bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of heavy grazing on burrow choice in the pygmy bluetongue lizard, Tiliqua adelaidensis
Authors: Pettigrew Melissa , Bull C. Michael
Published: September 2011

Context
Grazing pressure has directly altered and indirectly influenced natural ecosystems worldwide, and has affected and displaced many native species. The endangered pygmy bluetongue lizard Tiliqua adelaidensis is endemic to the mid-north of South Australia. It inhabits remnant native grasslands where it is reliant on the presence of natural spider burrows constructed by lycosid and mygalomorph spiders as refuge sites. These lizards spend the majority of the day associated with their burrow either in the burrow itself or basking at its entrance. The remnant native grasslands of South Australia have endured 200 years of agricultural changes and the introduction of domestic stock has meant that grazing pressure has substantially increased. The vegetation around a burrow is considered to be important in providing shelter for the lizard. However, too much vegetation may reduce basking opportunities and visibility of prey. Stock grazing has been maintained on the majority of sites that contain pygmy bluetongue populations and it is presumed that the lizards can tolerate some form of grazing. However, the level of grazing intensity directly influences the vegetation structure that surrounds the lizard burrows.

Aims
We aimed to investigate the consequences of severe grazing pressure on the choice of burrows by lizards, and on their burrow related behaviour.

Methods
We simulated heavy grazing pressure by manually removing aboveground vegetation in the field in replicated quadrats that contained artificial burrows, and by providing bare substrate in half of experimental enclosures in the laboratory.

Key results
In the field, lizards only occupied the artificial burrows in control quadrats, where vegetation had been left intact. In the laboratory, lizards that occupied both burrows basked for longer at the burrow entrance where vegetation was present.

Conclusions
Heavy grazing management that results in the majority of vegetation being removed could have a negative impact on pygmy bluetongue lizard recruitment and sustainability.

Implications
Grazing regimes should be carefully monitored to consider the needs of species that rely heavily on microhabitat structure for their persistence. For the endangered pygmy bluetongue lizard, heavy grazing should be avoided to promote amounts of vegetation suitable to sustain viable populations.
Ruth Lehmann: Germ cells do things differently
Authors: Sedwick Caitlin
Published: September 2011

Lehmann studies the developmental program that sets the germ line apart from somatic cells.
Cytoskeleton in motion: the dynamics of keratin intermediate filaments in epithelia
Authors: Windoffer Reinhard , Beil Michael , Magin Thomas M. , Leube Rudolf E.
Published: September 2011

Epithelia are exposed to multiple forms of stress. Keratin intermediate filaments are abundant in epithelia and form cytoskeletal networks that contribute to cell type–specific functions, such as adhesion, migration, and metabolism. A perpetual keratin filament turnover cycle supports these functions. This multistep process keeps the cytoskeleton in motion, facilitating rapid and protein biosynthesis–independent network remodeling while maintaining an intact network. The current challenge is to unravel the molecular mechanisms underlying the regulation of the keratin cycle in relation to actin and microtubule networks and in the context of epithelial tissue function.
Coatomer and dimeric ADP ribosylation factor 1 promote distinct steps in membrane scission
Authors: Beck Rainer , Prinz Simone , Diestelkötter-Bachert Petra , Röhling Simone , Adolf Frank , Hoehner Kathrin , Welsch Sonja , Ronchi Paolo , Brügger Britta , Briggs John A.G. , Wieland Felix
Published: September 2011

Formation of coated vesicles requires two striking manipulations of the lipid bilayer. First, membrane curvature is induced to drive bud formation. Second, a scission reaction at the bud neck releases the vesicle. Using a reconstituted system for COPI vesicle formation from purified components, we find that a dimerization-deficient Arf1 mutant, which does not display the ability to modulate membrane curvature in vitro or to drive formation of coated vesicles, is able to recruit coatomer to allow formation of COPI-coated buds but does not support scission. Chemical cross-linking of this Arf1 mutant restores vesicle release. These experiments show that initial curvature of the bud is defined primarily by coatomer, whereas the membrane curvature modulating activity of dimeric Arf1 is required for membrane scission.
Cdk1 uncouples CtIP-dependent resection and Rad51 filament formation during M-phase double-strand break repair
Authors: Peterson Shaun E. , Li Yinyin , Chait Brian T. , Gottesman Max E. , Baer Richard , Gautier Jean
Published: September 2011

