bluuebunny/crossref_metadata_2025 huggingface dataset:
Extension of Simons’ inequality
Authors: Kivisoo Kersti , Oja Eve
Published: August 2005

We prove the following extended version of Simons’ inequality and present its applications. LetSSbe a set andTTbe a subset ofSS. LetCCbe a subset of a Hausdorff topological vector space which is invariant under infinite convex combinations. Letf:C×S⟶Rf: C\times S \longrightarrow \mathbb {R}be a bounded function such that the functionsf(⋅,t):C⟶Rf(\,\cdot \,,\,t):C\longrightarrow \mathbb {R}are convex for allt∈Tt \in Tandf(λx,s)=λf(x,s)f(\lambda x,\,s)=\lambda f(x,\,s)wheneverλ>0\lambda >0,x,λx∈Cx,\,\lambda x \in Cands∈S.s\in S.Let(xn)(x_n)be a sequence inCC. Assume that, for every<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="x element-of upper C 1 equals left-brace sigma-summation Underscript n equals 1 Overscript normal infinity Endscripts lamda Subscript n Baseline x Subscript n Baseline colon lamda Subscript n Baseline greater-than-or-equal-to 0 comma sigma-summation Underscript n equals 1 Overscript normal infinity Endscripts lamda Subscript n Baseline equals 1 right-brace">x∈C1={∑n=1∞λnxn:λn≥0,∑n=1∞λn=1}x \in C_1 =\left \{\sum _{n=1}^{\infty }\lambda _n\,x_n\,:\quad \lambda _n\geq 0,\,\sum _{n=1}^{\infty }\lambda _n=1\,\right \}, there existst∈Tt \in Tsatisfyingf(x,t)=sups∈Sf(x,s)f(x,\,t)=\sup _{s\in S} f(x,\,s). Then\[<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="inf Underscript x element-of upper C 1 Endscripts sup Underscript s element-of upper S Endscripts f left-parenthesis x comma s right-parenthesis less-than-or-equal-to sup Underscript t element-of upper T Endscripts limit sup Underscript n Endscripts f left-parenthesis x Subscript n Baseline comma t right-parenthesis period">infx∈C1sups∈Sf(x,s)≤supt∈Tlim supnf(xn,t).\inf _{x\in C_1}\sup _{s\in S}f(x,\,s) \leq \sup _{t\in T}\limsup _{n}f(x_n,\,t).\]If−C1⊂C-C_1\subset C, then the setC1C_1in the above inequality can be replaced byconv{x1,x2,…}\textrm {conv}\{x_1, x_2, \ldots \}.
Addendum to “Dense subsets of the boundary of a Coxeter system”
Authors: Hosaka Tetsuya
Published: August 2005

In this paper, we investigate boundaries of parabolic subgroups of Coxeter groups. Let

(
W
,
S
)

(W,S)

be a Coxeter system and let

T
T

be a subset of

S
S

such that the parabolic subgroup

W
T

W_T

is infinite. Then we show that if a certain set is quasi-dense in

W
W

, then

W
∂
Σ
(

W
T

,
T
)

W \partial \Sigma (W_T,T)

is dense in the boundary

∂
Σ
(
W
,
S
)

\partial \Sigma (W,S)

of the Coxeter system

(
W
,
S
)

(W,S)

, where

∂
Σ
(

W
T

,
T
)

\partial \Sigma (W_T,T)

is the boundary of

(

W
T

,
T
)

(W_T,T)

.
How Diffusion of Power in Parliaments Affects Voter Choice
Authors: Kedar Orit
Published: August 2005

I analyze how the diffusion of power in parliaments affects voter choice. Using a two-step research design, I first estimate an individual-level model of voter choice in 14 parliamentary democracies, allowing voters to hold preferences both for the party most similar to them ideologically and for the party that pulls policy in their direction. While in systems in which power is concentrated the two motivations converge, in consensual systems they diverge: since votes will likely be watered down by bargaining in the parliament, outcome-oriented choice in consensual systems often leads voters to endorse parties whose positions differ from their own views. In the second step, I utilize institutional measures of power diffusion in the parliament to account for the degree to which voters in different polities pursue one motivation versus the other. I demonstrate that the more power diffusion and compromise built into the political system via institutional mechanisms, the more voters compensate for the watering down of their vote by endorsing parties whose positions differ from their own views.
Against the current: an inter-oceanic whale migration event
Authors: Pomilla Cristina , Rosenbaum Howard C
Published: August 2005

Humpback whales seasonally migrate long distances between tropical and polar regions. However, inter-oceanic exchange is rare and difficult to document. Using skin biopsy samples collected in the Indian Ocean and in the South Atlantic Ocean, and a genetic capture–recapture approach based on microsatellite genotyping, we were able to reveal the first direct genetic evidence of the inter-oceanic migration of a male humpback whale. This exceptional migration to wintering grounds of two different ocean basins questions traditional notions of fidelity to an ocean basin, and demonstrates how the behaviour of highly mobile species may be elucidated from combining genetics with long-term field studies. Our finding has implications for management of humpback whale populations, as well as for hypotheses concerning cultural transmission of behaviour.
Ancient DNA reveals Holocene loss of genetic diversity in a South American rodent
Authors: Chan Yvonne L , Lacey Eileen A , Pearson Oliver P , Hadly Elizabeth A
Published: August 2005

