bluuebunny/crossref_metadata_2025 huggingface dataset:
Megakaryocytes derived from embryonic stem cells implicate CalDAG-GEFI in integrin signaling
Authors: Eto Koji , Murphy Ronan , Kerrigan Steve W. , Bertoni Alessandra , Stuhlmann Heidi , Nakano Toru , Leavitt Andrew D. , Shattil Sanford J.
Published: October 2002

Fibrinogen binding to integrin αIIbβ3 mediates platelet aggregation and requires agonist-induced “inside-out” signals that increase αIIbβ3 affinity. Agonist regulation of αIIbβ3 also takes place in megakaryocytes, the bone marrow cells from which platelets are derived. To facilitate mechanistic studies of inside-out signaling, we describe here the generation of megakaryocytes in quantity from murine embryonic stem (ES) cells. Coculture of ES cells for 8–12 days with OP9 stromal cells in the presence of thrombopoietin, IL-6, and IL-11 resulted in the development of large, polyploid megakaryocytes that produced proplatelets. These cells expressed αIIbβ3 and platelet glycoprotein Ibα but were devoid of hematopoietic stem cell, erythrocyte, and leukocyte markers. Mature megakaryocytes, but not megakaryocyte progenitors, specifically bound fibrinogen by way of αIIbβ3 in response to platelet agonists. Retrovirus-mediated expression of the reporter gene, green fluorescent protein, in ES cell-derived megakaryocytes did not affect viability or αIIbβ3 function. On the other hand, retroviral expression of CalDAG-GEFI, a Rap1 exchange factor identified by megakaryocyte gene profiling as a candidate integrin regulator, enhanced agonist-induced activation of Rap1b and fibrinogen binding to αIIbβ3 (
P
< 0.01). These results establish that ES cells are a ready source of mature megakaryocytes for integrin studies and other biological applications, and they implicate CalDAG-GEFI in inside-out signaling to αIIbβ3.
Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: Shifting the angiogenic balance
Authors: Ma Li , del Soldato Piero , Wallace John L.
Published: October 2002

Delayed gastric ulcer healing is a well recognized problem associated with the use of cyclooxygenase (COX) inhibitors. In contrast, NO-releasing COX inhibitors do not interfere with ulcer healing. These divergent effects may in part be due to differences in their effects on platelets, which are known to influence ulcer healing. Therefore, we compared the effects of a nonselective COX inhibitor (flurbiprofen), a nitric oxide-releasing COX inhibitor (HCT-1026), and a selective COX-2 inhibitor (celecoxib) on gastric ulcer healing, angiogenesis, and platelet/serum levels of vascular endothelial growth factor (VEGF) and endostatin. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily treatment with the test drugs was started 3 days later and continued for 1 week. Celecoxib and flurbiprofen impaired angiogenesis and delayed ulcer healing, as well as increasing serum endostatin levels relative to those of VEGF. HCT-1026 did not delay ulcer healing nor impair angiogenesis, and also did not change the ratio of serum endostatin to VEGF. Incubation of human umbilical vein endothelial cells with serum from celecoxib- or flurbiprofen-treated rats resulted in suppressed proliferation and increased apoptosis, effects that were reversed by an antiendostatin antibody. These results demonstrate a previously unrecognized mechanism through which nonsteroidal antiinflammatory drugs can delay ulcer healing, namely, through altering the balance of anti- and proangiogenic factors in the serum. The absence of a delaying effect of HCT-1026 on ulcer healing may be related to the maintenance of a more favorable balance in serum levels of pro- and antiangiogenic growth factors.
Regulation of transgene expression in plants with polydactyl zinc finger transcription factors
Authors: Ordiz M. Isabel , Barbas Carlos F. , Beachy Roger N.
Published: October 2002

Designer zinc finger transcription factors (TFs
ZF
) have been developed to control the expression of transgenes and endogenous genes in mammalian cells. Application of TFs
ZF
technology in plants would enable a wide range of both basic and applied studies. In this paper, we report the use of TFs
ZF
to target a defined 18-bp DNA sequence to control gene expression in plant cells and in transgenic plants. A β-glucuronidase reporter gene was activated by using the designed six-zinc finger protein 2C7 expressed as a fusion with the herpes simplex virus VP16 transcription factor activation domain. Reporter gene expression was activated 5- to 30-fold by using TFs
ZF
in BY-2 protoplasts, whereas expression was increased as much as 450 times in transgenic tobacco plants. Use of a phloem-specific promoter to drive expression of the TFs
ZF
resulted in activation of the reporter gene in vascular tissues. Transgenic tobacco plants that produce 2C7 transcription factors were phenotypically normal through two generations, suggesting that the factors exerted no adverse effects. This study demonstrates the utility of zinc finger technology in plants, setting the stage for its application in basic and applied agricultural biotechnology.
An IL-4-independent and CD25-mediated function of c-maf in promoting the production of Th2 cytokines
Authors: Hwang Eun Sook , White Ian Alexander , Ho I-Cheng
Published: October 2002

