bluuebunny/crossref_metadata_2025 huggingface dataset:
Governing health and safety at lower tiers of the computer industry global value chain
Authors: Nadvi Khalid , Raj‐Reichert Gale
Published: March 2015

Global brands remain under increasing pressure to ensure labor standards and codes of conduct are met by their suppliers. Little is known about how this is addressed by lower tier suppliers. We investigate whether, and how, occupational health and safety standards permeate down the computer industry value chain. We compare first and second tier suppliers' engagement with a private voluntary industry code, the Electronic Industry Code of Conduct, and the publicly regulated European Union Directive on the Restriction of Hazardous Substances. We find the industry code absent at the lower tier, yet second tier suppliers do implement the European Union Directive. This is achieved without support from public agencies or global value chain linkages. Our findings question the emphasis placed on chain governance in studies of labor compliance in global value chains, and suggest that alternative and complementary approaches may be required for effective labor compliance throughout the value chain.
A Review of Health‐related Support Provision within the UK Work Programme – What's on the Menu?
Authors: Ceolta‐Smith Jenny , Salway Sarah , Tod Angela Mary
Published: March 2015

In common with other European welfare states, a large proportion of those who are out of work and claiming welfare benefits in the UK have long‐term health conditions. The need to reduce the number of people who are claiming sickness related unemployment benefits by supporting them into paid work has been highlighted as a priority across the political spectrum since the late 1990s. However, recent years have seen a significant shift in UK welfare‐to‐work policy, with the introduction of the Work Programme in 2011. This unified programme diverges from earlier approaches in several important respects. The shift includes a move towards so‐called ‘black box’ commissioning, through which contracted organizations are given far greater freedom to design and deliver their interventions. Therefore, important questions arise regarding whether and how support for claimants with health conditions will be provided across Work Programme areas and the implications for claimant outcomes. This article begins to address these questions by reviewing Work Programme Prime Contractors' (Primes) proposed approaches as set out in their bids. Using a structured, interpretive analytical framework, bid documents prepared by the 18 Primes were reviewed and synthesized. The findings showed that individuals facing similar health‐related obstacles to employment can expect to receive very different levels and types of support depending on which Primes' programme they are assigned to join. This review suggests that policy needs to ensure that claimants' health‐related barriers to employment are addressed. Research to explore how claimants' health‐related needs are being met in practice is also recommended.
Supporting the UK's Workless – An International Comparative Perspective
Authors: Danson Mike , McKay Ailsa , Sullivan Willie
Published: March 2015

Within and between nations, spatial inequalities in relation to health, labour markets and employment shape the barriers faced by those trapped on disability benefits, and thus create challenges for public policy. To provide context for such analyses and policy discussions, this article presents evidence on levels of poverty, welfare support and inequality across Europe. It compares and contrasts especially the position and support for those out of or at the margins of the labour market under different welfare states to reveal the significant differences between the UK on the one hand and the Nordic and Benelux countries on the other hand. Applying insights from theories and practices of endogenous growth, universalism and inclusion, it is demonstrated that lessons are to be learnt from the better economic and social performances of the more inclusive and coherent nations of northern Europe. In particular, it is argued that the very high levels of poverty and inequality inherent in the neo‐liberal policies of the UK cannot generate the conditions for simultaneously reducing public sector deficits and stimulating demand so that worklessness and exclusion inevitably will continue. The article concludes that an alternative social democratic paradigm is required based on solidarity, equity and fiscal responsibility to address this self‐defeating feedback.
Keeping the gate closed: functions of the polycomb repressive complex PRC2 in development
Authors: Mozgova Iva , Köhler Claudia , Hennig Lars
Published: March 2015

Plant ontogeny relies on the correct timing and sequence of transitions between individual developmental phases. These are specified by gene expression patterns that are established by the balanced action of activators and repressors. Polycomb repressive complexes (PRCs) represent an evolutionarily conserved system of epigenetic gene repression that governs the establishment and maintenance of cell, tissue and organ identity, contributing to the correct execution of the developmental programs. PRC2 is a four‐subunit histone methyltransferase complex that catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), which contributes to the change of chromatin structure and long‐lasting gene repression. Here, we review the composition and molecular function of the different known PRC2 complexes in plants, and focus on the role of PRC2 in mediating the establishment of different developmental phases and transitions between them.
Topology of Endoplasmic Reticulum‐Associated Cellular and Viral Proteins Determined with Split‐GFP
Authors: Hyun Seong‐In , Maruri‐Avidal Liliana , Moss Bernard
Published: March 2015

The split green fluorescent protein (GFP) system was adapted for investigation of the topology of ER‐associated proteins. A 215‐amino acid fragment of GFP (S1–10) was expressed in the cytoplasm as a free protein or fused to the N‐terminus of calnexin and in the ER as an intraluminal protein or fused to the C‐terminus of calnexin. A 16‐amino acid fragment of GFP (S11) was fused to the N‐ or C‐terminus of the target protein. Fluorescence occurred when both GFP fragments were in the same intracellular compartment. After validation with the cellular proteins PDI and tapasin, we investigated two vaccinia virus proteins (L2 and A30.5) of unknown topology that localize to the ER and are required for assembly of the viral membrane. Our results indicated that the N‐ and C‐termini of L2 faced the cytoplasmic and luminal sides of the ER, respectively. In contrast both the N‐ and C‐termini of A30.5 faced the cytoplasm. The system offers advantages for quickly determining the topology of intracellular proteins: the S11 tag is similar in length to commonly used epitope tags; multiple options are available for detecting fluorescence in live or fixed cells; transfection protocols are adaptable to numerous expression systems and can enable high throughput applications.
In vitro evaluation of cytomegalovirus‐specific hyperimmune globulins vs. standard intravenous immunoglobulins
Authors: Miescher S. M. , Huber T. M. , Kühne M. , Lieby P. , Snydman D. R. , Vensak J. L. , Berger M.
Published: March 2015