DNA double-strand break (DSB) resection, which results in RPA-bound single-stranded DNA (ssDNA), is activated in S phase by Cdk2. RPA-ssDNA activates the ATR-dependent checkpoint and homology-directed repair (HDR) via Rad51-dependent mechanisms. On the other hand, the fate of DSBs sustained during vertebrate M phase is largely unknown. We use cell-free Xenopus laevis egg extracts to examine the recruitment of proteins to chromatin after DSB formation. We find that S-phase extract recapitulates a two-step resection mechanism. M-phase chromosomes are also resected in cell-free extracts and cultured human cells. In contrast to the events in S phase, M-phase resection is solely dependent on MRN-CtIP. Despite generation of RPA-ssDNA, M-phase resection does not lead to ATR activation or Rad51 chromatin association. Remarkably, we find that Cdk1 permits resection by phosphorylation of CtIP but also prevents Rad51 binding to the resected ends. We have thus identified Cdk1 as a critical regulator of DSB repair in M phase. Cdk1 induces persistent ssDNA-RPA overhangs in M phase, thereby preventing both classical NHEJ and Rad51-dependent HDR.
Comparative RNAi screening identifies a conserved core metazoan actinome by phenotype
Authors: Rohn Jennifer L. , Sims David , Liu Tao , Fedorova Marina , Schöck Frieder , Dopie Joseph , Vartiainen Maria K. , Kiger Amy A. , Perrimon Norbert , Baum Buzz
Published: September 2011

Although a large number of actin-binding proteins and their regulators have been identified through classical approaches, gaps in our knowledge remain. Here, we used genome-wide RNA interference as a systematic method to define metazoan actin regulators based on visual phenotype. Using comparative screens in cultured Drosophila and human cells, we generated phenotypic profiles for annotated actin regulators together with proteins bearing predicted actin-binding domains. These phenotypic clusters for the known metazoan “actinome” were used to identify putative new core actin regulators, together with a number of genes with conserved but poorly studied roles in the regulation of the actin cytoskeleton, several of which we studied in detail. This work suggests that although our search for new components of the core actin machinery is nearing saturation, regulation at the level of nuclear actin export, RNA splicing, ubiquitination, and other upstream processes remains an important but unexplored frontier of actin biology.
The nucleolus directly regulates p53 export and degradation
Authors: Boyd Mark T. , Vlatković Nikolina , Rubbi Carlos P.
Published: September 2011

The correlation between stress-induced nucleolar disruption and abrogation of p53 degradation is evident after a wide variety of cellular stresses. This link may be caused by steps in p53 regulation occurring in nucleoli, as suggested by some biochemical evidence. Alternatively, nucleolar disruption also causes redistribution of nucleolar proteins, potentially altering their interactions with p53 and/or MDM2. This raises the fundamental question of whether the nucleolus controls p53 directly, i.e., as a site where p53 regulatory processes occur, or indirectly, i.e., by determining the cellular localization of p53/MDM2-interacting factors. In this work, transport experiments based on heterokaryons, photobleaching, and micronucleation demonstrate that p53 regulatory events are directly regulated by nucleoli and are dependent on intact nucleolar structure and function. Subcellular fractionation and nucleolar isolation revealed a distribution of ubiquitylated p53 that supports these findings. In addition, our results indicate that p53 is exported by two pathways: one stress sensitive and one stress insensitive, the latter being regulated by activities present in the nucleolus.
Bringing Rad52 foci into focus
Authors: Thorpe Peter H. , Alvaro David , Lisby Michael , Rothstein Rodney
Published: September 2011

In 2007, we published the results of a genome-wide screen for ORFs that affect the frequency of Rad52 foci in yeast. That paper was published within the constraints of conventional online publishing tools, and it provided only a glimpse into the actual screen data. New tools in the JCB DataViewer now show how these data can—and should—be shared.
New Tools for JCB
Authors: Williams Elizabeth H. , Misteli Tom
Published: September 2011

New technologies and approaches in cell biology research necessitate new venues for information sharing and publication. JCB continues its support of innovation in publishing with the launch of Tools, a new article type for the description of methods and high-throughput datasets, and of a new interface for the JCB DataViewer for hosting high-content screening datasets in their entirety.
The Origins and Implications of Language Effects in Multilingual Surveys: A MIMIC Approach with Application to Latino Political Attitudes
Authors: Pérez Efrén O.
Published: September 2011

The study of Latino public opinion has renewed interest in the relationship between language and survey response. However, extant research generally relies on statistical methods that cannot distinguish between two related yet distinct types of language effects in Latino surveys: (1) differences inattitudeand (2) differences inmeasuresof attitude. The former reflects varied levels of a latent attitude between English and Spanish interviewees. The latter—formally known as Differential Item Functioning (DIF)—refers to linguistic differences in the interpretation of survey items, which lead Latino respondents to misreport their level of attitude. This paper proposes Multiple Indicators Multiple Causes models to decouple these two types of language effects. Using this modeling framework, I examine language differences in measures of subjective and factual political attitudes from theLatino National Survey(2006). I find that the language of interview systematically colors Latinos' interpretation of survey items, even after controlling for measurement error and individual differences in the latent variable being assessed. I then show through an applied analysis how ignoring language DIF can yield misleading inferences about hypothesized relationships between variables. Together, these findings highlight a need for greater theoretical work on the psychological origins of language effects in multilingual political surveys.
Towards a model-based integration of co-registered electroencephalography/functional magnetic resonance imaging data with realistic neural population meshes
Authors: Bojak I. , Oostendorp Thom F. , Reid Andrew T. , Kötter Rolf
Published: September 2011