c-maf is a T helper (Th)2 cell-specific transcription factor, which promotes the differentiation of Th2 cells mainly by an IL-4-dependent mechanism. It remains unclear whether c-maf possesses any IL-4-independent function in regulating the production of Th2 cytokines. Here, we provide evidence demonstrating that c-maf, independent of IL-4, is essential for normal induction of CD25 in developing Th2 cells. The levels of CD25 are significantly higher in developing Th2 cells than in developing Th1 cells duringin vitrodifferentiation. In addition, timely blockade of IL-2 receptor signaling selectively inhibits the production of Th2 cytokines, but not IFN-γ or IL-2. Taken together, our results uncover an IL-4-independent and CD25-mediated function of c-maf in promoting the production of Th2 cytokines.
Crystallographic findings on the internally uncoupled and near-rigor states of myosin: Further insights into the mechanics of the motor
Authors: Himmel D. M. , Gourinath S. , Reshetnikova L. , Shen Y. , Szent-Györgyi A. G. , Cohen C.
Published: October 2002

Here we report a 2.3-Å crystal structure of scallop myosin S1 complexed with ADP⋅BeF
x
, as well as three additional structures (at 2.8–3.8 Å resolution) for this S1 complexed with ATP analogs, some of which are cross-linked by
para
-phenyl dimaleimide, a short intramolecular cross-linker. In all cases, the complexes are characterized by an unwound SH1 helix first seen in an unusual 2.5-Å scallop myosin-MgADP structure and described as corresponding to a previously unrecognized actin-detached internally uncoupled state. The unwinding of the SH1 helix effectively uncouples the converter/lever arm module from the motor and allows cross-linking by
para
-phenyl dimaleimide, which has been shown to occur only in weak actin-binding states of the molecule. Mutations near the metastable SH1 helix that disable the motor can be accounted for by viewing this structural element as a clutch controlling the transmission of torque to the lever arm. We have also determined a 3.2-Å nucleotide-free structure of scallop myosin S1, which suggests that in the near-rigor state there are two conformations in the switch I loop, depending on whether nucleotide is present. Analysis of the subdomain motions in the weak actin-binding states revealed by x-ray crystallography, together with recent electron microscopic results, clarify the mechanical roles of the parts of the motor in the course of the contractile cycle and suggest how strong binding to actin triggers both the power stroke and product release.
Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation
Authors: Seki Yoh-ichi , Hayashi Katsuhiko , Matsumoto Akira , Seki Noriyasu , Tsukada Jun , Ransom John , Naka Tetsuji , Kishimoto Tadamitsu , Yoshimura Akihiko , Kubo Masato
Published: October 2002

The development of helper T (Th) cell subsets, which secrete distinct cytokines, plays an important role in determining the type of immune response. The IL-4-mediated Janus kinase–signal transducer and activator of transcription signaling pathway is crucial for mediating Th2 cell development. Notably, this pathway is selectively impaired in Th1 cells, although the molecular basis of this impairment remains unclear. We show here that during Th1 differentiation a reduction in the association of Janus kinase 1 with the IL-4 receptor (IL-4R) correlated with the appearance of the suppressor of cytokine signaling-5 (SOCS5). SOCS5 protein was preferentially expressed in committed Th1 cells and interacted with the cytoplasmic region of the IL-4Rα chain irrespective of receptor tyrosine phosphorylation. This unconventional interaction of SOCS5 protein with the IL-4R resulted in the inhibition of IL-4-mediated signal transducer and activator of transcription-6 activation. T cells from transgenic mice constitutively expressing SOCS5 exhibited a significant reduction of IL-4-mediated Th2 development. Therefore, the induced SOCS5 protein in Th1 differentiation environment may play an important role by regulating Th1 and Th2 balance.
Structure of the inhibitory region of troponin by site directed spin labeling electron paramagnetic resonance
Authors: Brown Louise J. , Sale Ken L. , Hills Ron , Rouviere Clement , Song Likai , Zhang Xiaojun , Fajer Piotr G.
Published: October 2002

