly, more susceptible than the wild-type virus to T-705 and exhibited lower fidelity in polymerase assays. Furthermore, the K159R A239G variant was found to be highly attenuated in mice. We thus demonstrate that the conserved lysine in the F1 motif of the RdRp of +ssRNA viruses is involved in the broad-spectrum antiviral activity of T-705 and that it is a key amino acid for the proper functioning of the enzyme.

IMPORTANCE
In this study, we report the key role of a highly conserved lysine residue of the viral polymerase in the broad-spectrum antiviral activity of favipiravir (T-705) against positive-sense single-stranded RNA viruses. Substitutions of this conserved lysine have a major negative impact on the functionality of the RdRp. Furthermore, we show that this lysine is involved in the fidelity of the RdRp and that the RdRp fidelity influences the sensitivity of the virus for the antiviral efficacy of T-705. Consequently, these results provide insights into the mechanism of the antiviral activity of T-705 and may lay the basis for the design of novel chemical scaffolds that may be endowed with a more potent broad-spectrum antiviral activity than that of T-705.
Impact of Antibodies and Strain Polymorphisms on Cytomegalovirus Entry and Spread in Fibroblasts and Epithelial Cells
Authors: Cui Xiaohong , Freed Daniel C. , Wang Dai , Qiu Ping , Li Fengsheng , Fu Tong-Ming , Kauvar Lawrence M. , McVoy Michael A.
Published: April 2017

Cytomegalovirus (CMV) entry into fibroblasts differs from entry into epithelial cells. CMV also spreads cell to cell and can induce syncytia. To gain insights into these processes, 27 antibodies targeting epitopes in CMV virion glycoprotein complexes, including glycoprotein B (gB), gH/gL, and the pentamer, were evaluated for their effects on viral entry and spread. No antibodies inhibited CMV spread in fibroblasts, including those with potent neutralizing activity against fibroblast entry, while all antibodies that neutralized epithelial cell entry also inhibited spread in epithelial cells and a correlation existed between the potencies of these two activities. This suggests that exposure of virions to the cell culture medium is obligatory during spread in epithelial cells but not in fibroblasts. In fibroblasts, the formation of syncytiumlike structures was impaired not only by antibodies to gB or gH/gL but also by antibodies to the pentamer, suggesting a potential role for the pentamer in promoting fibroblast fusion. Four antibodies reacted with linear epitopes near the N terminus of gH, exhibited strain specificity, and neutralized both epithelial cell and fibroblast entry. Five other antibodies recognized conformational epitopes in gH/gL and neutralized both fibroblast and epithelial cell entry. That these antibodies were strain specific for neutralizing fibroblast but not epithelial cell entry suggests that polymorphisms external to certain gH/gL epitopes may influence antibody neutralization during fibroblast but not epithelial cell entry. These findings may have implications for elucidating the mechanisms of CMV entry, spread, and antibody evasion and may assist in determining which antibodies may be most efficacious following active immunization or passive administration.

IMPORTANCE
Cytomegalovirus (CMV) is a significant cause of birth defects among newborns infected
in utero
and morbidity and mortality in transplant and AIDS patients. Monoclonal antibodies and vaccines targeting humoral responses are under development for prophylactic or therapeutic use. The findings reported here (i) confirm that cell-to-cell spread of CMV is sensitive to antibody inhibition in epithelial cells but not fibroblasts, (ii) demonstrate that antibodies can restrict the formation
in vitro
of syncytiumlike structures that resemble syncytial cytomegalic cells that are associated with CMV disease
in vivo
, and (iii) reveal that neutralization of CMV by antibodies to certain epitopes in gH or gH/gL is both strain and cell type dependent and can be governed by polymorphisms in sequences external to the epitopes. These findings serve to elucidate the mechanisms of CMV entry, spread, and antibody evasion and may have important implications for the development of CMV vaccines and immunotherapeutics.
Tetherin Inhibits Cell-Free Virus Dissemination and Retards Murine Leukemia Virus Pathogenesis
Authors: Liberatore Rachel A. , Mastrocola Emily J. , Powell Chelsea , Bieniasz Paul D.
Published: April 2017