Brain activity can be measured with several non-invasive neuroimaging modalities, but each modality has inherent limitations with respect to resolution, contrast and interpretability. It is hoped that multimodal integration will address these limitations by using the complementary features of already available data. However, purely statistical integration can prove problematic owing to the disparate signal sources. As an alternative, we propose here an advanced neural population model implemented on an anatomically sound cortical mesh with freely adjustable connectivity, which features proper signal expression through a realistic head model for the electroencephalogram (EEG), as well as a haemodynamic model for functional magnetic resonance imaging based on blood oxygen level dependent contrast (fMRI BOLD). It hence allows simultaneous and realistic predictions of EEG and fMRI BOLD from the same underlying model of neural activity. As proof of principle, we investigate here the influence on simulated brain activity of strengthening visual connectivity. In the future we plan to fit multimodal data with this neural population model. This promises novel, model-based insights into the brain's activity in sleep, rest and task conditions.
Assessing interactions in the brain with exact low-resolution electromagnetic tomography
Authors: Pascual-Marqui Roberto D. , Lehmann Dietrich , Koukkou Martha , Kochi Kieko , Anderer Peter , Saletu Bernd , Tanaka Hideaki , Hirata Koichi , John E. Roy , Prichep Leslie , Biscay-Lirio Rolando , Kinoshita Toshihiko
Published: September 2011

Scalp electric potentials (electroencephalogram; EEG) are contingent to the impressed current density unleashed by cortical pyramidal neurons undergoing post-synaptic processes. EEG neuroimaging consists of estimating the cortical current density from scalp recordings. We report a solution to this inverse problem that attains exact localization: exact low-resolution brain electromagnetic tomography (eLORETA). This non-invasive method yields high time-resolution intracranial signals that can be used for assessing functional dynamic connectivity in the brain, quantified by coherence and phase synchronization. However, these measures are non-physiologically high because of volume conduction and low spatial resolution. We present a new method to solve this problem by decomposing them into instantaneous and lagged components, with the lagged part having almost pure physiological origin.
The multiple time scales of sleep dynamics as a challenge for modelling the sleeping brain
Authors: Olbrich Eckehard , Claussen Jens Christian , Achermann Peter
Published: September 2011

A particular property of the sleeping brain is that it exhibits dynamics on very different time scales ranging from the typical sleep oscillations such as sleep spindles and slow waves that can be observed in electroencephalogram (EEG) segments of several seconds duration over the transitions between the different sleep stages on a time scale of minutes to the dynamical processes involved in sleep regulation with typical time constants in the range of hours. There is an increasing body of work on mathematical and computational models addressing these different dynamics, however, usually considering only processes on a single time scale. In this paper, we review and present a new analysis of the dynamics of human sleep EEG at the different time scales and relate the findings to recent modelling efforts pointing out both the achievements and remaining challenges.
Circadian regulation of sleep–wake behaviour in nocturnal rats requires multiple signals from suprachiasmatic nucleus
Authors: Fleshner Michelle , Booth Victoria , Forger Daniel B. , Diniz Behn Cecilia G.
Published: September 2011

The dynamics of sleep and wake are strongly linked to the circadian clock. Many models have accurately predicted behaviour resulting from dynamic interactions between these two systems without specifying physiological substrates for these interactions. By contrast, recent experimental work has identified much of the relevant physiology for circadian and sleep–wake regulation, but interaction dynamics are difficult to study experimentally. To bridge these approaches, we developed a neuronal population model for the dynamic, bidirectional, neurotransmitter-mediated interactions of the sleep–wake and circadian regulatory systems in nocturnal rats. This model proposes that the central circadian pacemaker, located within the suprachiasmatic nucleus (SCN) of the hypothalamus, promotes sleep through single neurotransmitter-mediated signalling to sleep–wake regulatory populations. Feedback projections from these populations to the SCN alter SCN firing patterns and fine-tune this modulation. Although this model reproduced circadian variation in sleep–wake dynamics in nocturnal rats, it failed to describe the sleep–wake dynamics observed in SCN-lesioned rats. We thus propose two alternative, physiologically based models in which neurotransmitter- and neuropeptide-mediated signalling from the SCN to sleep–wake populations introduces mechanisms to account for the behaviour of both the intact and SCN-lesioned rat. These models generate testable predictions and offer a new framework for modelling sleep–wake and circadian interactions.
Non-homogeneous extracellular resistivity affects the current-source density profiles of up–down state oscillations
Authors: Bazhenov Maxim , Lonjers Peter , Skorheim Steven , Bedard Claude , Destexhe Alain
Published: September 2011