Background and Objectives

To evaluate standard intravenous immunoglobulin (IVIG) as an alternative to intravenous cytomegalovirus hyperimmune immunoglobulin (CMVIG) for prophylaxis and therapy of cytomegalovirus (CMV) disease, we measured the ELISA and neutralizing titres of CMV‐specific antibodies in CMVIG and IVIG preparations.

Materials and Methods

Anti‐CMV‐IgG ELISA and neutralizing titres (fibroblast‐based test) in CMVIG CG (Cytogam®, n = 20), CMVIG CT (Cytotect® CP, n = 3), IVIG P (Privigen®, n = 32) and IVIG K/G (Kiovig®/Gammagard®, n = 5) were compared, and IgG subclasses 1–4 were determined by nephelometry.

Results

Cytomegalovirus hyperimmune immunoglobulins contained more than fourfold higher CMV ELISA and CMV‐neutralizing activity per gram of IgG than the standard IVIGs. Pooled data for all four products showed a significant correlation between anti‐CMV‐IgG ELISA and neutralizing titres (r = 0·93, P < 0·001). There was a good correlation between the IgG3 content and CMV‐neutralizing antibodies amongst lots of CMVIGs (r = 0·91, P = 0·01), but this did not extend to the IVIGs. CMVIG CG contained the highest CMV‐neutralizing activity (3497 ± 395 PEIU/g IgG) of any product tested.

Conclusion

The higher anti‐CMV neutralization capacity of CMVIG per gram of IgG vs. standard IVIG suggests that standard IVIGs are not equivalent to or interchangeable with CMVIG.
Automated point‐of‐care testing for ABO agglutination test: proof of concept and validation
Authors: El Kenz H. , Corazza F.
Published: March 2015

Background and objectives

ABO‐incompatible red blood cell transfusions still represent an important hazard in transfusion medicine. Therefore, some countries have introduced a systematic bedside ABO agglutination test checking that the right blood is given to the right patient. However, this strategy requires an extremely time‐consuming learning programme and relies on a subjective interpretation of ABO test cards agglutination. We developed a prototype of a fully automated device performing the bedside agglutination test that could be completed by reading of a barcoded wristband. This POCT checks the ABO compatibility between the patient and the blood bag.

Materials and methods

Proof of concept and analytical validation of the prototype has been completed on 451 blood samples: 238 donor packed red blood cells, 137 consecutive unselected patients for whom a blood group determination had been ordered and on 76 patient samples selected with pathology that could possibly interfere with or impair performances of the assay.

Results

We observed 100% concordance for ABO blood groups between the POCT and the laboratory instrument.

Conclusion

These preliminary results demonstrate the feasibility of ABO determination with a simple POCT device eliminating manipulation and subjective interpretation responsible for transfusion errors. This device should be linked to the blood bank system allowing all cross‐check of the results.
Block–Göttsche invariants from wall-crossing
Authors: Filippini S. A. , Stoppa J.
Published: March 2015

We show how some of the refined tropical counts of Block and Göttsche emerge from the wall-crossing formalism. This leads naturally to a definition of a class of putative$q$-deformed Gromov–Witten invariants. We prove that this coincides with another natural$q$-deformation, provided by a result of Reineke and Weist in the context of quiver representations, when the latter is well defined.
Impact of the F508del mutation on ovine CFTR, a Cl− channel with enhanced conductance and ATP‐dependent gating
Authors: Cai Zhiwei , Palmai‐Pallag Timea , Khuituan Pissared , Mutolo Michael J. , Boinot Clément , Liu Beihui , Scott‐Ward Toby S. , Callebaut Isabelle , Harris Ann , Sheppard David N.
Published: March 2015

Key points

Malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), a gated pathway for chloride movement, causes the common life‐shortening genetic disease cystic fibrosis (CF).

Towards the development of a sheep model of CF, we have investigated the function of sheep CFTR.

We found that sheep CFTR was noticeably more active than human CFTR, while the most common CF mutation, F508del, had reduced impact on sheep CFTR function.

Our results demonstrate that subtle changes in protein structure have marked effects on CFTR function and the consequences of the CF mutation F508del.