The relative contributions of cell-free virion circulation and direct cell-to-cell transmission to retroviral dissemination and pathogenesis are unknown. Tetherin/Bst2 is an antiviral protein that blocks enveloped virion release into the extracellular milieu but may not inhibit cell-to-cell virus transmission. We developed live-cell imaging assays which show that tetherin does not affect Moloney murine leukemia virus (MoMLV) spread, and only minimally affects vesicular stomatitis virus (VSV) spread, to adjacent cells in a monolayer. Conversely, cell-free MLV and VSV virion yields and VSV spread to distal cells were dramatically reduced by tetherin. To elucidate the roles of tetherin and cell-free virions during
in vivo
viral dissemination and pathogenesis, we developed mice carrying an inducible human tetherin (hTetherin) transgene. While ubiquitous hTetherin expression was detrimental to the growth and survival of mice, restriction of hTetherin expression to hematopoietic cells gave apparently healthy mice. The expression of hTetherin in hematopoietic cells had little or no effect on the number of MoMLV-infected splenocytes and thymocytes. However, hTetherin expression significantly reduced cell-free plasma viremia and also delayed MoMLV-induced disease. Overall, these results suggest that MoMLV spread within hematopoietic tissues and cell monolayers involves cell-to-cell transmission that is resistant to tetherin but that virion dissemination via plasma is inhibited by tetherin and is required for full MoMLV pathogenesis.

IMPORTANCE
Retroviruses are thought to spread primarily via direct cell-to-cell transmission, yet many have evolved to counteract an antiviral protein called tetherin, which may selectively inhibit cell-free virus release. We generated a mouse model with an inducible tetherin transgene in order to study how tetherin affects retroviral dissemination and on which cell types its expression is required to do so. We first developed a novel
in vitro
live-cell imaging assay to demonstrate that while tetherin does indeed dramatically reduce cell-free virus spreading, it has little to no effect on direct cell-to-cell transmission of either vesicular stomatitis virus (VSV) or the retrovirus MoMLV. Using our transgenic mouse model, we found that tetherin expression on hematopoietic cells resulted in the specific reduction of MoMLV cell-free plasma viremia but not the number of infected hematopoietic cells. The delay in disease associated with this scenario suggests a role for cell-free virus in retroviral disease progression.
Human milk oligosaccharide composition predicts risk of necrotising enterocolitis in preterm infants
Authors: Autran Chloe A , Kellman Benjamin P , Kim Jae H , Asztalos Elizabeth , Blood Arlin B , Spence Erin C Hamilton , Patel Aloka L , Hou Jiayi , Lewis Nathan E , Bode Lars
Published: April 2017

Objective

Necrotising enterocolitis (NEC) is one of the most common and often fatal intestinal disorders in preterm infants. Markers to identify at-risk infants as well as therapies to prevent and treat NEC are limited and urgently needed. NEC incidence is significantly lower in breast-fed compared with formula-fed infants. Infant formula lacks human milk oligosaccharides (HMO), such as disialyllacto-N-tetraose (DSLNT), which prevents NEC in neonatal rats. However, it is unknown if DSLNT also protects human preterm infants.

Design

We conducted a multicentre clinical cohort study and recruited 200 mothers and their very low birthweight infants that were predominantly human milk-fed. We analysed HMO composition in breast milk fed to infants over the first 28 days post partum, matched each NEC case with five controls and used logistic regression and generalised estimating equation to test the hypothesis that infants who develop NEC receive milk with less DSLNT than infants who do not develop NEC.

Results

Eight infants in the cohort developed NEC (Bell stage 2 or 3). DSLNT concentrations were significantly lower in almost all milk samples in NEC cases compared with controls, and its abundance could identify NEC cases prior to onset. Aggregate assessment of DSLNT over multiple days enhanced the separation of NEC cases and control subjects.

