Showing papers by "University College London published in 2000"

Nonlinear dimensionality reduction by locally linear embedding.

Abstract: Many areas of science depend on exploratory data analysis and visualization. The need to analyze large amounts of multivariate data raises the fundamental problem of dimensionality reduction: how to discover compact representations of high-dimensional data. Here, we introduce locally linear embedding (LLE), an unsupervised learning algorithm that computes low-dimensional, neighborhood-preserving embeddings of high-dimensional inputs. Unlike clustering methods for local dimensionality reduction, LLE maps its inputs into a single global coordinate system of lower dimensionality, and its optimizations do not involve local minima. By exploiting the local symmetries of linear reconstructions, LLE is able to learn the global structure of nonlinear manifolds, such as those generated by images of faces or documents of text.

An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells

Abstract: In a diverse group of organisms that includes Caenorhabditis elegans, Drosophila, planaria, hydra, trypanosomes, fungi and plants, the introduction of double-stranded RNAs inhibits gene expression in a sequence-specific manner. These responses, called RNA interference or post-transcriptional gene silencing, may provide anti-viral defence, modulate transposition or regulate gene expression. We have taken a biochemical approach towards elucidating the mechanisms underlying this genetic phenomenon. Here we show that 'loss-of-function' phenotypes can be created in cultured Drosophila cells by transfection with specific double-stranded RNAs. This coincides with a marked reduction in the level of cognate cellular messenger RNAs. Extracts of transfected cells contain a nuclease activity that specifically degrades exogenous transcripts homologous to transfected double-stranded RNA. This enzyme contains an essential RNA component. After partial purification, the sequence-specific nuclease co-fractionates with a discrete, approximately 25-nucleotide RNA species which may confer specificity to the enzyme through homology to the substrate mRNAs.

Navigation-related structural change in the hippocampi of taxi drivers

Abstract: Structural MRIs of the brains of humans with extensive navigation experience, licensed London taxi drivers, were analyzed and compared with those of control subjects who did not drive taxis. The posterior hippocampi of taxi drivers were significantly larger relative to those of control subjects. A more anterior hippocampal region was larger in control subjects than in taxi drivers. Hippocampal volume correlated with the amount of time spent as a taxi driver (positively in the posterior and negatively in the anterior hippocampus). These data are in accordance with the idea that the posterior hippocampus stores a spatial representation of the environment and can expand regionally to accommodate elaboration of this representation in people with a high dependence on navigational skills. It seems that there is a capacity for local plastic change in the structure of the healthy adult human brain in response to environmental demands.

Codon-Substitution Models for Heterogeneous Selection Pressure at Amino Acid Sites

Abstract: Comparison of relative fixation rates of synonymous (silent) and nonsynonymous (amino acid-altering) mutations provides a means for understanding the mechanisms of molecular sequence evolution. The nonsynonymous/synonymous rate ratio (omega = d(N)d(S)) is an important indicator of selective pressure at the protein level, with omega = 1 meaning neutral mutations, omega 1 diversifying positive selection. Amino acid sites in a protein are expected to be under different selective pressures and have different underlying omega ratios. We develop models that account for heterogeneous omega ratios among amino acid sites and apply them to phylogenetic analyses of protein-coding DNA sequences. These models are useful for testing for adaptive molecular evolution and identifying amino acid sites under diversifying selection. Ten data sets of genes from nuclear, mitochondrial, and viral genomes are analyzed to estimate the distributions of omega among sites. In all data sets analyzed, the selective pressure indicated by the omega ratio is found to be highly heterogeneous among sites. Previously unsuspected Darwinian selection is detected in several genes in which the average omega ratio across sites is 1. Genes undergoing positive selection include the beta-globin gene from vertebrates, mitochondrial protein-coding genes from hominoids, the hemagglutinin (HA) gene from human influenza virus A, and HIV-1 env, vif, and pol genes. Tests for the presence of positively selected sites and their subsequent identification appear quite robust to the specific distributional form assumed for omega and can be achieved using any of several models we implement. However, we encountered difficulties in estimating the precise distribution of omega among sites from real data sets.