Cross‐species comparative studies are a powerful approach to understanding the epithelial Cl− channel cystic fibrosis transmembrane conductance regulator (CFTR), which is defective in the genetic disease cystic fibrosis (CF). Here, we investigate the single‐channel behaviour of ovine CFTR and the impact of the most common CF mutation, F508del‐CFTR, using excised inside‐out membrane patches from transiently transfected CHO cells. Like human CFTR, ovine CFTR formed a weakly inwardly rectifying Cl− channel regulated by PKA‐dependent phosphorylation, inhibited by the open‐channel blocker glibenclamide. However, for three reasons, ovine CFTR was noticeably more active than human CFTR. First, single‐channel conductance was increased. Second, open probability was augmented because the frequency and duration of channel openings were increased. Third, with enhanced affinity and efficacy, ATP more strongly stimulated ovine CFTR channel gating. Consistent with these data, the CFTR modulator phloxine B failed to potentiate ovine CFTR Cl− currents. Similar to its impact on human CFTR, the F508del mutation caused a temperature‐sensitive folding defect, which disrupted ovine CFTR protein processing and reduced membrane stability. However, the F508del mutation had reduced impact on ovine CFTR channel gating in contrast to its marked effects on human CFTR. We conclude that ovine CFTR forms a regulated Cl− channel with enhanced conductance and ATP‐dependent channel gating. This phylogenetic analysis of CFTR structure and function demonstrates that subtle changes in structure have pronounced effects on channel function and the consequences of the CF mutation F508del.
Three-Dimensional Dynamic Model of TEHD Tilting-Pad Journal Bearing—Part II: Parametric Studies
Authors: Suh Junho , Palazzolo Alan
Published: March 2015

This paper presents a new analysis method for a thermo-elasto-hydro-dynamic (TEHD) tilting pad journal bearing (TPJB) system to reach a static equilibrium condition adopting nonlinear transient dynamic solver, whereas earlier studies have used iteration schemes such as Newton–Raphson method. The theoretical TPJB model discussed in Part I of this research is combined into a newly developed algorithm to perform a bearing dynamic analysis and present dynamic coefficients. In the nonlinear transient dynamic solver, physical and modal coordinates coexist for computational efficiency, and transformation between modal and physical coordinate is performed at each numerical integration time step. Variable time step Runge–Kutta numerical integration scheme is adopted for a reliable and fast calculation. Nonlinear time transient dynamic analysis and steady thermal analysis are combined to find the static equilibrium condition of the TPJB system, where the singular matrix issue of flexible pad finite element (FE) model is resolved. The flexible pad TPJB model was verified by comparison with other numerical results. Simulation results corresponding with the theoretical model explained in Part I are presented and discussed. It explains how the TPJB dynamic behavior is influenced by a number of eigenvector of flexible pad FE model and pad thickness. Preload change under fluid and thermal load is examined.
A Strongly Coupled Fluid Structure Interaction Solution for Transient Soft Elastohydrodynamic Lubrication Problems in Reciprocating Rod Seals Based on a Combined Moving Mesh Method
Authors: Gao Haiping , Li Baoren , Fu Xiaoyun , Yang Gang
Published: March 2015

Soft elastohydrodynamic lubrication (EHL) problems widely exist in hydraulic reciprocating rod seals and pose great challenges because of high nonlinearity and strong coupling effects, especially when the EHL problems are of high dimensions. In this paper, a strongly coupled fluid structure interaction (FSI) model is proposed to solve the transient soft EHL problems in U-cup hydraulic reciprocating rod seals. The Navier–Stokes equations, rather than the Reynolds equation, are employed to govern the whole fluid field in the soft EHL problems, with the nonlinearity of the solid taken into consideration. The governing equations of the fluid and solid fields are combined into one equation system and solved monolithically. To determine the displacements of nodes of the fluid field, a new moving mesh method based on the combination of the Laplace equation and the leader–follower methods is put forward. At last, the proposed FSI model runs successfully with the moving mesh method, and the boundaries of the hydrodynamic lubrication zones and the hydrostatic zones are formed automatically and change dynamically during the coupling process. The results are as follows: The soft EHL problems show typical characteristics, like the constriction effects of the lubricating films, and the law of dynamic development of the lubricating films and the fluid pressures is revealed. The minimum stroke lengths needed to generate complete lubricating films vary with the rod speeds and movement directions, so the design of the rod seals should be paid close attention to, in particular the rod seals of short stroke lengths. Furthermore, along with the dynamic development processes of the fluid pressures during the instroke of U-cup seals, the lubricating film humps expand and locate between the fluid pressure abrupt points and the outlet zones. After the U-cup seals reach the steady-states, the fluid abrupt points disappear and no changes of the film humps are observed. Theoretically, the proposed method can be popularized to solve similar soft EHL problems.
Development of Stress Intensity Factors for Surface Cracks With Large Aspect Ratio in Plates
Authors: Li Yinsheng , Hasegawa Kunio , Katsumata Genshichiro , Osakabe Kazuya , Okada Hiroshi
Published: March 2015

A number of surface cracks with large aspect ratio have been detected in components of nuclear power plants (NPPs) in recent years. The depths of these cracks are even larger than the half of crack lengths. When a crack is detected during in-service inspections, methods provided in ASME Boiler and Pressure Vessel Code Section XI or JSME Rules on fitness-for-service for NPPs can be used to assess the structural integrity of cracked components. The solution of the stress intensity factor (SIF) is very important in the structural integrity assessment. However, in the current codes, the solutions of the SIF are provided for semi-elliptical surface cracks with a limitation of a/ℓ ≤ 0.5, where a is the crack depth, and ℓ is the crack length. In this study, the solutions of the SIF were calculated using finite element analysis (FEA) with quadratic hexahedron elements for semi-elliptical surface cracks with large aspect ratio in plates. The crack dimensions were focused on the range of a/ℓ = 0.5–4.0 and a/t = 0.0–0.8, where t is the wall thickness. Solutions were provided at both the deepest and the surface points of the surface cracks. Furthermore, some of solutions were compared with the available existing results as well as with solutions obtained using FEA with quadratic tetrahedral elements and the virtual crack closure-integral method (VCCM). Finally, it was concluded that the solutions proposed in this paper are applicable in engineering applications.
New Results to a Three-Dimensional Chaotic System With Two Different Kinds of Nonisolated Equilibria
Authors: Wang Haijun , Li Xianyi
Published: March 2015