Conclusions

DSLNT content in breast milk is a potential non-invasive marker to identify infants at risk of developing NEC, and screen high-risk donor milk. In addition, DSLNT could serve as a natural template to develop novel therapeutics against this devastating disorder.
Probing quantum critical points by Fisher information at finite temperature
Authors: Wang Qian , Wang Wen-Ge
Published: April 2017

We study the quantum Fisher information (QFI) of a one-dimensional anisotropic XY chain in a transverse field with three-spin interaction. It is shown that the QFI, computed at a finite temperature, can be used to estimate the critical point (CP) of the quantum phase transition (QPT) at zero temperature. The accuracy of the obtained result depends on both the anisotropy parameter of the chain and the local observable used in the computation of QFI.
ANTECEDENTS AND CONSEQUENCES OF IPPD EFFECTIVENESS
Authors: RAUNIAR RUPAK , RAWSKI GREG , HUDSON DONALD
Published: April 2017

Team is the primary mechanism through which product development projects are executed. Despite regular theoretical discussions on the importance of cross-functional team and concurrent engineering to improve new product development projects, empirical studies on consequence of integrated product and process development (IPPD) effectiveness on teamwork is largely missing in existing product development literature. IPDD projects execute concurrent activities that go through several iterations before the deliverable of each stage are finalised. Based on information processing theory and goal-setting theory for team, this study hypothesise shared project mission, clarity of the project target, and customer and supplier involvement positively influences effectiveness of IPPD project. We further hypothesise that such effective IPPD leads to teamwork which can have a positive impact on project performance in terms of product development cost, product development time, and customer satisfaction. Primary data collected from 191 IPPD projects from U.S. automotive industry were analysed using structural equation modelling technique. All the hypotheses representing antecedents of effective IPPD and the consequence of effective IPPD were found to be supported in the current study.
Cell-free vascular grafts: Recent developments and clinical potential
Authors: Row Sindhu , Santandreu Ana , Swartz Daniel D. , Andreadis Stelios T.
Published: April 2017

Recent advances in vascular tissue engineering have led to the development of cell-free grafts that are available off-the-shelf for on demand surgery. Challenges associated with cell-based technologies including cell sourcing, cell expansion and long-term bioreactor culture motivated the development of completely cell-free vascular grafts. These are based on decellularized arteries, decellularized cultured cell-based tissue engineered grafts or biomaterials functionalized with biological signals that promote in situ tissue regeneration. Clinical trials undertaken to demonstrate the applicability of these grafts are also discussed. This comprehensive review summarizes recent developments in vascular graft technologies, with potential applications in coronary artery bypass procedures, lower extremity bypass, vascular injury and trauma, congenital heart diseases and dialysis access shunts, to name a few.
Building an experimental model of the human body with non-physiological parameters
Authors: Labuz Joseph M. , Moraes Christopher , Mertz David R. , Leung Brendan M. , Takayama Shuichi
Published: April 2017

New advances in engineering and biomedical technology have enabled recent efforts to capture essential aspects of human physiology in microscale, in-vitro systems. The application of these advances to experimentally model complex processes in an integrated platform — commonly called a ‘human-on-a-chip (HOC)’ — requires that relevant compartments and parameters be sized correctly relative to each other and to the system as a whole. Empirical observation, theoretical treatments of resource distribution systems and natural experiments can all be used to inform rational design of such a system, but technical and fundamental challenges (e.g. small system blood volumes and context-dependent cell metabolism, respectively) pose substantial, unaddressed obstacles. Here, we put forth two fundamental principles for HOC design: inducing in-vivo-like cellular metabolic rates is necessary and may be accomplished in-vitro by limiting O2availability and that the effects of increased blood volumes on drug concentration can be mitigated through pharmacokinetics-based treatments of solute distribution. Combining these principles with natural observation and engineering workarounds, we derive a complete set of design criteria for a practically realizable, physiologically faithful, five-organ millionth-scale ([Formula: see text]) microfluidic model of the human body.
The petroleum system of the Tenere Basin: oil geochemistry from the SH-1 wildcat well in eastern Niger
Authors: Liu Bang , Zhang Guangya , Mao Fengjun , Liu Jiguo , Cheng Dingsheng , Lü Mingsheng
Published: April 2017