Understanding how animal populations have evolved in response to palaeoenvironmental conditions is essential for predicting the impact of future environmental change on current biodiversity. Analyses of ancient DNA provide a unique opportunity to track population responses to prehistoric environments. We explored the effects of palaeoenvironmental change on the colonial tuco-tuco (
Ctenomys sociabilis
), a highly endemic species of Patagonian rodent that is currently listed as threatened by the IUCN. By combining surveys of modern genetic variation from throughout this species' current geographic range with analyses of DNA samples from fossil material dating back to 10 000 ybp, we demonstrate a striking decline in genetic diversity that is concordant with environmental events in the study region. Our results highlight the importance of non-anthropogenic factors in loss of diversity, including reductions in smaller mammals such as rodents.
Female preference for conspecific males based on olfactory cues in a Lake Malawi cichlid fish
Authors: Plenderleith Martin , Oosterhout Cock van , Robinson Rosanna L , Turner George F
Published: August 2005

Research on reproductive isolation in African cichlid fishes has largely focused on the role of nuptial colours, but other sensory modes may play an important role in mate choice. Here, we compare the relative importance of visual and olfactory cues in mate recognition by females of a Lake Malawi cichlid species. Female
Pseudotropheus emmiltos
were given a choice of spawning next to a conspecific male or a male of the closely-related sympatric
Pseudotropheus fainzilberi
. Significant preference for conspecific males only occurred when olfactory cues were present. This suggests that divergence of olfactory signals may have been an important influence on the explosive radiation of the East African species flock.
Non-random association of opsin alleles in wild groups of red-bellied tamarins (
Saguinus labiatus
) and maintenance of the colour vision polymorphism
Authors: Surridge Alison K , Suárez Sandra S , Buchanan-Smith Hannah M , Mundy Nicholas I
Published: August 2005

The remarkable X-linked colour vision polymorphism observed in many New World primates is thought to be maintained by balancing selection. Behavioural tests support a hypothesis of heterozygote advantage, as heterozygous females (with trichromatic vision) exhibit foraging benefits over homozygous females and males (with dichromatic vision) when detecting ripe fruit on a background of leaves. Whilst most studies to date have examined the functional relevance of polymorphic colour vision in the context of foraging behaviour, alternative hypotheses proposed to explain the polymorphism have remained unexplored. In this study we examine colour vision polymorphism, social group composition and breeding success in wild red-bellied tamarins
Saguinus labiatus
. We find that the association of males and females within tamarin social groups is non-random with respect to colour vision genotype, with identified mating partners having the greatest allelic diversity. The observed distribution of alleles may be driven by inbreeding avoidance and implies an important new mechanism for maintaining colour vision polymorphism. This study also provides the first preliminary evidence that wild trichromatic females may have increased fitness compared with dichromatic counterparts, as measured by breeding success and longevity.
Dynamic allostery of protein alpha helical coiled-coils
Authors: Hawkins Rhoda J , McLeish Tom C.B
Published: August 2005

Alpha helical coiled-coils appear in many important allosteric proteins such as the dynein molecular motor and bacteria chemotaxis transmembrane receptors. As a mechanism for transmitting the information of ligand binding to a distant site across an allosteric protein, an alternative to conformational change in the mean static structure is an induced change in the pattern of the internal dynamics of the protein. We explore how ligand binding may change the intramolecular vibrational free energy of a coiled-coil, using parameterized coarse-grained models, treating the case of dynein in detail. The models predict that coupling of slide, bend and twist modes of the coiled-coil transmits an allosteric free energy of ∼2
k
B
T
, consistent with experimental results. A further prediction is a quantitative increase in the effective stiffness of the coiled-coil without any change in inherent flexibility of the individual helices. The model provides a possible and experimentally testable mechanism for transmission of information through the alpha helical coiled-coil of dynein.
Modelling cell lifespan and proliferation: is likelihood to die or to divide independent of age?
Authors: Dowling Mark R , Milutinović Dejan , Hodgkin Philip D
Published: August 2005

In cell lifespan studies the exponential nature of cell survival curves is often interpreted as showing the rate of death is independent of the age of the cells within the population. Here we present an alternative model where cells that die are replaced and the age and lifespan of the population pool is monitored until a steady state is reached. In our model newly generated individual cells are given a determined lifespan drawn from a number of known distributions including the lognormal, which is frequently found in nature. For lognormal lifespans the analytic steady-state survival curve obtained can be well-fit by a single or double exponential, depending on the mean and standard deviation. Thus, experimental evidence for exponential lifespans of one and/or two populations cannot be taken as definitive evidence for time and age independence of cell survival. A related model for a dividing population in steady state is also developed. We propose that the common adoption of age-independent, constant rates of change in biological modelling may be responsible for significant errors, both of interpretation and of mathematical deduction. We suggest that additional mathematical and experimental methods must be used to resolve the relationship between time and behavioural changes by cells that are predominantly unsynchronized.
Mussel (
Mytilus edulis
) byssus deposition in response to variations in surface wettability
Authors: Aldred N , Ista L.K , Callow M.E , Callow J.A , Lopez G.P , Clare A.S
Published: August 2005