In the paper by Liu et al. (2009, “A Novel Three-Dimensional Autonomous Chaos System,” Chaos Solitons Fractals, 39(4), pp. 1950–1958), the three-dimensional (3D) chaotic system x·=-ax-ey2,y·=by-kxz,z·=-cz+mxy is investigated, and some of its dynamics according to theoretical and numerical analyses only for the parameters (a, e, b, k, c, m) = (1, 1, 2.5, 4, 5, 4) are discussed. In 2013, the same chaotic system x·1=-ax1- fx2x3,x·2=cx2-dx1x3,x·3=-bx3+ex22 by Li et al. (2013, “Analysis of a Novel Three-Dimensional Chaotic System,” Optik, 124(13), pp. 1516–1522) was mainly discussed by numerical simulation. In this article, by some deeper investigations, combining some numerical simulations, we formulate some new results of the system. First, after some problems in the first paper are pointed out, we display that its parameters e, k, and m may be kicked out by some homothetic transformations. Second, some of its rich nonlinear dynamics hiding and not found previously, such as the stability and Hopf bifurcation of its isolated equilibria, the behavior of its nonisolated equilibria, the existence of singular orbits (including singularly degenerate heteroclinic cycle, homoclinic and heteroclinic orbits, etc.), and its dynamics at infinity, etc., are clearly formulated. What's more interesting, we find, this system has two different kinds of nonisolated equilibria Ex and Ez, and new chaotic attractors can be bifurcated out with the disappearance of Ex, but this system has no such properties at Ez. In the meantime, several problems about the existence of singular orbits deserving further investigations are presented. Our results better complement and improve the known ones.
Wear Resistance of Polymers With Encapsulated Epoxy-Amine Self-Healing Chemistry
Authors: Win Khun Nay , Zhang He , Yang Jinglei
Published: March 2015

In this study, epoxy resin was microencapsulated through in situ polymerization in an oil-in-water emulsion, and amine was loaded into etched glass bubbles (GBs) as a curing agent for the microencapsulated epoxy resin. The purpose was to develop a two-component-self-healing system. The two healing agent carriers were co-incorporated in the epoxy matrix to form novel epoxy composites for tribological applications. The tribological results clearly showed that an increase in healing agent carrier content significantly decreased the friction and wear of the epoxy composites tested against a 6 mm steel ball under different normal loads. This was due to the self-lubricating and self-healing of the composites with released core liquids via the rupture of healing agent carriers during the wear test. It could be concluded that the co-incorporation of two healing agent carriers was a potential way to achieve a significant improvement in the tribological properties of epoxy matrix composites.
Games Centered Approaches in Teaching Children & Adolescents: Systematic Review of Associated Student Outcomes
Authors: Miller Andrew
Published: March 2015

The purpose of this systematic review was to investigate the weight of scientific evidence regarding student outcomes (physical, cognitive and affective) of a Game Centered Approach (GCA) when the quality of a study was taken into account in the interpretation of collective findings. A systematic search of five electronic databases (Sports Discuss, ERIC, A+ Education, PsychInfo and PROQUEST Education) was conducted from their year of inception to 30 January 2014. Included studies were longitudinal or experimental/quasi-experimental studies involving children or adolescents that quantitatively assessed (using repeat measures and/or comparison with a control group) the effects upon student outcomes when an intervention involved the use of a GCA. The search identified 15 articles examining the effects of GCA on student outcomes that met the criteria for inclusion. The weight of evidence provided by the included studies identified an association between a GCA and the outcomes of declarative knowledge, support during game play and affective outcomes of perceived competence, interest/enjoyment and effort/importance. Development of technical skill, procedural knowledge and game play skills of decision making and skill execution are not supported by the level of evidence currently provided. Intervention volume appears to have a large effect on the development of game based decision making and skill execution, with a positive association between these outcomes and use of GCA interventions greater than eight hours in volume. More longitudinal and intervention research examining the use of a GCA and potential psychological, physiological and behavioral outcomes in children and adolescents is recommended.
Assisting Preservice Teachers Toward More Motivationally Supportive Instruction
Authors: Perlman Dana
Published: March 2015

The purpose of this study was to examine the influence of an intervention grounded in Self-Determination Theory on preservice teachers’ instructional behaviors and the motivational responses of their students. A total of 62 preservice physical education teachers enrolled in a secondary physical education content and methods course were randomly assigned to either a treatment (n = 31) or a control group (n = 31). The study employed a pretest/posttest design and data were collected through: (a) observation of preservice teachers’ instruction, (b) a survey measuring preservice teachers’ perceptions of their autonomy support, and (c) a survey measuring secondary students’ motivation. Data analysis used repeated-measures ANOVAs to examine differences between the groups. Results indicated significant changes in autonomy-support for both teachers and students exposed to the intervention.
Time-restricted feeding attenuates age-related cardiac decline in
Drosophila
Authors: Gill Shubhroz , Le Hiep D. , Melkani Girish C. , Panda Satchidananda
Published: March 2015

Midnight snacks are bad for the heart

Circadian clocks help animals coordinate their active and rest periods with the daily cycles of light and darkness. As anyone who has suffered jet lag or worked night shifts knows, losing this coordination can have deleterious effects. Gill
et al.
compared fruit flies that were allowed to eat at any time with flies that were only allowed to eat during the day (when they are active). The flies with restricted feeding times slept better and had a slower decline in heart function as they aged. They also showed less weight gain, even though both groups of flies consumed about the same amount.