Site-directed spin labeling EPR (SDSL-EPR) was used to determine the structure of the inhibitory region of TnI in the intact cardiac troponin ternary complex. Maeda and collaborators have modeled the inhibitory region of TnI (
skeletal 96–112
: the structural motif that communicates the Ca
2+
signal to actin) as a kinked α-helix [Vassylyev, D., Takeda, S., Wakatsuki, S., Maeda, K. & Maeda, Y. (1998)
Proc. Natl. Acad. Sci. USA
95, 4847–4852), whereas Trewhella and collaborators have proposed the same region to be a flexible β-hairpin [Tung, C. S., Wall, M. E., Gallagher, S. C. & Trewhella, J. (2000)
Protein Sci.
9, 1312–1326]. To distinguish between the two models, residues 129–145 of cardiac TnI were mutated sequentially to cysteines and labeled with the extrinsic spin probe, MTSSL. Sequence-dependent solvent accessibility was measured as a change in power saturation of the spin probe in the presence of the relaxation agent. In the ternary complex, the 129–137 region followed a pattern characteristic of a regular 3.6 residues/turn α-helix. The following region, residues 138–145, showed no regular pattern in solvent accessibility. Measurements of 4 intradomain distances within the inhibitory sequence, using dipolar EPR, were consistent with an α-helical structure. The difference in side-chain mobility between the ternary (C⋅I⋅T) and binary (C⋅I) complexes revealed a region of interaction of TnT located at the N-terminal end of the inhibitory sequence, residues 130–135. The above findings for the troponin complex in solution do not support either of the computational models of the binary complex; however, they are in very good agreement with a preliminary report of the x-ray structure of the cardiac ternary complex [Takeda, S. Yamashita, A., Maeda, K. & Maeda, Y. (2002)
Biophys. J.
82, 832].
Mdm-2 and ubiquitin-independent p53 proteasomal degradation regulated by NQO1
Authors: Asher Gad , Lotem Joseph , Sachs Leo , Kahana Chaim , Shaul Yosef
Published: October 2002

The tumor suppressor p53 is a labile protein whose level is known to be regulated by the Mdm-2–ubiquitin–proteasome degradation pathway. We have found another pathway for p53 proteasomal degradation regulated by NAD(P)H quinone oxidoreductase 1 (NQO1). Inhibition of NQO1 activity by dicoumarol induces p53 and p73 proteasomal degradation. A mutant p53 (p53
[22,23]
), which is resistant to Mdm-2-mediated degradation, was susceptible to dicoumarol-induced degradation. This finding indicates that the NQO1-regulated proteasomal p53 degradation is Mdm-2-independent. The tumor suppressor p14
ARF
and the viral oncogenes SV40 LT and adenovirus E1A that are known to stabilize p53 inhibited dicoumarol-induced p53 degradation. Unlike Mdm-2-mediated degradation, the NQO1-regulated p53 degradation pathway was not associated with accumulation of ubiquitin-conjugated p53.
In vitro
studies indicate that dicoumarol-induced p53 degradation was ubiquitin-independent and ATP-dependent. Inhibition of NQO1 activity in cells with a temperature-sensitive E1 ubiquitin-activating enzyme induced p53 degradation and inhibited apoptosis at the restrictive temperature without ubiquitination. Mdm-2 failed to induce p53 degradation under these conditions. Our results establish a Mdm-2- and ubiquitin-independent mechanism for proteasomal degradation of p53 that is regulated by NQO1. The lack of NQO1 activity that stabilizes a tumor suppressor such as p53 can explain why humans carrying a polymorphic inactive NQO1 are more susceptible to tumor development.
Random polynomials having few or no real zeros
Authors: Dembo Amir , Poonen Bjorn , Shao Qi-Man , Zeitouni Ofer
Published: October 2002

Consider a polynomial of large degreennwhose coefficients are independent, identically distributed, nondegenerate random variables having zero mean and finite moments of all orders. We show that such a polynomial has exactlykkreal zeros with probabilityn−b+o(1)n^{-b+o(1)}asn→∞n \rightarrow \inftythrough integers of the same parity as the fixed integerk≥0k \ge 0. In particular, the probability that a random polynomial of large even degreennhas no real zeros isn−b+o(1)n^{-b+o(1)}. The finite, positive constantbbis characterized via the centered, stationary Gaussian process of correlation functionsech(t/2){\mathrm {sech}} (t/2). The value ofbbdepends neither onkknor upon the specific law of the coefficients. Under an extra smoothness assumption about the law of the coefficients, with probabilityn−b+o(1)n^{-b+o(1)}one may specify also the approximate locations of thekkzeros on the real line. The constantbbis replaced byb/2b/2in case the i.i.d. coefficients have a nonzero mean.
Derived Hilbert schemes
Authors: Ciocan-Fontanine Ionuţ , Kapranov Mikhail
Published: October 2002

We construct the derived version of the Hilbert scheme parametrizing subschemes in a given projective scheme

X
X

with given Hilbert polynomial

h
h

. This is a dg-manifold (smooth dg-scheme)

R
H
i
l

b
h

(
X
)

RHilb_h(X)

which carries a natural family of commutative (up to homotopy) dg-algebras, which over the usual Hilbert scheme is given by truncations of the homogeneous coordinate rings of subschemes in

X
X

. In particular,

R
H
i
l

b
h

(
X
)

RHilb_h(X)

differs from

R
Q
u
o

t
n

(

O

X

)

RQuot_n({\mathcal O_X})

, the derived Quot scheme constructed in our previous paper, which carries only a family of

A
∞

A_\infty

-modules over the coordinate algebra of

X
X

. As an application, we construct the derived version of the moduli stack of stable maps of algebraic curves to a given projective variety

Y
Y

, thus realizing the original suggestion of M. Kontsevich.
On a lattice problem of H. Steinhaus
Authors: Jackson Steve , Mauldin R.
Published: October 2002