Mussels (
Mytilus edulis
) are economically important in their role as an aquaculture species and also with regard to marine biofouling. They attach tenaciously to a wide variety of submerged surfaces by virtue of collagenous attachment threads termed ‘byssi’. The aim of this study was to characterize the spreading of the byssal attachment plaque, which mediates attachment to the surface, on a range of surfaces in response to changes in wettability. To achieve this, well characterized self-assembled monolayers of ω-terminated alkanethiolates on gold were used, allowing correlation of byssal plaque spreading with a single surface characteristic—wettability. The present results were inconsistent with those from previous studies, in that there was a positive correlation between plaque size and surface wettability; a trend which is not explained by conventional wetting theory for a three-phase system. A recent extension to wetting theory with regard to hydrophilic proteins is discussed and the results of settlement assays are used to attempt reconciliation of these results with those of similar previous studies and, also, with recent data presented for the spreading of
Ulva linza
spore adhesive.
Wave packet pseudomodes of variable coefficient differential operators
Authors: Trefethen Lloyd N
Published: August 2005

The pseudospectra of non-selfadjoint linear ordinary differential operators with variable coefficients are considered. It is shown that when a certain winding number or twist condition is satisfied, closely related to Hörmander's commutator condition for partial differential equations,ϵ-pseudoeigenfunctions of such operators for exponentially small values ofϵexist in the form of localized wave packets. In contrast to related results of Davies and of Dencker, Sjöstrand & Zworski, the symbol need not be smooth. Applications in fluid mechanics, non-hermitian quantum mechanics and other areas are presented with the aid of high-accuracy numerical computations.
Eddy current coil interaction with a right-angled conductive wedge
Authors: Theodoulidis T.P , Bowler J.R
Published: August 2005

The time-harmonic electromagnetic field in an electrically conductive right-angled wedge due to an inductive excitation by circular coil in air has been calculated. Using a formulation in Cartesian coordinates, the problem domain is truncated in a dimension whose axis is normal to a wedge face, and an approximate series solution found using elementary functions satisfying Maxwell's equations in the quasi-static limit. The coil impedance variation with position and frequency is calculated and compared with measurements made on a coil near the edge of a large aluminium block which approximates the effect of a conductive quarter-space. The comparison between theory and experiment shows very close agreement.
Women's sexual interests across the ovulatory cycle depend on primary partner developmental instability
Authors: Gangestad Steven W , Thornhill Randy , Garver-Apgar Christine E
Published: August 2005

Normally ovulating women have been found to report greater sexual attraction to men other than their own partners when near ovulation relative to the luteal phase. One interpretation is that women possess adaptations to be attracted to men possessing (ancestral) markers of genetic fitness when near ovulation, which implies that women's interests should depend on qualities of her partner. In a sample of 54 couples, we found that women whose partners had high developmental instability (high fluctuating asymmetry) had greater attraction to men other than their partners, and less attraction to their own partners, when fertile.
Fading out of vole and predator cycles?
Authors: Hörnfeldt Birger , Hipkiss Tim , Eklund Ulf
Published: August 2005

Northern voles and lemmings are famous for their spectacular multiannual population cycles with high amplitudes. Such cyclic vole populations in Scandinavia have shown an unexpected and marked long-term decline in density since the early 1970s, particularly with a marked shift to lower spring densities in the early 1980s. The vole decline, mainly characterized by a strongly decreased rate of change in numbers over winter, is associated with an increased occurrence of mild and wet winters brought about by a recent change in the North Atlantic Oscillation. This has led to a decrease in winter stability and has shortened the period with protective snow cover, the latter considered as an important prerequisite for the occurrence of multiannual, high-amplitude cycles in vole populations. Although the vole decline is predicted to be negative for predators' reproduction and abundance, empirical data showing this are rare. Here we show that the dynamics of a predator–prey system (Tengmalm's owl,
Aegolius funereus
, and voles), have in recent years gradually changed from 3–4 yr, high-amplitude cycles towards more or less annual fluctuations only.
Second to fourth digit ratio and face shape
Authors: Fink Bernhard , Grammer Karl , Mitteroecker Philipp , Gunz Philipp , Schaefer Katrin , Bookstein Fred L , Manning John T
Published: August 2005

The average human male face differs from the average female face in size and shape of the jaws, cheek-bones, lips, eyes and nose. It is possible that this dimorphism is determined by sex steroids such as testosterone (T) and oestrogen (E), and several studies on the perception of such characteristics have been based on this assumption, but those studies focussed mainly on the relationship of male faces with circulating hormone levels; the corresponding biology of the female face remains mainly speculative. This paper is concerned with the relative importance of prenatal T and E levels (assessed via the 2D : 4D finger length ratio, a proxy for the ratio of T/E) and sex in the determination of facial form as characterized by 64 landmark points on facial photographs of 106 Austrians of college age. We found that (i) prenatal sex steroid ratios (in terms of 2D : 4D) and actual chromosomal sex dimorphism operate differently on faces, (ii) 2D : 4D affects male and female face shape by similar patterns, but (iii) is three times more intense in men than in women. There was no evidence that these effects were confounded by allometry or facial asymmetry. Our results suggest that studies on the perception of facial characteristics need to consider differential effects of prenatal hormone exposure and actual chromosomal gender in order to understand how characteristics have come to be rated ‘masculine’ or ‘feminine’ and the consequences of these perceptions in terms of mate preferences.
Aromatase is pre-synaptic and sexually dimorphic in the adult zebra finch brain
Authors: Peterson R. Scott , Yarram Lakshmi , Schlinger Barney A , Saldanha Colin J
Published: August 2005