Rhythmic local field potential (LFP) oscillations observed during deep sleep are the result of synchronized electrical activities of large neuronal ensembles, which consist of alternating periods of activity and silence, termed ‘up’ and ‘down’ states, respectively. Current-source density (CSD) analysis indicates that the up states of these slow oscillations are associated with current sources in superficial cortical layers and sinks in deep layers, while the down states display the opposite pattern of source–sink distribution. We show here that a network model of up and down states displays this CSD profile only if a frequency-filtering extracellular medium is assumed. When frequency filtering was modelled as inhomogeneous conductivity, this simple model had considerably more power in slow frequencies, resulting in significant differences in LFP and CSD profiles compared with the constant-resistivity model. These results suggest that the frequency-filtering properties of extracellular media may have important consequences for the interpretation of the results of CSD analysis.
Quantitative modelling of sleep dynamics
Authors: Robinson P. A. , Phillips A. J. K. , Fulcher B. D. , Puckeridge M. , Roberts J. A.
Published: September 2011

Arousal is largely controlled by the ascending arousal system of the hypothalamus and brainstem, which projects to the corticothalamic system responsible for electroencephalographic (EEG) signatures of sleep. Quantitative physiologically based modelling of brainstem dynamics theory is described here, using realistic parameters, and links to EEG are outlined. Verification against a wide range of experimental data is described, including arousal dynamics under normal conditions, sleep deprivation, stimuli, stimulants and jetlag, plus key features of wake and sleep EEGs.
Characterizing the complexity of brain and mind networks
Authors: Zamora-López Gorka , Russo Eleonora , Gleiser Pablo M. , Zhou Changsong , Kurths Jürgen
Published: September 2011

Recent studies of brain connectivity and language with methods of complex networks have revealed common features of organization. These observations open a window to better understand the intrinsic relationship between the brain and the mind by studying how information is either physically stored or mentally represented. In this paper, we review some of the results in both brain and linguistic networks, and we illustrate how modelling approaches can serve to comprehend the relationship between the structure of the brain and its function. On the one hand, we show that brain and neural networks display dynamical behaviour with optimal complexity in terms of a balance between their capacity to simultaneously segregate and integrate information. On the other hand, we show how principles of neural organization can be implemented into models of memory storage and recognition to reproduce spontaneous transitions between memories, resembling phenomena of memory association studied in psycholinguistic experiments.
The thalamic low-threshold Ca
2+
potential: a key determinant of the local and global dynamics of the slow (<1 Hz) sleep oscillation in thalamocortical networks
Authors: Crunelli Vincenzo , Errington Adam C. , Hughes Stuart W. , Tóth Tibor I.
Published: September 2011

During non-rapid eye movement sleep and certain types of anaesthesia, neurons in the neocortex and thalamus exhibit a distinctive slow (<1 Hz) oscillation that consists of alternating UP and DOWN membrane potential states and which correlates with a pronounced slow (<1 Hz) rhythm in the electroencephalogram. While several studies have claimed that the slow oscillation is generated exclusively in neocortical networks and then transmitted to other brain areas, substantial evidence exists to suggest that the full expression of the slow oscillation in an intact thalamocortical (TC) network requires the balanced interaction of oscillator systems in both the neocortex and thalamus. Within such a scenario, we have previously argued that the powerful low-threshold Ca
2+
potential (LTCP)-mediated burst of action potentials that initiates the UP states in individual TC neurons may be a vital signal for instigating UP states in related cortical areas. To investigate these issues we constructed a computational model of the TC network which encompasses the important known aspects of the slow oscillation that have been garnered from earlier
in vivo
and
in vitro
experiments. Using this model we confirm that the overall expression of the slow oscillation is intricately reliant on intact connections between the thalamus and the cortex. In particular, we demonstrate that UP state-related LTCP-mediated bursts in TC neurons are proficient in triggering synchronous UP states in cortical networks, thereby bringing about a synchronous slow oscillation in the whole network. The importance of LTCP-mediated action potential bursts in the slow oscillation is also underlined by the observation that their associated dendritic Ca
2+
signals are the only ones that inform corticothalamic synapses of the TC neuron output, since they, but not those elicited by tonic action potential firing, reach the distal dendritic sites where these synapses are located.
The sleeping brain as a complex system
Authors: Olbrich Eckehard , Achermann Peter , Wennekers Thomas
Published: September 2011