The SH-1 wildcat well, firstly encountering oil, proved the existence of a working petroleum system in the Tenere Basin, but the origin of oil and its generation history is not fully understood. In this regard, one crude oil and nine Upper Cretaceous source rock samples from the SH-1 wildcat well in the Tenere Basin were characterized by a variety of biomarker parameters and stable carbon isotopic composition. The oil from the Tenere Basin displays a low pristine/phytane (Pr/Ph) ratio, low C
29
/C
30
and C
35
/C
34
hopane ratios, low C
22
/C
21
and high C
24
/C
23
tricyclic terpane ratios, and high gammacerane index (gammacerane/C
30
hopane), suggesting shale source rocks deposited under an anoxic and relatively high-salinity environment. Relatively high C
29
sterane concentrations, a low value of the regular steranes/17
α
(H)-hopanes ratio and a canonical variable from stable carbon isotopic composition larger than 0.47 indicate that the oil is mainly derived from terrestrial higher plants. Both aromatic maturity parameters and sterane isomerization parameters suggest that the oil was generated from an early mature source rock. Correlation between oils from the Tenere Basin and those from the Termit Basin confirms that these oils belong to the same genetic family. The oil–source rock correlation suggests that the oil from the Tenere Basin originated from the Upper Cretaceous marine source rocks, and the Yogou Formation can be considered as effective source potential.
Advance Reservation Games
Authors: Simhon Eran , Starobinski David
Published: April 2017

Advance reservation (AR) services form a pillar of several branches of the economy, including transportation, lodging, dining, and, more recently, cloud computing. In this work, we use game theory to analyze a slotted AR system in which customers differ in their lead times. For each given time slot, the number of customers requesting service is a random variable following a general probability distribution. Based on statistical information, the customers decide whether or not to make an advance reservation of server resources in future slots for a fee. We prove that only two types of equilibria are possible: either none of the customers makes AR or only customers with lead time greater than some threshold make AR. Our analysis further shows that the fee that maximizes the provider’s profit may lead to other equilibria, one of which yields zero profit. In order to prevent ending up with no profit, the provider can elect to advertise a lower fee yielding a guaranteed but smaller profit. We refer to the ratio of the maximum possible profit to the maximum guaranteed profit as the price of conservatism. When the number of customers is a Poisson random variable, we prove that the price of conservatism is one in the single-server case, but can be arbitrarily high in a many-server system.
Strengthening Integrated Care Through Population-Focused Primary Care Services: International Experiences Outside the United States
Authors: Loewenson Rene , Simpson Sarah
Published: April 2017

Many high- and middle-income countries (HMICs) are experiencing a burden of comorbidity and chronic diseases. Together with increasing patient expectations, this burden is raising demand for population health–oriented innovation in health care. Using desk review and country case studies, we examine strategies applied in HMICs outside the United States to address these challenges, with a focus on and use of a new framework for analyzing primary care (PC). The article outlines how a population health approach has been supported by focusing assessment on and clustering services around social groups and multimorbidity, with support for community roles. It presents ways in which early first contact and continuity of PC, PC coordination of referral, multidisciplinary team approaches, investment in PC competencies, and specific payment and incentive models have all supported comprehensive approaches. These experiences locate PC as a site of innovation, where information technology and peer-to-peer learning networks support learning from practice.
Abnormal cardiovascular response to exercise in hypertension: contribution of neural factors
Authors: Mitchell Jere H.
Published: April 2017