It is shown that there is a subset

S
S

of

R

2

\mathbb {R}^2

such that each isometric copy of

Z

2

\mathbb {Z}^2

(the lattice points in the plane) meets

S
S

in exactly one point. This provides a positive answer to a problem of H. Steinhaus.
Biomechanics of the giant reedArundo donax
Authors: Spatz H.-Ch. , Beismann H. , Brüchert F. , Emanns A. , Speck Th.
Published: October 2002

The quantitative description of local buckling of hollow plant stems requires the knowledge of Young's modulus in the longitudinal and tangential directions for the different tissues of which the stem is composed. For thick–walled stems the shear modulus for the radial–tangential plane is needed for an advanced treatment of the process of ovalization. The primary causes of failure can be predicted if critical compressive strains in the longitudinal direction and critical tensile strains in the tangential direction are known. All of these mechanical properties and their variation along the length of the stem can be measured inArundo donax.
Dyar's Rule and the Investment Principle: optimal moulting strategies if feeding rate is size–dependent and growth is discontinuous
Authors: Hutchinson John M. C. , McNamara John M. , Houston Alasdair I. , Vollrath Fritz
Published: October 2002

We consider animals whose feeding rate depends on the size of structures that grow only by moulting (e.g. spiders' legs). Our Investment Principle predicts optimum size increases at each moult; under simplifying assumptions these are a function of the scaling of feeding rate with size, the efficiency of moulting and the optimum size increase at the preceding moult. We show how to test this quantitatively, and make the qualitative prediction that size increases and instar durations change monotonically through development. Thus, this version of the model does not predict that proportional size increases necessarily remain constant, which is the pattern described by Dyar's Rule. A literature survey shows that in nature size increases tend to decline and instar durations to increase, but exceptions to monotonicity occur frequently: we consider how relaxing certain assumptions of the model could explain this. Having specified various functions relating fitness to adult size and time of emergence, we calculate (using dynamic programming) the effect of manipulating food availability, time of hatching and size of the initial (or some intermediate) instar. The associated norms of reaction depend on the fitness function and differ from those when growth follows Dyar's Rule or is continuous. We go on to consider optimization of the number of instars. The Investment Principle then predicts upper and lower limits to observed size increases and explains why increases usually change little or decline through development. This is thus a new adaptive explanation for Dyar's Rule and for the most common deviation from the Rule.
A discrete cell model with adaptive signalling for aggregation ofDictyostelium discoideum
Authors: Dallon John C. , Othmer Hans G.
Published: October 2002

Dictyostelium discoideum(Dd) is a widely studied model system from which fundamental insights into cell movement, chemotaxis, aggregation and pattern formation can be gained. In this system aggregation results from the chemotactic response by dispersed amoebae to a travelling wave of the chemoattractant cAMP. We have developed a model in which the cells are treated as discrete points in a continuum field of the chemoattractant, and transduction of the extracellular cAMP signal into the intracellular signal is based on the G protein model developed by Tang and Othmer. The model reproduces a number of experimental observations and gives further insight into the aggregation process. We investigate different rules for cell movement, the factors that influence stream formation, the effect on aggregation of noise in the choice of the direction of movement, and when spiral waves of chemoattractant and cell density are likely to occur. Our results give new insight into the origin of spiral waves and suggest that streaming is due to a finite amplitude instability.
Optical investigations of physiology. A study of intrinsic and extrinsic biomedical contrast
Authors: Chance Britton , Luo Qingming , Nioka Shoko , Alsop David C. , Detre John A.
Published: October 2002

The utility and performance of optical studies of tissue depends upon the contrast and the changes of contrast in health and disease and in functional activity. The contrast is determined both by the optical properties of extrinsic and intrinsic chromophores and scatterers but especially upon the changes evoked by physiological activity and pathological states. Here, we have focused upon absorption changes of the intrinsic probe, blood absorbance changes due to cortical hypoxia and to haematomas, giving, for particular conditions, absorbance changes of 0.15 and over 0.4 (∠)OD, respectively. Functional activity may give changes of blood volume of over 0.05 (∠)OD with some variability due to individual responses that is best expressed as histogram displays of the distribution of response among a significant population. Responses have been observed in prefrontal parietal and occipital functions (242 tests). Extrinsic probes afford signals dependent upon the dose tolerance of the subject and can readily equal or exceed the blood volume and oxygenation signals, and currently afford vascular volume and flow indications. However, contrast agents for the functional activity of cellular function are ultimately to be expected. Finally, light–scattering changes afford osmolyte–related responses and are here shown to indicate a large signal attributed to cortical depolarization and K+release in hypoxia/ischaemia. Thus, the optical method affords imaging of manifold contrasts that greatly enhance its specificity and sensitivity for diagnostic procedures.
Measurements of scattering and absorption changes in muscle and brain
Authors: Gratton Enrico , Fantini Sergio , Franceschini Maria Angela , Gratton Gabriele , Fabiani Monica
Published: October 2002