‘Complexity science’ is a rapidly developing research direction with applications in a multitude of fields that study complex systems consisting of a number of nonlinear elements with interesting dynamics and mutual interactions. This Theme Issue ‘The complexity of sleep’ aims at fostering the application of complexity science to sleep research, because the brain in its different sleep stages adopts different global states that express distinct activity patterns in large and complex networks of neural circuits. This introduction discusses the contributions collected in the present Theme Issue. We highlight the potential and challenges of a complex systems approach to develop an understanding of the brain in general and the sleeping brain in particular. Basically, we focus on two topics: the complex networks approach to understand the changes in the functional connectivity of the brain during sleep, and the complex dynamics of sleep, including sleep regulation. We hope that this Theme Issue will stimulate and intensify the interdisciplinary communication to advance our understanding of the complex dynamics of the brain that underlies sleep and consciousness.
Contribution of vaccines to our understanding of pneumococcal disease
Authors: Klugman Keith P.
Published: September 2011

Pneumonia is the leading cause of mortality in children in developing countries and is also the leading infectious cause of death in adults. The most important cause of pneumonia is the Gram-positive bacterial pathogen,
Streptococcus pneumoniae
, also known as the pneumococcus. It has thus become the leading vaccine-preventable cause of death and is a successful and diverse human pathogen. The development of conjugate pneumococcal vaccines has made possible the prevention of pneumococcal disease in infants, but has also elucidated aspects of pneumococcal biology in a number of ways. Use of the vaccine as a probe has increased our understanding of the burden of pneumococcal disease in children globally. Vaccination has also elucidated the clinical spectrum of vaccine-preventable pneumococcal infections; the identification of a biological niche for multiple pneumococcal serotypes in carriage and the differential invasiveness of pneumococcal serotypes; the impact of pneumococcal transmission among children on disease burden in adults; the role of carriage as a precursor to pneumonia; the plasticity of a naturally transformable pathogen to respond to selective pressure through capsular switching and the accumulation of antibiotic-resistance determinants; and the role of pneumococcal infections in hospitalization and mortality associated with respiratory viral infections, including both seasonal and pandemic influenza. Finally, there has been a recent demonstration that pneumococcal pneumonia in children may be an important cause of hospitalization for those with underlying tuberculosis.
Evaluation of vaccines against enteric infections: a clinical and public health research agenda for developing countries
Authors: Clemens John
Published: September 2011

Enteric infections are a major cause of morbidity and mortality in developing countries. To date, vaccines have played a limited role in public health efforts to control enteric infections. Licensed vaccines exist for cholera and typhoid, but these vaccines are used primarily for travellers; and there are two internationally licensed vaccines for rotavirus, but they are mainly used in affluent countries. The reasons that enteric vaccines are little used in developing countries are multiple, and certainly include financial and political constraints. Also important is the need for more cogent evidence on the performance of enteric vaccines in developing country populations. A partial inventory of research questions would include: (i) does the vaccine perform well in the most relevant settings? (ii) does the vaccine perform well in all epidemiologically relevant age groups? (iii) is there adequate evidence of vaccine safety once the vaccines have been deployed in developing countries? (iv) how effective is the vaccine when given in conjunction with non-vaccine cointerventions? (v) what is the level of vaccine protection against all relevant outcomes? and (vi) what is the expected population level of vaccine protection, including both direct and herd vaccine protective effects? Provision of evidence addressing these questions will help expand the use of enteric vaccines in developing countries.
Accelerating introduction of new vaccines: barriers to introduction and lessons learned from the recent
Haemophilus influenzae
type b vaccine experience
Authors: Hajjeh Rana
Published: September 2011

Adoption of new vaccines in developing countries is critical to reducing child mortality and meeting Millennium Development Goal 4. However, such introduction has historically suffered from significant delays that can be attributed to various factors including (i) lack of recognition of the value of a vaccine, (ii) factors related to weak health systems, and (iii) policy considerations. Recently, the Global Alliance for Vaccines and Immunization (GAVI) supported efforts to accelerate the introduction of
Haemophilus influenzae
type b (Hib) vaccines in developing countries, which resulted in a significant surge in vaccine adoption by these countries. The experience with Hib vaccines, as well as similar efforts by GAVI to support the introduction of new pneumococcal and rotavirus vaccines, provides a strategy for new vaccine adoption that is reviewed in this paper, providing a useful model to help accelerate the uptake of other life-saving vaccines. This strategy addresses barriers for vaccine adoption by focusing on three major areas: (i) communications to increase awareness about the various factors needed for evidence-based decisions that meet a country's health goals; (ii) research activities to answer key questions that support vaccine introduction and long-term programme sustainability; and (iii) coordination with the various stakeholders at global, regional and country levels to ensure successful programme implementation.
Twenty-first century vaccines
Authors: Rappuoli Rino
Published: September 2011