Science
, this issue p.
1265
A young multilayered terrane of the northern Mare Imbrium revealed by Chang’E-3 mission
Authors: Xiao Long , Zhu Peimin , Fang Guangyou , Xiao Zhiyong , Zou Yongliao , Zhao Jiannan , Zhao Na , Yuan Yuefeng , Qiao Le , Zhang Xiaoping , Zhang Hao , Wang Jiang , Huang Jun , Huang Qian , He Qi , Zhou Bin , Ji Yicai , Zhang Qunying , Shen Shaoxiang , Li Yuxi , Gao Yunze
Published: March 2015

Onsite radar shows what lies beneath

In more active periods of the Moon's history, volcanic eruptions created lava plains that formed layers of dark basalt. Without subsurface probing, we can only examine the most recent flows. After the soft landing of the Chang'E-3 spacecraft, Xiao
et al.
made penetrating radar measurements of the lunar crust with the Yutu rover. Several subsurface layers suggest multiple geologic processes at play throughout the crustal history, including multiple lava flows and the weathering-induced creation of dust and rocky debris.

Science
, this issue p.
1226
K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac
Authors: Dong Yin Yao , Pike Ashley C. W. , Mackenzie Alexandra , McClenaghan Conor , Aryal Prafulla , Dong Liang , Quigley Andrew , Grieben Mariana , Goubin Solenne , Mukhopadhyay Shubhashish , Ruda Gian Filippo , Clausen Michael V. , Cao Lishuang , Brennan Paul E. , Burgess-Brown Nicola A. , Sansom Mark S. P. , Tucker Stephen J. , Carpenter Elisabeth P.
Published: March 2015

A sensitive regulator of cellular potassium

A class of potassium channels called K2P channels modulates resting membrane potential in most cells. The channels are regulated by multiple ligands, including the antidepressant drug Prozac, as well as factors such as mechanical stretch and voltage. Dong
et al.
determined the structure of the human K2P channel, TREK-2, in two conformations and bound to a metabolite of Prozac. The structures show how ligand binding or mechanical stretch might induce switching between the states. Although both states have open channels, one appears primed for gating. A Prozac metabolite binds to the primed state and prevents conformational switching. K2P channels are not a target of Prozac, but their inhibition may contribute to side effects.

Science
, this issue p.
1256
As Ebola fades, a new threat
Authors: Roberts Leslie
Published: March 2015

With health services devastated in the wake of Ebola, experts are bracing for a deadly measles outbreak in West Africa.
The synthesis machine
Authors: Service Robert F.
Published: March 2015

An automatic device that makes small organic molecules could revolutionize drug discovery.
Toward substitution with no regrets
Authors: Zimmerman Julie B. , Anastas Paul T.
Published: March 2015

Advances in chemical design are needed to create safe alternatives to harmful chemicals
Direct evidence for human reliance on rainforest resources in late Pleistocene Sri Lanka
Authors: Roberts Patrick , Perera Nimal , Wedage Oshan , Deraniyagala Siran , Perera Jude , Eregama Saman , Gledhill Andrew , Petraglia Michael D. , Lee-Thorp Julia A.
Published: March 2015

Pleistocene humans in tropical rainforest

The tropical rainforest environment is nutritionally poor and tricky to navigate as compared to open habitats. This poses challenges for human subsistence. There has been little evidence to suggest that human populations relied on rainforest resources before the start of the Holocene, 10,000 years ago. Roberts
et al.
analyzed earlier fossil human and animal tooth enamel from Sri Lanka. The diet of these humans suggests rainforest rather than open-habitat foraging. Thus, humans were effectively exploiting rainforests in Sri Lanka since at least 20,000 years ago throughout periods of considerable climatic and environmental flux.

Science
, this issue p.
1246
Get the science right when paying for nature's services
Authors: Naeem S. , Ingram J. C. , Varga A. , Agardy T. , Barten P. , Bennett G. , Bloomgarden E. , Bremer L. L. , Burkill P. , Cattau M. , Ching C. , Colby M. , Cook D. C. , Costanza R. , DeClerck F. , Freund C. , Gartner T. , Goldman-Benner R. , Gunderson J. , Jarrett D. , Kinzig A. P. , Kiss A. , Koontz A. , Kumar P. , Lasky J. R. , Masozera M. , Meyers D. , Milano F. , Naughton-Treves L. , Nichols E. , Olander L. , Olmsted P. , Perge E. , Perrings C. , Polasky S. , Potent J. , Prager C. , Quétier F. , Redford K. , Saterson K. , Thoumi G. , Vargas M. T. , Vickerman S. , Weisser W. , Wilkie D. , Wunder S.
Published: March 2015