Non–invasive techniques for the study of human brain function based on changes of the haemoglobin content or on changes of haemoglobin saturation have recently been proposed. Among the new methods , near–infrared transmission and reflection measurements may have significant advantages and complement well–established methods such as functional magnetic resonance imaging and positron emission tomography. Near–infrared measurements can be very fast, comparable in speed to electrophysiological measurements, but are better localized. We will present the demonstration of measurements of millisecond signals due to brain activity in humans following stimulation of the visual cortex. However, major unresolved questions remain about the origin of the signals observed. Optical measurements on exposed cortex in animals show that both the absorption and the scattering coefficient are affected by neural activity. Model calculations show that the signals we detected may originate from rapid changes of the scattering coefficient in a region about 1 to 2 cm below the scalp. We discuss our measurement protocol, which is based on a frequency–domain instrument, and the algorithm to separate the absorption from the scattering contribution in the overall optical response. Our method produces excellent separation between scattering and absorption in relatively homogeneous masses such as large muscles. The extrapolation of our measurement protocol to a complex structure such as the human head is critically evaluated.
Soil resources and their assessment
Authors: Webster R.
Published: October 2002

The assessment of the soil resource of any region has two parts, namely, an inventory of the kinds of soil and their distribution, and knowledge of the way each kind can be used and its performance under a range of circumstances. Soil varies substantially and intricately over short distances in most parts of the world. Inventory by field survey and air–photo interpretation must be done at a local scale. Inventories may be combined so that an individual nation state or region of similar size can know what kinds of soil it has, how much and where they are, how much each can produce, how to manage each in perpetuity, and the risks of degradation in use. Local classifications, with classes defined simply and identifiably on aerial photographs, will serve for mapping, and in combination with classical statistics can provide sound estimates from stratified sampling and agronomic experimentation.

Sound assessment should also be at this local scale initially. This should combine fundamental understanding of the soil's behaviour, strategic agronomic research on regional stations, and on–farm trials. The last are crucial for estimating productivity of the soil in practice.

Data from all sources can be stored, sorted and displayed by geographic information systems that now have abundant capacity. They should be indexed by soil class and other attributes, with clear distinction being made between assessments of productive potential and basic data. They should be publicly accessible, to ensure that data are readily available and never lost.

Estimates of the soil resource and its productivity for large regions, nation states, and the world can be compiled from local surveys by sampling through a ‘bottom–up’ procedure.
Managing soils for long-term productivity
Authors: Syers J. K.
Published: October 2002

Meeting the goal of long–term agricultural productivity requires that soil degradation be halted and reversed. Soil fertility decline is a key factor in soil degradation and is probably the major cause of declining crop yields. There is evidence that the contribution of declining soil fertility to soil degradation has been underestimated.

Sensitivity to soil degradation is implicit in the assessment of the sustainability of land management practices, with wide recognition of the fact that soils vary in their ability to resist change and recover subsequent to stress. The concept of resilience in relation to sustainability requires further elaboration and evaluation.

In the context of soil degradation, a decline in soil fertility is primarily interpreted as the depletion of organic matter and plant nutrients. Despite a higher turnover rate of organic matter in the tropics there is no intrinsic difference between the organic matter content of soils from tropical and temperate regions. The level of organic matter in a soil is closely related to the above and below ground inputs. In the absence of adequate organic material inputs and where cultivation is continuous, soil organic matter declines progressively. Maintaining the quantity and quality of soil organic matter should be a guiding principle in developing management practices

Soil microbial biomass serves as an important reservoir of nitrogen (N), phosphorus (P) and sulphur (S), and regulates the cycling of organic matter and nutrients. Because of its high turnover rate, microbial biomass reacts quickly to changes in management and is a sensitive indicator for monitoring and predicting changes in soil organic matter. Modelling techniques have been reasonably successful in predicting changes in soil organic matter with different organic material inputs, but there is little information from the tropics.

Nutrient depletion through harvested crop components and residue removal, and by leaching and soil erosion accentuates the often very low inherent fertility of many soils in the tropics. An integrated approach involving inorganic and organic inputs is required where animal and plant residues are returned, as far as practicable. Chemical fertilizers alone cannot achieve long–term productivity on many soils and organic material inputs are required to maintain soil organic matter levels and crop productivity. A major research effort is required to develop improved strategies for halting and reversing soil degradation if long–term productivity is to be secured.
Actuarial considerations on genetic testing
Authors: Grys D. J. Le
Published: October 2002