Oestrogens organize and activate circuits within the vertebrate central nervous system. Oestrogen synthesis occurs via the expression of aromatase, a P
450
enzyme detected in microsomes and more recently in pre-synaptic boutons. Synaptic aromatase has only been described in brain regions that express aromatase in many subcellular compartments, so its function remains poorly understood. To more thoroughly study the role of oestrogen synthesis at synaptic terminals, we examined the ultrastructural compartmentalization of aromatase in the zebra finch; a species in which high aromatase activity can be measured in brain areas that do not contain somal aromatase. Here, we report the presence of aromatase in pre-synaptic boutons in the hippocampus and the high vocal centre brain areas with low and undetectable somal aromatase, respectively, in addition to areas with abundant somal aromatase such as the preoptic area and caudomedial nidopallium. At these brain areas, males had more total synapses, more aromatase pre-synaptic boutons and importantly, the proportion of total synaptic profiles that expressed aromatase was significantly higher in males relative to females. Aromatase-positive pre-synaptic boutons were always observed innervating aromatase-negative post-synaptic elements. We conclude that oestrogen may be provided to discrete oestrogen-sensitive targets by synaptic aromatization. Further, some targets may be exposed to more oestrogen in males. The expression of aromatase in individual synapses of projection neurons represents a unique mechanism of neuroendocrine action. Neurons with steroidogenic capability may modulate distant targets with the specificity of axonal innervation.
Parasites affect song complexity and neural development in a songbird
Authors: Spencer Karen A , Buchanan Katherine L , Leitner Stefan , Goldsmith Arthur R , Catchpole Clive K
Published: August 2005

There is now considerable evidence that female choice drives the evolution of song complexity in many songbird species. However, the underlying basis for such choice remains controversial. The developmental stress hypothesis suggests that early developmental conditions can mediate adult song complexity by perturbing investment in the underlying brain nuclei during their initial growth. Here, we show that adult male canaries (Serinus canaria), infected with malaria (Plasmodium relictum) as juveniles, develop simpler songs as adults compared to uninfected individuals, and exhibit reduced development of the high vocal centre (HVC) song nucleus in the brain. Our results show how developmental stress not only affects the expression of a sexually selected male trait, but also the structure of the underlying song control pathway in the brain, providing a direct link between brain and behaviour. This novel experimental evidence tests both proximate and ultimate reasons for the evolution of complex songs and supports the Hamilton–Zuk hypothesis of parasite-mediated sexual selection. Together, these results propose how developmental costs may help to explain the evolution of honest advertising in the complex songs of birds.
Trends in body size across an environmental gradient: A differential response in scavenging and non-scavenging demersal deep-sea fish
Authors: Collins M.A , Bailey D.M , Ruxton G.D , Priede I.G
Published: August 2005

Body size trends across environmental gradients are widely reported but poorly understood. Here, we investigate contrasting relationships between size (body mass) and depth in the scavenging and predatory demersal ichthyofauna (800–4800 m) of the North-east Atlantic. The mean size of scavenging fish, identified as those regularly attracted to baited cameras, increased significantly with depth, while in non-scavengers there was a significant decline in size. The increase in scavenger size is a consequence of both intra and inter-specific effects. The observation of opposing relationships, in different functional groups, across the same environmental gradient indicates ecological rather than physiological causes. Simple energetic models indicate that the dissimilarity can be explained by different patterns of food distribution. While food availability declines with depth for both groups, the food is likely to be in large, randomly distributed packages for scavengers and as smaller but more evenly distributed items for predators. Larger size in scavengers permits higher swimming speeds, greater endurance as a consequence of larger energy reserves and lower mass specific metabolic rate, factors that are critical to survival on sporadic food items.
Causes of exotic bird establishment across oceanic islands
Authors: Cassey Phillip , Blackburn Tim M , Duncan Richard P , Gaston Kevin J
Published: August 2005

The probability that exotic species will successfully establish viable populations varies between regions, for reasons that are currently unknown. Here, we use data for exotic bird introductions to 41 oceanic islands and archipelagos around the globe to test five hypotheses for this variation: the effects of introduction effort, competition, predation, human disturbance and habitat diversity (island biogeography). Our analyses demonstrate the primary importance of introduction effort for avian establishment success across regions, in concordance with previous analyses within regions. However, they also reveal a strong negative interaction across regions between establishment success and predation; exotic birds are more likely to fail on islands with species-rich mammalian predator assemblages.
The extent of protist diversity: insights from molecular ecology of freshwater eukaryotes
Authors: Šlapeta Jan , Moreira David , López-García Purificación
Published: August 2005