Few projects adequately address design and evaluation
Modeling infectious disease dynamics in the complex landscape of global health
Authors: Heesterbeek Hans , Anderson Roy M. , Andreasen Viggo , Bansal Shweta , De Angelis Daniela , Dye Chris , Eames Ken T. D. , Edmunds W. John , Frost Simon D. W. , Funk Sebastian , Hollingsworth T. Deirdre , House Thomas , Isham Valerie , Klepac Petra , Lessler Justin , Lloyd-Smith James O. , Metcalf C. Jessica E. , Mollison Denis , Pellis Lorenzo , Pulliam Juliet R. C. , Roberts Mick G. , Viboud Cecile ,   Isaac Newton Institute IDD Collaboration
Published: March 2015

Mathematical modeling of infectious diseases

The spread of infectious diseases can be unpredictable. With the emergence of antibiotic resistance and worrying new viruses, and with ambitious plans for global eradication of polio and the elimination of malaria, the stakes have never been higher. Anticipation and measurement of the multiple factors involved in infectious disease can be greatly assisted by mathematical methods. In particular, modeling techniques can help to compensate for imperfect knowledge, gathered from large populations and under difficult prevailing circumstances. Heesterbeek
et al.
review the development of mathematical models used in epidemiology and how these can be harnessed to develop successful control strategies and inform public health policy.

Science
, this issue
10.1126/science.aaa4339
Salmonella Serotype Determination Utilizing High-Throughput Genome Sequencing Data
Authors: Zhang Shaokang , Yin Yanlong , Jones Marcus B. , Zhang Zhenzhen , Deatherage Kaiser Brooke L. , Dinsmore Blake A. , Fitzgerald Collette , Fields Patricia I. , Deng Xiangyu
Published: March 2015

Serotyping forms the basis of national and international surveillance networks for
Salmonella
, one of the most prevalent foodborne pathogens worldwide (1
–
3). Public health microbiology is currently being transformed by whole-genome sequencing (WGS), which opens the door to serotype determination using WGS data. SeqSero (
www.denglab.info/SeqSero
) is a novel Web-based tool for determining
Salmonella
serotypes using high-throughput genome sequencing data. SeqSero is based on curated databases of
Salmonella
serotype determinants (
rfb
gene cluster,
fliC
and
fljB
alleles) and is predicted to determine serotype rapidly and accurately for nearly the full spectrum of
Salmonella
serotypes (more than 2,300 serotypes), from both raw sequencing reads and genome assemblies. The performance of SeqSero was evaluated by testing (i) raw reads from genomes of 308
Salmonella
isolates of known serotype; (ii) raw reads from genomes of 3,306
Salmonella
isolates sequenced and made publicly available by GenomeTrakr, a U.S. national monitoring network operated by the Food and Drug Administration; and (iii) 354 other publicly available draft or complete
Salmonella
genomes. We also demonstrated
Salmonella
serotype determination from raw sequencing reads of fecal metagenomes from mice orally infected with this pathogen. SeqSero can help to maintain the well-established utility of
Salmonella
serotyping when integrated into a platform of WGS-based pathogen subtyping and characterization.
Molecular Diagnosis of Toxoplasmosis in Immunocompromised Patients: a 3-Year Multicenter Retrospective Study
Authors: Robert-Gangneux Florence , Sterkers Yvon , Yera Hélène , Accoceberry Isabelle , Menotti Jean , Cassaing Sophie , Brenier-Pinchart Marie-Pierre , Hennequin Christophe , Delhaes Laurence , Bonhomme Julie , Villena Isabelle , Scherer Emeline , Dalle Frédéric , Touafek Feriel , Filisetti Denis , Varlet-Marie Emmanuelle , Pelloux Hervé , Bastien Patrick
Published: March 2015

Toxoplasmosis is a life-threatening infection in immunocompromised patients (ICPs). The definitive diagnosis relies on parasite DNA detection, but little is known about the incidence and burden of disease in HIV-negative patients. A 3-year retrospective study was conducted in 15 reference laboratories from the network of the French National Reference Center for Toxoplasmosis, in order to record the frequency of
Toxoplasma gondii
DNA detection in ICPs and to review the molecular methods used for diagnosis and the prevention measures implemented in transplant patients. During the study period, of 31,640 PCRs performed on samples from ICPs, 610 were positive (323 patients). Blood (
n
= 337 samples), cerebrospinal fluid (
n
= 101 samples), and aqueous humor (
n
= 100 samples) were more frequently positive. Chemoprophylaxis schemes in transplant patients differed between centers. PCR follow-up of allogeneic hematopoietic stem cell transplant (allo-HSCT) patients was implemented in 8/15 centers. Data from 180 patients (13 centers) were further analyzed regarding clinical setting and outcome. Only 68/180 (38%) patients were HIV
+
; the remaining 62% consisted of 72 HSCT, 14 solid organ transplant, and 26 miscellaneous immunodeficiency patients. Cerebral toxoplasmosis and disseminated toxoplasmosis were most frequently observed in HIV and transplant patients, respectively. Of 72 allo-HSCT patients with a positive PCR result, 23 were asymptomatic; all were diagnosed in centers performing systematic blood PCR follow-up, and they received specific treatment. Overall survival of allo-HSCT patients at 2 months was better in centers with PCR follow-up than in other centers (
P
< 0.01). This study provides updated data on the frequency of toxoplasmosis in HIV-negative ICPs and suggests that regular PCR follow-up of allo-HSCT patients could guide preemptive treatment and improve outcome.
Subtyping Novel Zoonotic Pathogen Cryptosporidium Chipmunk Genotype I
Authors: Guo Yaqiong , Cebelinski Elizabeth , Matusevich Christine , Alderisio Kerri A. , Lebbad Marianne , McEvoy John , Roellig Dawn M. , Yang Chunfu , Feng Yaoyu , Xiao Lihua
Published: March 2015