In the UK the majority of life insurers employ relatively liberal underwriting standards so that people can easily gain access to life assurance cover. Up to 95%of applicants are accepted at standard terms. If genetic testing becomes widespread then the buying habits of the public may change. Proportionately more people with a predisposition to major types of disease may take life assurance cover while people with no predisposition may take proportionately less. A model is used to show the possible effect. However, the time–scales are long and the mortality of assured people is steadily improving. The change in buying habits may result in the rate of improvement slowing down. In the whole population, the improvement in mortality is likely to continue and could improve faster if widespread genetic testing results in earlier diagnosis and treatment. Life insurers would not call for genetic tests and need not see the results of previous tests except for very large sums assured. In the UK, life insurers are unlikely to change their underwriting standards and are extremely unlikely to bring in basic premium rating systems that give discounts on the premium or penalty points according to peoples' genetic profile. The implications of widespread genetic testing on medical insurance and some health insurance covers may be more extreme.
Social and psychological issues associated with the new genetics
Authors: Macintyre Sally
Published: October 2002

This paper discusses two prevailing views— optimistic and pessimistic— about the potential benefits and risks arising from developments in human genetics, and argues that we do not yet have enough evidence to assess which elements (if any) of either view are likely to be correct.
Knowledge-based vision and simple visual machines
Authors: Cliff Dave , Jason Noble
Published: October 2002

The vast majority of work in machine vision emphasizes the representation of perceived objects and events: it is these internal representations that incorporate the ‘knowledge’ in knowledge–based vision or form the ‘modelsrsquo; in model–based vision. In this paper, we discuss simple machine vision systems developed by artificial evolution rather than traditional engineering design techniques, and note that the task of identifying internal representations within such systems is made difficult by the lack of an operational definition of representation at the causal mechanistic level. Consequently, we question the nature and indeed the existence of representations posited to be used within natural vision systems (i.e. animals). We conclude that representations argued for on apriorigrounds by external observers of a particular vision system may well be illusory, and are at best place–holders for yet–to–be–identified causal mechanistic interactions. That is, applying the knowledge–based vision approach in the understanding of evolved systems (machines or animals) may well lead to theories and models that are internally consistent, computationally plausible, and entirely wrong.
Movement, activity and action: the role of knowledge in the perception of motion
Authors: Bobick Aaron F.
Published: October 2002

This paper presents several approaches to the machine perception of motion and discusses the role and levels of knowledge in each. In particular, different techniques of motion understanding as focusing on one of movement, activity or action are described.
Movements
are the most atomic primitives, requiring no contextual or sequence knowledge to be recognized; movement is often addressed using either view–invariant or view–specific geometric techniques.
Activity
refers to sequences of movements or states, where the only real knowledge required is the statistics of the sequence; much of the recent work in gesture understanding falls within this category of motion perception. Finally,
actions
are larger–scale events, which typically include interaction with the environment and causal relationships; action understanding straddles the grey division between perception and cognition, computer vision and artificial intelligence. These levels are illustrated with examples drawn mostly from the group's work in understanding motion in video imagery. It is argued that the utility of such a division is that it makes explicit the representational competencies and manipulations necessary for perception.
Model-based interpretation of complex and variable images
Authors: Taylor C. J. , Cootes T. F. , Lanitis A. , Edwards G. , Smyth P. , Kotcheff A. C. W.
Published: October 2002

The ultimate goal of machine vision is image understanding—the ability not only to recover image structure but also to know what it represents. By definition, this involves the use of models which describe and label the expected structure of the world. Over the past decade, model–based vision has been applied successfully to images of man–made objects. It has proved much more difficult to develop model–based approaches to the interpretation of images of complex and variable structures such as faces or the internal organs of the human body (as visualized in medical images). In such cases it has been problematic even to recover image structure reliably, without a model to organize the often noisy and incomplete image evidence. The key problem is that of variability. To be useful, a model needs to be specific—that is, to be capable of representing only ‘legal’ examples of the modelled object(s). It has proved difficult to achieve this whilst allowing for natural variability. Recent developments have overcome this problem; it has been shown that specific patterns of variability in shape and grey–level appearance can be captured by statistical models that can be used directly in image interpretation. The details of the approach are outlined and practical examples from medical image interpretation and face recognition are used to illustrate how previously intractable problems can now be tackled successfully. It is also interesting to ask whether these results provide any possible insights into natural vision; for example, we show that the apparent changes in shape which result from viewing three–dimensional objects from different viewpoints can be modelled quite well in two dimensions; this may lend some support to the ‘characteristic views’ model of natural vision.
Top-down processes in object identification: evidence from experimental psychology, neuropsychology and functional anatomy
Authors: Humphreys Glyn W. , Riddoch M. Jane , Price Cathy J.
Published: October 2002

Many models of object identification are bottom–up and serial in nature; processing at a first stage needs to be complete before it is passed on to a subsequent stage, and there is no top–down feedback from the later to the earlier stages. However, data on picture identification in normal observers contradict a strict serial account of processing, since effects of variables on early and late stages of object identification combine in an interactive rather than an additive manner. Recent neuropsychological and functional anatomical data also indicate that object identification involves top–down activation of earlier stages of visual processing. In neuropsychological patients, subtle perceptual deficits can produce naming problems, even when there is good access to associated semantic knowledge; in functional activation studies, there is increased activity in visual processing areas when conditions require object naming relative to object recognition. These studies provide evidence that increased visual processing occurs in identification tasks, suggesting that there is re–current feedback during the identification process.
The surface glycoconjugates of trypanosomatid parasites
Authors: Ferguson Michael A. J.
Published: October 2002