Classical studies on protist diversity of freshwater environments worldwide have led to the idea that most species of microbial eukaryotes are known. One exemplary case would be constituted by the ciliates, which have been claimed to encompass a few thousands of ubiquitous species, most of them already described. Recently, molecular methods have revealed an unsuspected protist diversity, especially in oceanic as well as some extreme environments, suggesting the occurrence of a hidden diversity of eukaryotic lineages. In order to test if this holds also for freshwater environments, we have carried out a molecular survey of small subunit ribosomal RNA genes in water and sediment samples of two ponds, one oxic and another suboxic, from the same geographic area. Our results show that protist diversity is very high. The majority of phylotypes affiliated within a few well established eukaryotic kingdoms or phyla, including alveolates, cryptophytes, heterokonts, Cercozoa, Centroheliozoa and haptophytes, although a few sequences did not display a clear taxonomic affiliation. The diversity of sequences within groups was very large, particularly that of ciliates, and a number of them were very divergent from known species, which could define new intra-phylum groups. This suggests that, contrary to current ideas, the diversity of freshwater protists is far from being completely described.
CD4+regulatory cells as a potential immunotherapy
Authors: Fehérvari Zoltán , Sakaguchi Shimon
Published: August 2005

CD4+regulatory T (TR) cells represent a unique lineage of thymically generated lymphocytes capable of powerfully suppressing immune responses. A large body of experimental data has now confirmed the key role played by these cells in the maintenance of self-tolerance. Increasingly, the importance of these cells is also being recognized in a host of other clinically relevant areas such as transplantation, tumour immunity, allergy and microbial immunity. Additionally, it is also possible to generate TRcells by using a variety ofex vivoexperimental approaches. We will focus here on harnessing the suppressive abilities of both these families of regulatory cells and how this should give us access to a potent cell-based immunotherapy appropriate for clinical application.
Axotrophin and leukaemia inhibitory factor (LIF) in transplantation tolerance
Authors: Metcalfe Su M
Published: August 2005

Immune self-tolerance is controlled by a subset of T lymphocytes that are regulatory (Treg) and epigenetically programmed to suppress auto-reactive immune effector cells
in vivo
. By extrapolation, donor-specific transplantation tolerance might be controlled by donor-specific Treg that have acquired the appropriate epigenetic program for tolerance. Although such tolerance has yet to be achieved in man, proof of concept comes from mouse models where regulatory transplantation tolerance can be induced within the complex micro-environment of the spleen or draining lymph node. By studying whole spleen cell populations in a murine model of transplantation tolerance we have incorporated a complexity of environmental factors when looking for specific features that characterize tolerance versus aggression. This approach has revealed unexpected patterns of gene activity in tolerance and most notably that a novel stem cell gene,
axotrophin
, regulates T lymphocyte responsiveness both in terms of proliferation and in release of leukaemia inhibitory factor (LIF). Since LIF is a regulator of stem cells in addition to being a key neuropoietic cytokine, these preliminary results linking both axotrophin and LIF to transplantation tolerance lead us to propose that regulatory pathways encoded during the epigenetic development of Treg cells are related to pathways that regulate fate determination of stem cells.
T cell tolerance induced by therapeutic antibodies
Authors: Cobbold Stephen P
Published: August 2005

Ever since the discovery of Medawar, over 50 years ago, that immunological tolerance was an acquired phenomenon that could be manipulated in neonatal mice, the ability to induce therapeutic tolerance against autoantigens, allergens and organ grafts has been a major driving force in immunology. Within the last 20 years we have found that a brief treatment with monoclonal antibodies that block certain functional molecules on the surface of the T cell is able to reprogramme the established immune repertoire of the adult mouse, allowing indefinite acceptance of allografts or effective curing of autoimmune diseases. We are only now just beginning to define many of the regulatory mechanisms that induce and maintain the tolerant state with the aim of being able to safely and reliably apply these technologies to human clinical situations.
Homeostatic T cell proliferation as a barrier to T cell tolerance
Authors: Hickman Somia P , Turka Laurence A
Published: August 2005

The maintenance of T cell numbers in the periphery is mediated by distinct homeostatic mechanisms that ensure the proper representation of naïve and memory T cells. Homeostatic proliferation refers to the process by which T cells in lymphopenic hosts divide in the absence of cognate antigen to reconstitute the peripheral lymphoid compartment. During this process T cells acquire effector-memory like properties, including the ability to respond to low doses of antigen in the absence of CD28 costimulation. Furthermore, this capacity is retained long after proliferation has ceased. Accumulating data implicates homeostatic proliferation in autoimmune diseases and transplant rejection, and suggests that it may represent a barrier to tolerance in protocols that use T cell depletion. Implementing combination therapies that aim to promote the development and expansion of regulatory T cell populations while specifically targeting alloresponsive T cells may be the soundest approach to attaining allograft tolerance in the aftermath of T cell depletion and homeostatic proliferation.
Glial grafting for demyelinating disease
Authors: Tepavčević V , Blakemore W.F
Published: August 2005