Cryptosporidium
chipmunk genotype I is an emerging zoonotic pathogen in humans. The lack of subtyping tools makes it impossible to determine the role of zoonotic transmission in epidemiology. To identify potential subtyping markers, we sequenced the genome of a human chipmunk genotype I isolate. Altogether, 9,509,783 bp of assembled sequences in 853 contigs were obtained, with an N50 of 117,886 bp and >200-fold coverage. Based on the whole-genome sequence data, two genetic markers encoding the 60-kDa glycoprotein (gp60) and a mucin protein (ortholog of cgd1_470) were selected for the development of a subtyping tool. The tool was used for characterizing chipmunk genotype I in 25 human specimens from four U.S. states and Sweden, one specimen each from an eastern gray squirrel, a chipmunk, and a deer mouse, and 4 water samples from New York. At the gp60 locus, although different subtypes were seen among the animals, water, and humans, the 15 subtypes identified differed mostly in the numbers of trinucleotide repeats (TCA, TCG, or TCT) in the serine repeat region, with only two single nucleotide polymorphisms in the nonrepeat region. Some geographic differences were found in the subtype distribution of chipmunk genotype I from humans. In contrast, only two subtypes were found at the mucin locus, which differed from each other in the numbers of a 30-bp minisatellite repeat. Thus,
Cryptosporidium
chipmunk genotype I isolates from humans and wildlife are genetically similar, and zoonotic transmission might play a potential role in human infections.
Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection
Authors: Li Fang , Wang Yueyun , Yu Lan , Cao Shengbo , Wang Ke , Yuan Jiaolong , Wang Chong , Wang Kunlun , Cui Min , Fu Zhen F.
Published: March 2015

Japanese encephalitis is an acute zoonotic, mosquito-borne disease caused by Japanese encephalitis virus (JEV). Japanese encephalitis is characterized by extensive inflammation in the central nervous system (CNS) and disruption of the blood-brain barrier (BBB). However, the pathogenic mechanisms contributing to the BBB disruption are not known. Here, using a mouse model of intravenous JEV infection, we show that virus titers increased exponentially in the brain from 2 to 5 days postinfection. This was accompanied by an early, dramatic increase in the level of inflammatory cytokines and chemokines in the brain. Enhancement of BBB permeability, however, was not observed until day 4, suggesting that viral entry and the onset of inflammation in the CNS occurred prior to BBB damage.In vitrostudies revealed that direct infection with JEV could not induce changes in the permeability of brain microvascular endothelial cell monolayers. However, brain extracts derived from symptomatic JEV-infected mice, but not from mock-infected mice, induced significant permeability of the endothelial monolayer. Consistent with a role for inflammatory mediators in BBB disruption, the administration of gamma interferon-neutralizing antibody ameliorated the enhancement of BBB permeability in JEV-infected mice. Taken together, our data suggest that JEV enters the CNS, propagates in neurons, and induces the production of inflammatory cytokines and chemokines, which result in the disruption of the BBB.

IMPORTANCEJapanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, resulting in 70,000 cases each year, in which approximately 20 to 30% of cases are fatal, and a high proportion of patients survive with serious neurological and psychiatric sequelae. Pathologically, JEV infection causes an acute encephalopathy accompanied by BBB dysfunction; however, the mechanism is not clear. Thus, understanding the mechanisms of BBB disruption in JEV infection is important. Our data demonstrate that JEV gains entry into the CNS prior to BBB disruption. Furthermore, it is not JEV infectionper se, but the inflammatory cytokines/chemokines induced by JEV infection that inhibit the expression of TJ proteins and ultimately result in the enhancement of BBB permeability. Neutralization of gamma interferon (IFN-γ) ameliorated the enhancement of BBB permeability in JEV-infected mice, suggesting that IFN-γ could be a potential therapeutic target. This study would lead to identification of potential therapeutic avenues for the treatment of JEV infection.
Dynamics of Human Cytomegalovirus Infection in CD34+Hematopoietic Cells and Derived Langerhans-Type Dendritic Cells
Authors: Coronel Roxanne , Takayama Sachiko , Juwono Timothy , Hertel Laura
Published: March 2015

Acquisition of human cytomegalovirus (CMV) usually occurs by contact between contaminated bodily fluids, such as urine and saliva, and host mucosal cells. Langerhans-type dendritic cells (LC) are the only type of immune cells found in the outermost layers of the oral mucosae, where they not only provide a first line of defense against CMV but can easily be targeted by orally administered vaccines, while their bone marrow resident progenitors are important sites of virus latency. In this work, we tracked the progress of infection in CD34+progenitor cells, immature LC (iLC), and mature LC (mLC) exposed to the clinical-like strain TB40-BAC4 or to the vaccine strain AD169varATCC, prior to their long-term maintenance under either immature or mature conditions. We show that the genomes of both strains are efficiently maintained in CD34+cells during their differentiation into iLC, although this requires the presence of larger amounts of input AD169varATCC DNA. Lipopolysaccharide- and CD40 ligand-induced maturation of iLC derived from latently infected progenitors was not associated with robust viral genome replication and progeny production, while maturation of directly infected iLC increased and prolonged expression of the viral immediate early proteins. While effective replication of viral genomes from both strains occurred only in mLC, both iLC and mLC produced viral progeny, suggesting that both types of LC may contribute to CMV horizontal transmissionin vivo.