In the twentieth century, vaccination has been possibly the greatest revolution in health. Together with hygiene and antibiotics, vaccination led to the elimination of many childhood infectious diseases and contributed to the increase in disability-free life expectancy that in Western societies rose from 50 to 78–85 years (Crimmins, E. M. & Finch, C. E. 2006
Proc. Natl Acad. Sci. USA
103, 498–503; Kirkwood, T. B. 2008
Nat. Med
10, 1177–1185). In the twenty-first century, vaccination will be expected to eliminate the remaining childhood infectious diseases, such as meningococcal meningitis, respiratory syncytial virus, group A streptococcus, and will address the health challenges of this century such as those associated with ageing, antibiotic resistance, emerging infectious diseases and poverty. However, for this to happen, we need to increase the public trust in vaccination so that vaccines can be perceived as the best insurance against most diseases across all ages.
Vaccines and global health
Authors: Greenwood Brian , Salisbury David , Hill Adrian V. S.
Published: September 2011

Vaccines have made a major contribution to global health in recent decades but they could do much more. In November 2011, a Royal Society discussion meeting, ‘New vaccines for global health’, was held in London to discuss the past contribution of vaccines to global health and to consider what more could be expected in the future. Papers presented at the meeting reviewed recent successes in the deployment of vaccines against major infections of childhood and the challenges faced in developing vaccines against some of the world's remaining major infectious diseases such as human immunodeficiency virus (HIV), malaria and tuberculosis. The important contribution that development of more effective veterinary vaccines could make to global health was also addressed. Some of the social and financial challenges to the development and deployment of new vaccines were reviewed. The latter issues were also discussed at a subsequent satellite meeting, ‘Accelerating vaccine development’, held at the Kavli Royal Society International Centre. Delegates at this meeting considered challenges to the more rapid development and deployment of both human and veterinary vaccines and how these might be addressed. Papers based on presentations at the discussion meeting and a summary of the main conclusions of the satellite meeting are included in this issue of Philosophical Transactions of the Royal Society B.
Vaccines against malaria
Authors: Hill Adrian V. S.
Published: September 2011

There is no licenced vaccine against any human parasitic disease and
Plasmodium falciparum
malaria, a major cause of infectious mortality, presents a great challenge to vaccine developers. This has led to the assessment of a wide variety of approaches to malaria vaccine design and development, assisted by the availability of a safe challenge model for small-scale efficacy testing of vaccine candidates. Malaria vaccine development has been at the forefront of assessing many new vaccine technologies including novel adjuvants, vectored prime-boost regimes and the concept of community vaccination to block malaria transmission. Most current vaccine candidates target a single stage of the parasite's life cycle and vaccines against the early pre-erythrocytic stages have shown most success. A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vector vaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy in humans, and the anti-sporozoite vaccine is currently in phase III trials. However, a more effective malaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-component vaccine targeting more than one life cycle stage. The most attractive near-term approach to develop such a product is to combine existing partially effective pre-erythrocytic vaccine candidates.
Accelerating vaccine development and deployment: report of a Royal Society satellite meeting
Authors: Bregu Migena , Draper Simon J. , Hill Adrian V. S. , Greenwood Brian M.
Published: September 2011

The Royal Society convened a meeting on the 17th and 18th November 2010 to review the current ways in which vaccines are developed and deployed, and to make recommendations as to how each of these processes might be accelerated. The meeting brought together academics, industry representatives, research sponsors, regulators, government advisors and representatives of international public health agencies from a broad geographical background. Discussions were held under Chatham House rules. High-throughput screening of new vaccine antigens and candidates was seen as a driving force for vaccine discovery. Multi-stakeholder, small-scale manufacturing facilities capable of rapid production of clinical grade vaccines are currently too few and need to be expanded. In both the human and veterinary areas, there is a need for tiered regulatory standards, differentially tailored for experimental and commercial vaccines, to allow accelerated vaccine efficacy testing. Improved cross-fertilization of knowledge between industry and academia, and between human and veterinary vaccine developers, could lead to more rapid application of promising approaches and technologies to new product development. Identification of best-practices and development of checklists for product development plans and implementation programmes were seen as low-cost opportunities to shorten the timeline for vaccine progression from the laboratory bench to the people who need it.
Cancer vaccines
Authors: Liu Margaret A.
Published: September 2011

While vaccines are primarily thought of in terms of their use for prevention of infectious diseases, they can potentially be used to prevent or treat cancer. This manuscript explores the rationale for vaccines and immunotherapies for cancer from both the scientific and the global needs perspectives. Pathogens that are aetiologic agents of certain cancers provide perhaps the most obvious successful examples of the prophylactic utility of vaccines (such as the hepatitis B vaccine) to prevent not just the infectious disease (hepatitis), but the potential subsequent cancer (hepatocellular carcinoma). The use of monoclonal antibodies illustrates the effectiveness of the immune system for cancer therapy. In addition, the increased understanding of the role and mechanisms of the immune system in the processes of immune surveillance, as well as of its failure during immunosuppression, have yielded better insights into how to design cancer vaccines and immunotherapies. Examples of targets for cancer vaccines will be discussed, as will the challenges and few successes in this arena.
Towards universal influenza vaccines?
Authors: Osterhaus Ab , Fouchier Ron , Rimmelzwaan Guus
Published: September 2011