Remyelination of demyelinated central nervous system (CNS) axons is considered as a potential treatment for multiple sclerosis, and it has been achieved in experimental models of demyelination by transplantation of pro-myelinating cells. However, the experiments undertaken have not addressed the need for tissue-type matching in order to achieve graft-mediated remyelination since they were performed in conditions in which the chance for graft rejection was minimized. This article focuses on the factors determining survival of allogeneic oligodendrocyte lineage cells and their contribution to the remyelination of demyelinating CNS lesions. The immune status of the CNS as well as the suitability of different models of demyelination for graft rejection studies are discussed, and ways of enhancing allogeneic oligodendrocyte-mediated remyelination are presented. Finally, the effects of glial graft rejection on host remyelination are described, highlighting the potential benefits of the acute CNS inflammatory response for myelin repair.
Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD)
Authors: Blazar Bruce R , Murphy William J
Published: August 2005

Haematopoietic stem cell transplantation (HSCT) offers promise for the treatment of haematological and immune disorders, solid tumours, and as a tolerance inducing regimen for organ transplantation. Allogeneic HSCTs engraftment requires immunosuppression and the anti-tumour effects are dependent upon the immune effector cells that are contained within or generated from the donor graft. However, significant toxicities currently limit its efficacy. These problems include: (i) graft-versus-host disease (GVHD) in which donor T cells attack the recipient resulting in multi-organ attack and morbidity, (ii) a profound period of immune deficiency following HSCT, and (iii) donor graft rejection. Currently available methods to prevent or treat GVHD with systemic immunosuppression can lead to impaired immune recovery, increased opportunistic infections, and higher relapse rates. This review will provide an overview of GVHD pathophysiology and discuss the roles of various cells, pathways, and factors in the GVHD generation process and in the preservation of graft-versus-tumour effects. Variables that need to be taken into consideration in attempting to extrapolate preclinical results to the clinical paradigm will be highlighted.
CAMPATH: from concept to clinic
Authors: Waldmann Herman , Hale Geoff
Published: August 2005

Lymphocyte depletion has a long history in the area of therapeutic immunosuppression. CAMPATH-1H (alemtuzumab) was generated in an attempt to replace anti-lymphocyte globulins in the transplant arena. Its efficacy in killing lymphocytes has established it as a licensed drug for the management of chronic lymphocyte leukaemia. Short-term therapy with alemtuzumab has demonstrated long-term benefit in a number of autoimmune conditions. This drug has the potential to facilitate recruitment of tolerance processes so enabling drug minimization in transplantation, autoimmune and hypersensitivity diseases.
Induction of transplantation tolerance in non-human primate preclinical models
Authors: Hale Douglas A , Dhanireddy Kiran , Bruno David , Kirk Allan D
Published: August 2005

Short-term outcomes following organ transplantation have improved considerably since the availability of cyclosporine ushered in the modern era of immunosuppression. In spite of this, many of the current limitations to progress in the field are directly related to the existing practice of relatively non-specific immunosuppression. These include increased risks of opportunistic infection and cancer, and toxicity associated with long-term immunosuppressive drug exposure. In addition, long-term graft loss continues to result in part from a failure to adequately control the anti-donor immune response. The development of a safe and reliable means of inducing tolerance would ameliorate these issues and improve the lives of transplant recipients, yet given the improving clinical standard of care, the translation of new therapies has become appropriately more cautious and dependent on increasingly predictive preclinical models. While convenient and easy to use, rodent tolerance models have not to date been reliably capable of predicting a therapy's potential efficacy in humans. Non-human primates possess an immune system that more closely approximates that found in humans, and have served as a more rigorous preclinical testing ground for novel therapies. Prior to clinical adaptation therefore, tolerance regimens should be vetted in non-human primates to ensure that there is sufficient potential for efficacy to justify the risk of its application.
Lipid rafts and regulation of the cytoskeleton during T cell activation
Authors: Meiri Karina F
Published: August 2005

The ability of polarized cells to initiate and sustain directional responses to extracellular signals is critically dependent on direct communication between spatially organized signalling modules in the membrane and the underlying cytoskeleton. Pioneering work in T cells has shown that the assembly of signalling modules critically depends on the functional compartmentalization of membrane lipids into ordered microdomains or lipid rafts. The significance of rafts in T cell activation lies not only in their ability to recruit the signalling partners that eventually assemble into a mature immunological synapse but also in their ability to regulate actin dynamics and recruit cytoskeletal associated proteins, thereby achieving the structural polarization underlying stability of the synapse—a critical prerequisite for activation to be sustained. Lipid rafts vary quite considerably in size and visualizing the smallest of themin vivohas been challenging. Nonetheless it is now been shown quite convincingly that a surprisingly large proportion—in the order of 50%—of external membrane lipids (chiefly cholesterol and glycosphingolipids) can be dynamically localized in these liquid ordered rafts. Complementary inner leaflet rafts are less well characterized, but contain phosphoinositides as an important functional component that is crucial for regulating the behaviour of the actin cytoskeleton. This paper provides an overview of the interdependency between signalling and cytoskeletal polarization, and in particular considers how regulation of the cytoskeleton plays a crucial role in the consolidation of rafts and their stabilization into the immunological synapse.
Development of tolerogenic strategies in the clinic
Authors: Knechtle Stuart J
Published: August 2005