Insect–transmitted protozoan parasites of the order Kinetoplastida, suborder Trypanosomatina, includeTrypanosoma brucei(aetiological agent of African sleeping sickness),Trypanosoma cruzi(aetiological agent of Chagas’ disease in South and Central America) andLeishmaniaspp. (aetiological agents of a variety of diseases throughout the tropics and sub–tropics). The structures of the most abundant cell–surface molecules of these organisms are reviewed and correlated with the different modes of parasitism of the three groups of parasites. The major surface molecules are all glycosylphosphatidylinositol (GPI)–anchored glycoproteins, such as the variant surface glycoproteins ofT. bruceiand the surface mucins ofT. cruzi, or complex glycophospholipids, such as the lipophosphoglycans and glycoinositolphospholipids of the leishmanias. Significantly, all of the aforementioned structures share a motif of Manα1–4GlcNα1–6–myo–inositol–1–HPO4–lipid and can therefore be considered to be members of a GPI superfamily.
Genetic and biochemical analysis of development in
Toxoplasma gondii
Authors: Boothroyd John C. , Black Michael , Bonnefoy Serge , Hehl Adrian , Knoll Laura J. , Manger Ian D. , Ortega–Barria Eduardo , Tomavo Stanislas
Published: October 2002

Toxoplasma gondii
has recently come under intense study as a model for intracellular parasitism because it has a number of properties that facilitate experimental manipulation. Attention is now being turned towards understanding the developmental biology of this complex parasite. The differentiation between the two asexual stages, the rapidly growing tachyzoites and the more slowly dividing, encysted bradyzoites, is of particular interest. Progression from the former to the latter is influenced by the host's immune response. This paper describes current progress on a number of research fronts, all aimed at understanding the triggers that push the tachyzoite–bradyzoite equilibrium in one or other direction and the changes that occur in gene expression (and ultimately metabolism and function). Chief among the techniques used for these studies are genetics and molecular genetics. Recent progress in these areas is described.
Hierarchical organization of cognitive memory
Authors: Mishkin Mortimer , Suzuki Wendy A. , Gadian David G. , Vargha–Khadem Faraneh
Published: October 2002

This paper addresses the question of the organization of memory processes within the medial temporal lobe. Evidence obtained in patients with late–onset amnesia resulting from medial temporal pathology has given rise to two opposing interpretations of the effects of such damage on long–term cognitive memory. One view is that cognitive memory, including memory for both facts and events, is served in a unitary manner by the hippocampus and its surrounding cortices; the other is that the basic function affected in amnesia is event memory, the memory for factual material often showing substantial preservation. Recent findings in patients with amnesia resulting from relatively selective hippocampal damage sustained early in life suggest a possible reconciliation of the two views. The new findings suggest that the hippocampus may be especially important for event as opposed to fact memory, with the surrounding cortical areas contributing to both. Evidence from neuroanatomical and neurobehavioural studies in monkeys is presented in support of this proposal.
Structure and function of the Nautilus statocyst
Authors: Neumeister H. , Budelmann B. U.
Published: October 2002

The two equilibrium receptor organs (statocysts) ofNautilusare ovoid sacks, half-filled with numerous small, free-moving statoconia and half with endolymph. The inner surface of each statocyst is lined with 130 000 to 150 000 primary sensory hair cells. The hair cells are of two morphological types. Type A hair cells carry 10 to 15 kinocilia arranged in a single ciliary row; they are present in the ventral half of the statocyst. TypeBhair cells carry 8 to 10 irregularly arranged kinocilia; they are present in the dorsal half of the statocyst. Both type of hair cells are morphologically polarized. To test whether these features allow theNautilusstatocyst to sense angular accelerations, behavioural experiments were performed to measure statocyst-dependent funnel movements during sinusoidal oscillations of restrainedNautilusaround a vertical body axis. Such dynamic rotatory stimulation caused horizontal phase-locked movements of the funnel. The funnel movements were either in the same direction (compensatory funnel response), or in the opposite direction (funnel follow response) to that of the applied rotation. Compensatory funnel movements were also seen during optokinetic stimulation (with a black and white stripe pattern) and during stimulations in which optokinetic and statocyst stimulations were combined.