Vaccination is the most cost-effective way to reduce the considerable disease burden of seasonal influenza. Although seasonal influenza vaccines are effective, their performance in the elderly and immunocompromised individuals would benefit from improvement. Major problems related to the development and production of pandemic influenza vaccines are response time and production capacity as well as vaccine efficacy and safety. Several improvements can be envisaged. Vaccine production technologies based on embryonated chicken eggs may be replaced by cell culture techniques. Reverse genetics techniques can speed up the generation of seed viruses and new mathematical modelling methods improve vaccine strain selection. Better understanding of the correlates of immune-mediated protection may lead to new vaccine targets besides the viral haemagglutinin, like the neuraminidase and M2 proteins. In addition, the role of cell-mediated immunity could be better exploited. New adjuvants have recently been shown to increase the breadth and the duration of influenza vaccine-induced protection. Other studies have shown that influenza vaccines based on different viral vector systems may also induce broad protection. It is to be expected that these developments may lead to more universal influenza vaccines that elicit broader and longer protection, and can be produced more efficiently.
Therapeutic vaccines for chronic diseases: successes and technical challenges
Authors: Bachmann Martin F. , Jennings Gary T.
Published: September 2011

Chronic, non-communicable diseases are the major cause of death and disability worldwide and have replaced infectious diseases as the major burden of society in large parts of the world. Despite the complexity of chronic diseases, relatively few predisposing risk factors have been identified by the World Health Organization. Those include smoking, alcohol abuse, obesity, high cholesterol and high blood pressure as the cause of many of these chronic conditions. Here, we discuss several examples of vaccines that target these risk factors with the aim of preventing the associated diseases and some of the challenges they face.
Innate immunity and adjuvants
Authors: Akira Shizuo
Published: September 2011

Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection.
Developing vaccines against foot-and-mouth disease and some other exotic viral diseases of livestock
Authors: Paton David J. , Taylor Geraldine
Published: September 2011

Vaccines remain the main tool for the control of livestock viral diseases that pose a serious threat to animal and occasionally human health, reduce food security, distort trade in animals and their products, and undermine agricultural development in poor countries. Globalization and climate change increase the likelihood for new patterns of emergence and spread of livestock viruses. Conventionally attenuated and killed virus products have had spectacular success, and recent examples include the global eradication of rinderpest and the control of bluetongue in the UK and northern Europe. However, in many cases, livestock vaccines could benefit from improvement in some properties (e.g. stability, speed of onset and duration of immunity, and breadth of cross-protection to different serotypes or strains) and in some cases are not available at all. Compared with human vaccines, uptake of livestock products is highly cost-sensitive and their use may also need to be compatible with post-vaccination screening methods to determine whether or not animals continue to be infected. Requirements and prospects for new or improved vaccines are described for some priority viral diseases with potential for transboundary spread, particularly for foot-and-mouth disease.
Cooperation between both Wnt/β-catenin and PTEN/PI3K/Akt signaling promotes primitive hematopoietic stem cell self-renewal and expansion
Authors: Perry John M. , He Xi C. , Sugimura Ryohichi , Grindley Justin C. , Haug Jeffrey S. , Ding Sheng , Li Linheng
Published: September 2011

Although self-renewal is the central property of stem cells, the underlying mechanism remains inadequately defined. Using a hematopoietic stem and progenitor cell (HSPC)-specific conditional induction line, we generated a compound genetic model bearing both Pten deletion and β-catenin activation. These double mutant mice exhibit a novel phenotype, including expansion of phenotypic long-term hematopoietic stem cells (LT-HSCs) without extensive differentiation. Unexpectedly, constitutive activation of β-catenin alone results in apoptosis of HSCs. However, together, the Wnt/β-catenin and PTEN/PI3k/Akt pathways interact to drive phenotypic LT-HSC expansion by inducing proliferation while simultaneously inhibiting apoptosis and blocking differentiation, demonstrating the necessity of complementary cooperation between the two pathways in promoting self-renewal. Mechanistically, β-catenin activation reduces multiple differentiation-inducing transcription factors, blocking differentiation partially through up-regulation of Inhibitor of differentiation 2 (Id2). In double mutants, loss of Pten enhances the HSC anti-apoptotic factor Mcl-1. All of these contribute in a complementary way to HSC self-renewal and expansion. While permanent, genetic alteration of both pathways in double mutant mice leads to expansion of phenotypic HSCs, these HSCs cannot function due to blocked differentiation. We developed a pharmacological approach to expand normal, functional HSCs in culture using factors that reversibly activate both Wnt/β-catenin and PI3K/Akt signaling simultaneously. We show for the first time that activation of either single pathway is insufficient to expand primitive HSCs, but in combination, both pathways drive self-renewal and expansion of HSCs with long-term functional capacity.
Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses
Authors: Cabili Moran N. , Trapnell Cole , Goff Loyal , Koziol Magdalena , Tazon-Vega Barbara , Regev Aviv , Rinn John L.
Published: September 2011