The study of tolerance in the clinic can be divided into three areas: (i) focused evaluation of existing tolerant transplant recipients as to their mechanism of tolerance; (ii) prospective tolerance trials, such as combined bone marrow and kidney transplantation as well as T cell depletion followed by subsequent weaning of immunosuppression; and (iii) immunologic assays to assess the likelihood of rejection or tolerance. Frankly, a very small number of patients have been transplanted with the intention of removing all immunosuppressive therapy, but several clinical trials with this aim are currently in progress, largely sponsored by the Immune Tolerance Network, a joint venture between the National Institutes of Health and the Juvenile Diabetes Research Foundation. Similarly, a reliable assay to assess tolerance has not yet been developed but a variety of approaches towards assessing rejection, and in some cases tolerance, are being developed. It would be accurate to state that many of the experimental and preclinical approaches to the induction of tolerance have resulted in better immunosuppression for human transplantation, but reliable tolerance strategies in humans have not yet been achieved. Combined bone marrow and kidney transplantation may be considered as one exception to this, but such a strategy is not generally applicable to the vast majority of solid organ transplant recipients. This review will summarize efforts to date, particularly focusing on kidney transplantation.
Regulation of T cell dependent immune responses by TIM family members
Authors: Mariat Christophe , Sánchez-Fueyo Alberto , Alexopoulos Sophoclis P , Kenny James , Strom Terry B , Zheng Xin Xiao
Published: August 2005

The T cell immunoglobulin mucin (TIM) proteins are type I membrane glycoproteins expressed on T cells and containing common structural motifs. While our understanding on the distribution and functions of TIM family members is still incomplete, data from several recent reports indicate that these proteins, together with T cell receptor and costimulatory signals, regulate the expansion and effector functions of T helper cells. In the current review, we provide evidences indicating that TIM-3 is capable of modulating the function of CD4+CD25+regulatory T cells and inhibiting aggressive Th1 mediated auto- and allo-immune responses. Similarly, additional data suggest that TIM-2 molecules function by negatively regulating Th2 immune responses. In contrast, TIM-1 appears to be an activation molecule for all T cells, although the mechanisms through which TIM-1 activates T cells remain to be elicited.
Cell transplantation for diabetes
Authors: Calne Roy
Published: August 2005

For 30 years there has been experimental work aimed at transplanting islets for the treatment of diabetes with a view to curing the disease and preventing the secondary complications. Many technical difficulties were experienced, first in isolating the islets without damaging them, and second in finding a suitable place to inject them, but until recently the results of a vascularized pancreas transplant have been superior to islet transplantation. In 2000, the group in Edmonton, headed by Shapiro, published encouraging results using a different immunosuppression in transplanting patients earlier in the course of their disease than had been attempted previously. The results were excellent at a year and good at 2 years in patients with Type I diabetes, however there was the rather worrying attrition at five years. Nevertheless, the Edmonton observations were proof of concept and have intensified interest in treating diabetes and other diseases where a specific protein synthesis was required by cell transplantation and/or genetic engineering. The recent interest in embryonic stem cells extenuated these efforts and progress is being made in defining the difficulties, which are greater than most workers would have predicted.

In this review, the subject is discussed explaining where progress needs to be made in order to provide treatment that would be of value to patients.
Quantitative Statistical Analysis of cis-Regulatory Sequences in ABA/VP1- and CBF/DREB1-Regulated Genes of Arabidopsis
Authors: Suzuki Masaharu , Ketterling Matthew G. , McCarty Donald R.
Published: August 2005

We have developed a simple quantitative computational approach for objective analysis of cis-regulatory sequences in promoters of coregulated genes. The program, designated MotifFinder, identifies oligo sequences that are overrepresented in promoters of coregulated genes. We used this approach to analyze promoter sequences of Viviparous1 (VP1)/abscisic acid (ABA)-regulated genes and cold-regulated genes, respectively, of Arabidopsis (Arabidopsis thaliana). We detected significantly enriched sequences in up-regulated genes but not in down-regulated genes. This result suggests that gene activation but not repression is mediated by specific and common sequence elements in promoters. The enriched motifs include several known cis-regulatory sequences as well as previously unidentified motifs. With respect to known cis-elements, we dissected the flanking nucleotides of the core sequences of Sph element, ABA response elements (ABREs), and the C repeat/dehydration-responsive element. This analysis identified the motif variants that may correlate with qualitative and quantitative differences in gene expression. While both VP1 and cold responses are mediated in part by ABA signaling via ABREs, these responses correlate with unique ABRE variants distinguished by nucleotides flanking the ACGT core. ABRE and Sph motifs are tightly associated uniquely in the coregulated set of genes showing a strict dependence on VP1 and ABA signaling. Finally, analysis of distribution of the enriched sequences revealed a striking concentration of enriched motifs in a proximal 200-base region of VP1/ABA and cold-regulated promoters. Overall, each class of coregulated genes possesses a discrete set of the enriched motifs with unique distributions in their promoters that may account for the specificity of gene regulation.
TANMEI/EMB2757 Encodes a WD Repeat Protein Required for Embryo Development in Arabidopsis
Authors: Yamagishi Kazutoshi , Nagata Noriko , Yee Kelly Matsudaira , Braybrook Siobhan A. , Pelletier Julie , Fujioka Shozo , Yoshida Shigeo , Fischer Robert L. , Goldberg Robert B. , Harada John J.
Published: August 2005