These morphological and behavioural findings show that the statocysts ofNautilus, in addition to their function as gravity receptor organs, are able to detect rotatory movements (angular accelerations) without the specialized receptor systems (crista/cupula systems) that are found in the statocysts of coleoid cephalopods. The findings further indicate that both statocyst and visual inputs control compensatory funnel movements.
Evolution of mixed maturation strategies in semelparous life histories: the crucial role of dimensionality of feedback environment
Authors: Heino Mikko , Metz J. A. J. , Kaitala Veijo
Published: October 2002

We study the evolution of age at maturity in a semelparous life history with two age classes. An individual may either breed in the first year of its life and die, or delay breeding to the second year. In this setting a mixed strategy means that a fraction of the individual's offspring breed in the first possible breeding event, while the remaining fraction delay breeding. Current theory seems to imply that mixed strategies are not evolutionarily stable strategies (ESSs) under a steady-state population dynamical regime. We show that a two-dimensional feedback environment may allow the evolution of mixed age at maturity. Furthermore, different phenotypes need to perceive the environment differently. The biological reasoning behind these conditions is different resource usage or predation pressure between two age classes. Thus, the conventional explanations for the occurrence of mixed strategies in natural populations, environmental stochasticity or complex dynamics, are not needed.
Genetics and the pathobiology of ageing
Authors: Martin George M.
Published: October 2002

Genetics offers a powerful approach to the elucidation of mechanisms underlying specific components of the senescent phenotype of our species. Perhaps thousands of gene variations have escaped the force of natural selection and thus play roles in the genesis of different patterns of ageing in man. It is possible that a subset of these genes may be of particular importance in how most people age. While variations at the Werner helicase locus could be one such example, several lines of evidence suggest that mutation at that locus leads to a ‘private’ mechanism of ageing. It will be important, however, to investigate polymorphisms underlying the regulation of expression of this gene in the general population. Polymorphisms (normally occurring variants of a gene, or sequence of DNA), rather than mutations, may also prove to be more relevant to our understanding of the differing susceptibilities of people to common disorders such as late onset Alzheimer's disease. Polymorphic forms of the Apolipoprotein E gene is a good example. It remains to be seen if the pathogenetic framework (beta amyloidosis) derived from studies of the several rare mutations responsible for early onset familial forms of the disease proves relevant to the pathogenesis of the vastly more prevalent sporadic forms of the disorder. In contrast to the satisfying progress on the genetics of the diseases of ageing, research on the genetic basis for unusually robust retention of structure and function in old age has been neglected and requires a higher priority for the future. Such research should include studies of environmental agents and should address mechanisms of ‘sageing’, a stage in the life course characterized by an extensive utilization of behavioural and physiological adaptations to compensate for functional declines. For the genetics of longevity, we have to turn to genetically tractable organisms such as nematodes and fruit flies. Such studies have provided significant support for the oxidative stress theory of ageing. It will be important to learn more about the age–related pathologies and pathophysiologies of these organisms.
Understanding ageing
Authors: Holliday Robin
Published: October 2002

A broad biological approach makes it possible to understand why ageing exists and also why different mammalian species have very different maximum logevities. The adult organism is maintained in a functional state by at least ten major mechanisms, which together comprise a substantial proportion of all biological processes. These maintenance mechanisms eventually fail, because the evolved physiological and anatomical design of higher animals is incompatible with continual survival. The lifespan of each mammalian species depends on the efficiency of maintenance of their cells, tissues and organisms, and there is much evidence that such maintenance is more effective in long–lived species, such as man, than in short–lived small mammals. It is also evident that there is an inverse relationship between reproductive potential and longevity, which would be expected if total metabolic resources are shared between investment in reproduction, and investment in the preservation of the adult body. It is proposed that the eventual failure of maintenance leads to the pathological changes seen in age–associated disease. Although we now have a biological understanding of the ageing process, much future research will be needed to uncover the cellular and molecular changes which give rise to age–associated diseases. The major aim of such research is to devise procedures to delay or prevent the onset of these diseases.
The environment of ageing
Authors: Tinker Anthea
Published: October 2002

The issue of housing and the wider environment for an ageing population is one where there are many unanswered questions. In this paper a number of key issues are discussed and for each of these the focus is on three aspects. These are the current situation, its reasonableness and what research is needed in order to make decisions about policy and practice.

The first three issues relate to the profile of older people themselves and the importance of home to them. The changing profile of older people is not just about an ageing population but also about the growing prominence of those with dementia, women, people from black and ethnic minority groups and one person households, yet little is known about the type of housing which should be provided. Of equal concern is the widening gap between those with a high standard of living (including housing) and those with a low standard of living. The importance of home to older people means that research must focus on how people can be enabled to remain there, and also on the costs, financial and otherwise, to carers and to society.

The next three issues relate to the type of housing older people live in and moves in later life. The startling change in the tenure pattern with a growth of owner occupation brings problems as does the decline in social housing. The advantages and disadvantages of the different types of housing, mainstream and specialized—for older people are relatively well known. However the balance between the two needs more research as does that on retirement communities. While it is well known that there are peaks of migration in old age and that moves are often made in haste, little is known about the process of decision making.

The final two topics concern links between housing and other aspects of older people's lives. On health more research is needed on temperature, mortality and morbidity, homelessness and accidents and especially on links between services.

These topics have implications for planning and design. The emphasis should be on a multidisciplinary approach using a variety of quantitative and qualitative techniques with an emphasis on dissemination.