Large intergenic noncoding RNAs (lincRNAs) are emerging as key regulators of diverse cellular processes. Determining the function of individual lincRNAs remains a challenge. Recent advances in RNA sequencing (RNA-seq) and computational methods allow for an unprecedented analysis of such transcripts. Here, we present an integrative approach to define a reference catalog of >8000 human lincRNAs. Our catalog unifies previously existing annotation sources with transcripts we assembled from RNA-seq data collected from ∼4 billion RNA-seq reads across 24 tissues and cell types. We characterize each lincRNA by a panorama of >30 properties, including sequence, structural, transcriptional, and orthology features. We found that lincRNA expression is strikingly tissue-specific compared with coding genes, and that lincRNAs are typically coexpressed with their neighboring genes, albeit to an extent similar to that of pairs of neighboring protein-coding genes. We distinguish an additional subset of transcripts that have high evolutionary conservation but may include short ORFs and may serve as either lincRNAs or small peptides. Our integrated, comprehensive, yet conservative reference catalog of human lincRNAs reveals the global properties of lincRNAs and will facilitate experimental studies and further functional classification of these genes.
Identification of Enzyme Activity Quantitative Trait Loci in aSolanum lycopersicum×Solanum pennelliiIntrogression Line Population
Authors: Steinhauser Marie-Caroline , Steinhauser Dirk , Gibon Yves , Bolger Marie , Arrivault Stéphanie , Usadel Björn , Zamir Dani , Fernie Alisdair R. , Stitt Mark
Published: September 2011

Activities of 28 enzymes from central carbon metabolism were measured in pericarp tissue of ripe tomato fruits from field trials with an introgression line (IL) population generated by introgressing segments of the genome of the wild relative Solanum pennellii (LA0716) into the modern tomato cultivar Solanum lycopersicum M82. Enzyme activities were determined using a robotized platform in optimized conditions, where the activities largely reflect the level of the corresponding proteins. Two experiments were analyzed from years with markedly different climate conditions. A total of 27 quantitative trait loci were shared in both experiments. Most resulted in increased enzyme activity when a portion of the S. lycopersicum genome was substituted with the corresponding portion of the genome of S. pennellii. This reflects the change in activity between the two parental genotypes. The mode of inheritance was studied in a heterozygote IL population. A similar proportion of quantitative trait loci (approximately 30%) showed additive, recessive, and dominant modes of inheritance, with only 5% showing overdominance. Comparison with the location of putative genes for the corresponding proteins indicates a large role of trans-regulatory mechanisms. These results point to the genetic control of individual enzyme activities being under the control of a complex program that is dominated by a network of trans-acting genes.
ArabidopsisTERMINAL FLOWER1 Is Involved in the Regulation of Flowering Time and Inflorescence Development through Transcriptional Repression
Authors: Hanano Shigeru , Goto Koji
Published: September 2011

TERMINAL FLOWER1 (TFL1) is a key regulator of flowering time and the development of the inflorescence meristem in Arabidopsis thaliana. TFL1 and FLOWERING LOCUS T (FT) have highly conserved amino acid sequences but opposite functions. For example, FT promotes flowering and TFL1 represses it; FT-overexpressing plants and TFL1 loss-of-function mutants have a similar phenotype production of terminal flowers in the shoot apex. FT is believed to function in a transcriptional activator complex by interacting with FD. Here, we demonstrate that TFL1 is involved in the transcriptional repression of genes that are activated by FT. We analyzed transgenic plants overexpressing TFL1 fused to a transcriptional repressor domain (TFL1-SRDX) or an activator domain (TFL1-VP16). Plants carrying 35S:TFL1-SRDX showed delayed flowering similar to 35S:TFL1 plants, and plants carrying 35S:TFL1-VP16 showed an early flowering phenotype and produced terminal flowers. Furthermore, the tfl1 and 35S:TFL1-VP16 plant phenotypes were strongly suppressed by the fd mutation, and TFL1 interacted with FD in the cell nucleus, as shown by bimolecular fluorescence complementation experiments. We conclude that TFL1 negatively modulates the FD-dependent transcription of target genes to fine-tune flowering time and the development of the inflorescence meristem.