We identified the Arabidopsis (Arabidopsis thaliana) tanmei/emb2757 (tan) mutation that causes defects in both embryo and seedling development. tan mutant embryos share many characteristics with the leafy cotyledon (lec) class of mutants in that they accumulate anthocyanin, are intolerant of desiccation, form trichomes on cotyledons, and have reduced accumulation of storage proteins and lipids. Thus, TAN functions both in the early and late phases of embryo development. Moreover, the TAN and LEC genes interact synergistically, suggesting that they do not act in series in the same genetic pathway but, rather, that they have overlapping roles during embryogenesis. tan mutants die as embryos, but immature mutant seeds can be germinated in culture. However, tan mutant seedlings are defective in shoot and root development, their hypocotyls fail to elongate in the dark, and they die as seedlings. We isolated the TAN gene and showed that the predicted polypeptide has seven WD repeat motifs, suggesting that TAN forms complexes with other proteins. Together, these results suggest that TAN interacts with other proteins to control many aspects of embryo development.
CML24, Regulated in Expression by Diverse Stimuli, Encodes a Potential Ca2+ Sensor That Functions in Responses to Abscisic Acid, Daylength, and Ion Stress
Authors: Delk Nikkí A. , Johnson Keith A. , Chowdhury Naweed I. , Braam Janet
Published: August 2005

Changes in intracellular calcium (Ca2+) levels serve to signal responses to diverse stimuli. Ca2+ signals are likely perceived through proteins that bind Ca2+, undergo conformation changes following Ca2+ binding, and interact with target proteins. The 50-member calmodulin-like (CML) Arabidopsis (Arabidopsis thaliana) family encodes proteins containing the predicted Ca2+-binding EF-hand motif. The functions of virtually all these proteins are unknown. CML24, also known as TCH2, shares over 40% amino acid sequence identity with calmodulin, has four EF hands, and undergoes Ca2+-dependent changes in hydrophobic interaction chromatography and migration rate through denaturing gel electrophoresis, indicating that CML24 binds Ca2+ and, as a consequence, undergoes conformational changes. CML24 expression occurs in all major organs, and transcript levels are increased from 2- to 15-fold in plants subjected to touch, darkness, heat, cold, hydrogen peroxide, abscisic acid (ABA), and indole-3-acetic acid. However, CML24 protein accumulation changes were not detectable. The putative CML24 regulatory region confers reporter expression at sites of predicted mechanical stress; in regions undergoing growth; in vascular tissues and various floral organs; and in stomata, trichomes, and hydathodes. CML24-underexpressing transgenics are resistant to ABA inhibition of germination and seedling growth, are defective in long-day induction of flowering, and have enhanced tolerance to CoCl2, molybdic acid, ZnSO4, and MgCl2. MgCl2 tolerance is not due to reduced uptake or to elevated Ca2+ accumulation. Together, these data present evidence that CML24, a gene expressed in diverse organs and responsive to diverse stimuli, encodes a potential Ca2+ sensor that may function to enable responses to ABA, daylength, and presence of various salts.
Differential Elicitation of Two Processing Proteases Controls the Processing Pattern of the Trypsin Proteinase Inhibitor Precursor in Nicotiana attenuata
Authors: Horn Martin , Patankar Aparna G. , Zavala Jorge A. , Wu Jianqiang , Dolečková-Marešová Lucie , Vůjtěchová Milana , Mareš Michael , Baldwin Ian T.
Published: August 2005

Trypsin proteinase inhibitors (TPIs) of Nicotiana attenuata are major antiherbivore defenses that increase dramatically in leaves after attack or methyl jasmonate (MeJA) elicitation. To understand the elicitation process, we characterized the proteolytic fragmentation and release of TPIs from a multidomain precursor by proteases in MeJA-elicited and unelicited plants. A set of approximately 6-kD TPI peptides was purified from leaves, and their posttranslational modifications were characterized. In MeJA-elicited plants, the diversity of TPI structures was greater than the precursor gene predicted. This elicited structural heterogeneity resulted from differential fragmentation of the linker peptide (LP) that separates the seven-domain TPI functional domains. Using an in vitro fluorescence resonance energy transfer assay and synthetic substrates derived from the LP sequence, we characterized proteases involved in both the processing of the TPI precursor and its vacuolar targeting sequence. Although both a vacuolar processing enzyme and a subtilisin-like protease were found to participate in a two-step processing of LP, only the activity of the subtilisin-like protease was significantly increased by MeJA elicitation. We propose that MeJA elicitation increases TPI precursor production and saturates the proteolytic machinery, changing the processing pattern of TPIs. To test this hypothesis, we elicited a TPI-deficient N. attenuata genotype that had been transformed with a functional NaTPI gene under control of a constitutive promoter and characterized the resulting TPIs. We found no alterations in the processing pattern predicted from the sequence: a result consistent with the saturation hypothesis.