IMPORTANCEHuman CMV is usually acquired via the oral and nasal mucosae. Langerhans-type dendritic cells (LC) are the only type of immune cells found in the outermost layers of these tissues. Understanding how CMV interacts with LC and their hematopoietic progenitors is thus essential to develop innovative means of defense against this virus. Here we show that the genomes of a virulent and an attenuated strain of CMV are maintained in hematopoietic progenitor cells during their differentiation into immature LC and that maturation of these cells by exposure to lipopolysaccharide and CD40 ligand is not sufficient to trigger virus reactivation. While the extents of viral protein expression and genome replication were broadest in directly infected mature LC populations, similar amounts of viral progeny were detected in the supernatants of immature and mature LC, suggesting that these immune cells of the oral mucosa are likely to be important for CMV transmission within the human population.
Murine Gammaherpesvirus 68 ORF48 Is an RTA-Responsive Gene Product and Functions in both Viral Lytic Replication and Latency during
In Vivo
Infection
Authors: Qi Jing , Han Chuanhui , Gong Danyang , Liu Ping , Zhou Sheng , Deng Hongyu
Published: March 2015

Replication and transcription activator (RTA) of gammaherpesvirus is an immediate early gene product and regulates the expression of many downstream viral lytic genes. ORF48 is also conserved among gammaherpesviruses; however, its expression regulation and function remained largely unknown. In this study, we characterized the transcription unit of
ORF48
from murine gammaherpesvirus 68 (MHV-68) and analyzed its transcriptional regulation. We showed that RTA activates the
ORF48
promoter via an RTA-responsive element (48pRRE). RTA binds to 48pRRE directly
in vitro
and also associates with ORF48 promoter
in vivo
. Mutagenesis of 48pRRE in the context of the viral genome demonstrated that the expression of ORF48 is activated by RTA through 48pRRE during
de novo
infection. Through site-specific mutagenesis, we generated an ORF48-null virus and examined the function of ORF48
in vitro
and
in vivo
. The ORF48-null mutation remarkably reduced the viral replication efficiency in cell culture. Moreover, through intranasal or intraperitoneal infection of laboratory mice, we showed that ORF48 is important for viral lytic replication in the lung and establishment of latency in the spleen, as well as viral reactivation from latency. Collectively, our study identified
ORF48
as an RTA-responsive gene and showed that ORF48 is important for MHV-68 replication both
in vitro
and
in vivo
.

IMPORTANCE
The replication and transcription activator (RTA), conserved among gammaherpesviruses, serves as a molecular switch for the virus life cycle. It works as a transcriptional regulator to activate the expression of many viral lytic genes. However, only a limited number of such downstream genes have been uncovered for MHV-68. In this study, we identified
ORF48
as an RTA-responsive gene of MHV-68 and mapped the
cis
element involved. By constructing a mutant virus that is deficient in ORF48 expression and through infection of laboratory mice, we showed that ORF48 plays important roles in different stages of viral infection
in vivo
. Our study provides insights into the transcriptional regulation and protein function of MHV-68, a desired model for studying gammaherpesviruses.
The pH Stability of Foot-and-Mouth Disease Virus Particles Is Modulated by Residues Located at the Pentameric Interface and in the N Terminus of VP1
Authors: Caridi Flavia , Vázquez-Calvo Angela , Sobrino Francisco , Martín-Acebes Miguel A.
Published: March 2015

The picornavirus foot-and-mouth disease virus (FMDV) is the etiological agent of a highly contagious disease that affects important livestock species. The FMDV capsid is highly acid labile, and viral particles lose infectivity due to their disassembly at pH values slightly below neutrality. This acid sensitivity is related to the mechanism of viral uncoating and genome penetration from endosomes. In this study, we have analyzed the molecular basis of FMDV acid-induced disassembly by isolating and characterizing a panel of novel FMDV mutants differing in acid sensitivity. Amino acid replacements altering virion stability were preferentially distributed in two different regions of the capsid: the N terminus of VP1 and the pentameric interface. Even more, the acid labile phenotype induced by a mutation located at the pentameric interface in VP3 could be compensated by introduction of an amino acid substitution in the N terminus of VP1. These results indicate that the acid sensitivity of FMDV can be considered a multifactorial trait and that virion stability is the fine-tuned product of the interaction between residues from different capsid proteins, in particular those located within the N terminus of VP1 or close to the pentameric interface.

IMPORTANCE
The viral capsid protects the viral genome from environmental factors and contributes to virus dissemination and infection. Thus, understanding of the molecular mechanisms that modulate capsid stability is of interest for the basic knowledge of the biology of viruses and as a tool to improve the stability of conventional vaccines based on inactivated virions or empty capsids. Using foot-and-mouth disease virus (FMDV), which displays a capsid with extreme acid sensitivity, we have performed a genetic study to identify the molecular determinants involved in capsid stability. A panel of FMDV mutants with differential sensitivity to acidic pH was generated and characterized, and the results showed that two different regions of FMDV capsid contribute to modulating viral particle stability. These results provide new insights into the molecular mechanisms of acid-mediated FMDV uncoating.