During both dynamic (e.g., endurance) and static (e.g., strength) exercise there are exaggerated cardiovascular responses in hypertension. This includes greater increases in blood pressure, heart rate, and efferent sympathetic nerve activity than in normal controls. Two of the known neural factors that contribute to this abnormal cardiovascular response are the exercise pressor reflex (EPR) and functional sympatholysis. The EPR originates in contracting skeletal muscle and reflexly increases sympathetic efferent nerve activity to the heart and blood vessels as well as decreases parasympathetic efferent nerve activity to the heart. These changes in autonomic nerve activity cause an increase in blood pressure, heart rate, left ventricular contractility, and vasoconstriction in the arterial tree. However, arterial vessels in the contracting skeletal muscle have a markedly diminished vasoconstrictor response. The markedly diminished vasoconstriction in contracting skeletal muscle has been termed functional sympatholysis. It has been shown in hypertension that there is an enhanced EPR, including both its mechanoreflex and metaboreflex components, and an impaired functional sympatholysis. These conditions set up a positive feedback or vicious cycle situation that causes a progressively greater decrease in the blood flow to the exercising muscle. Thus these two neural mechanisms contribute significantly to the abnormal cardiovascular response to exercise in hypertension. In addition, exercise training in hypertension decreases the enhanced EPR, including both mechanoreflex and metaboreflex function, and improves the impaired functional sympatholysis. These two changes, caused by exercise training, improve the muscle blood flow to exercising muscle and cause a more normal cardiovascular response to exercise in hypertension.
Protein phosphatase 2C is responsible for VP-induced dephosphorylation of AQP2 serine 261
Authors: Cheung Pui W. , Ueberdiek Lars , Day Jack , Bouley Richard , Brown Dennis
Published: April 2017

Aquaporin 2 (AQP2) trafficking is regulated by phosphorylation and dephosphorylation of serine residues in the AQP2 COOH terminus. Vasopressin (VP) binding to its receptor (V2R) leads to a cascade of events that result in phosphorylation of serine 256 (S256), S264, and S269, but dephosphorylation of S261. To identify which phosphatase is responsible for VP-induced S261 dephosphorylation, we pretreated cells with different phosphatase inhibitors before VP stimulation. Sanguinarine, a specific protein phosphatase (PP) 2C inhibitor, but not inhibitors of PP1, PP2A (okadaic acid), or PP2B (cyclosporine), abolished VP-induced S261 dephosphorylation. However, sanguinarine and VP significantly increased phosphorylation of ERK, a kinase that can phosphorylate S261; inhibition of ERK by PD98059 partially decreased baseline S261 phosphorylation. These data support a role of ERK in S261 phosphorylation but suggest that, upon VP treatment, increased phosphatase activity overcomes the increase in ERK activity, resulting in overall dephosphorylation of S261. We also found that sanguinarine abolished VP-induced S261 dephosphorylation in cells expressing mutated AQP2 S256A, suggesting that the phosphorylation state of S261 is independent of S256. Sanguinarine alone did not induce AQP2 membrane trafficking, nor did it inhibit VP-induced AQP2 membrane accumulation in cells and kidney tissues, suggesting that S261 does not play an observable role in acute AQP2 membrane accumulation. In conclusion, PP2C activity is required for S261 AQP2 dephosphorylation upon VP stimulation, which occurs independently of S256 phosphorylation. Understanding the pathways involved in modulating PP2C will help elucidate the role of S261 in cellular events involving AQP2.
Severe acute dehydration in a desert rodent elicits a transcriptional response that effectively prevents kidney injury
Authors: MacManes Matthew David
Published: April 2017

Animals living in desert environments are forced to survive despite severe heat, intense solar radiation, and both acute and chronic dehydration. These animals have evolved phenotypes that effectively address these environmental stressors. To begin to understand the ways in which the desert-adapted rodent Peromyscus eremicus survives, reproductively mature adults were subjected to 72 h of water deprivation, during which they lost, on average, 23% of their body weight. The animals reacted via a series of changes in the kidney, which included modulating expression of genes responsible for reducing the rate of transcription and maintaining water and salt balance. Extracellular matrix turnover appeared to be decreased, and apoptosis was limited. In contrast to the canonical human response, serum creatinine and other biomarkers of kidney injury were not elevated, suggesting that changes in gene expression related to acute dehydration may effectively prohibit widespread kidney damage in the cactus mouse.