Rho GTPases and their effector proteins.

Abstract: Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell-cycle progression and cell adhesion. About 30 potential effector proteins have been identified that interact with members of the Rho family, but it is still unclear which of these are responsible for the diverse biological effects of Rho GTPases. This review will discuss how Rho GTPases physically interact with, and regulate the activity of, multiple effector proteins and how specific effector proteins contribute to cellular responses. To date most progress has been made in the cytoskeleton field, and several biochemical links have now been established between GTPases and the assembly of filamentous actin. The main focus of this review will be Rho, Rac and Cdc42, the three best characterized mammalian Rho GTPases, though the genetic analysis of Rho GTPases in lower eukaryotes is making increasingly important contributions to this field.

Computational principles of movement neuroscience

Abstract: Unifying principles of movement have emerged from the computational study of motor control. We review several of these principles and show how they apply to processes such as motor planning, control, estimation, prediction and learning. Our goal is to demonstrate how specific models emerging from the computational approach provide a theoretical framework for movement neuroscience.

Statistical methods for detecting molecular adaptation.

Abstract: The past few years have seen the development of powerful statistical methods for detecting adaptive molecular evolution. These methods compare synonymous and nonsynonymous substitution rates in protein-coding genes, and regard a nonsynonymous rate elevated above the synonymous rate as evidence for darwinian selection. Numerous cases of molecular adaptation are being identified in various systems from viruses to humans. Although previous analyses averaging rates over sites and time have little power, recent methods designed to detect positive selection at individual sites and lineages have been successful. Here, we summarize recent statistical methods for detecting molecular adaptation, and discuss their limitations and possible improvements.

Estimating Synonymous and Nonsynonymous Substitution Rates Under Realistic Evolutionary Models

Abstract: Approximate methods for estimating the numbers of synonymous and nonsynonymous substitutions between two DNA sequences involve three steps: counting of synonymous and nonsynonymous sites in the two sequences, counting of synonymous and nonsynonymous differences between the two sequences, and correcting for multiple substitutions at the same site. We examine complexities involved in those steps and propose a new approximate method that takes into account two major features of DNA sequence evolution: transition/transversion rate bias and base/codon frequency bias. We compare the new method with maximum likelihood, as well as several other approximate methods, by examining infinitely long sequences, performing computer simulations, and analyzing a real data set. The results suggest that when there are transition/transversion rate biases and base/codon frequency biases, previously described approximate methods for estimating the nonsynonymous/synonymous rate ratio may involve serious biases, and the bias can be both positive and negative. The new method is, in general, superior to earlier approximate methods and may be useful for analyzing large data sets, although maximum likelihood appears to always be the method of choice.

The immune system. First of two parts.

Abstract: The immune system is an organization of cells and molecules with specialized roles in defending against infection. There are two fundamentally different types of responses to invading microbes. Innate (natural) responses occur to the same extent however many times the infectious agent is encountered, whereas acquired (adaptive) responses improve on repeated exposure to a given infection. The innate responses use phagocytic cells (neutrophils, monocytes, and macrophages), cells that release inflammatory mediators (basophils, mast cells, and eosinophils), and natural killer cells. The molecular components of innate responses include complement, acute-phase proteins, and cytokines such as the interferons.

Supporting trust in virtual communities

Abstract: At any given time, the stability of a community depends on the right balance of trust and distrust. Furthermore, we face information overload, increased uncertainty and risk taking as a prominent feature of modern living. As members of society, we cope with these complexities and uncertainties by relying trust, which is the basis of all social interactions. Although a small number of trust models have been proposed for the virtual medium, we find that they are largely impractical and artificial. In this paper we provide and discuss a trust model that is grounded in real-world social trust characteristics, and based on a reputation mechanism, or word-of-mouth. Our proposed model allows agents to decide which other agents' opinions they trust more and allows agents to progressively tune their understanding of another agent's subjective recommendations.

Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23

Abstract: Proper serum phosphate concentrations are maintained by a complex and poorly understood process. Identification of genes responsible for inherited disorders involving disturbances in phosphate homeostasis may provide insight into the pathways that regulate phosphate balance. Several hereditary disorders of isolated phosphate wasting have been described, including X-linked hypophosphataemic rickets1 (XLH), hypophosphataemic bone disease2 (HBD), hereditary hypophosphataemic rickets with hypercalciuria3 (HHRH) and autosomal dominant hypophosphataemic rickets4,5 (ADHR). Inactivating mutations of the gene PHEX, encoding a member of the neutral endopeptidase family of proteins, are responsible for XLH (refs 6,7). ADHR (MIM 193100) is characterized by low serum phosphorus concentrations, rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses4,5. Here we describe a positional cloning approach used to identify the ADHR gene which included the annotation of 37 genes within 4 Mb of genomic sequence. We identified missense mutations in a gene encoding a new member of the fibroblast growth factor (FGF) family, FGF23. These mutations in patients with ADHR represent the first mutations found in a human FGF gene.

Capital-skill complementarity and inequality: A macroeconomic analysis

Abstract: The supply and price of skilled labor relative to unskilled labor have changed dramatically over the postwar period. The relative quantity of skilled labor has increased substantially, and the skill premium, which is the wage of skilled labor relative to that of unskilled labor, has grown significantly since 1980. Many studies have found that accounting for the increase in the skill premium on the basis of observable variables is difficult and have concluded implicitly that latent skill-biased technological change must be the main factor responsible. This paper examines that view systematically. We develop a framework that provides a simple, explicit economic mechanism for understanding skill-biased technological change in terms of observable variables, and we use the framework to evaluate the fraction of variation in the skill premium that can be accounted for by changes in observed factor quantities. We find that with capital-skill complementarity, changes in observed inputs alone can account for most of the variations in the skill premium over the last 30 years.

Mapping the Two Faces of R&D: Productivity Growth in a Panel of OECD Industries

Abstract: Many writers have claimed that research and development (R&D) has two faces. In addition to the conventional role of stimulating innovation, R&D enhances technology transfer (absorptive capacity). We explore this idea empirically using a panel of industries across twelve OECD countries. We find R&D to be statistically and economically important in both technological catch-up and innovation. Human capital also plays an major role in productivity growth, but we only find a small effect of trade. In failing to take account of R&D-based absorptive capacity, existing U.S.-based studies may underestimate the return to R&D.

OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.

Abstract: Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin-related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.

Superconductivity on the border of itinerant-electron ferromagnetism in UGe2

Abstract: The absence of simple examples of superconductivity adjoining itinerant-electron ferromagnetism in the phase diagram has for many years cast doubt on the validity of conventional models of magnetically mediated superconductivity. On closer examination, however, very few systems have been studied in the extreme conditions of purity, proximity to the ferromagnetic state and very low temperatures required to test the theory definitively. Here we report the observation of superconductivity on the border of ferromagnetism in a pure system, UGe2, which is known to be qualitatively similar to the classic d-electron ferromagnets. The superconductivity that we observe below 1 K, in a limited pressure range on the border of ferromagnetism, seems to arise from the same electrons that produce band magnetism. In this case, superconductivity is most naturally understood in terms of magnetic as opposed to lattice interactions, and by a spin-triplet rather than the spin-singlet pairing normally associated with nearly antiferromagnetic metals.

Mitochondria and calcium: from cell signalling to cell death

Abstract: While a pathway for Ca2+ accumulation into mitochondria has long been established, its functional significance is only now becoming clear in relation to cell physiology and pathophysiology. The observation that mitochondria take up Ca2+ during physiological Ca2+ signalling in a variety of cell types leads to four questions: (i) ‘What is the impact of mitochondrial Ca2+ uptake on mitochondrial function?’ (ii) ‘What is the impact of mitochondrial Ca2+ uptake on Ca2+ signalling?’ (iii) ‘What are the consequences of impaired mitochondrial Ca2+ uptake for cell function?’ and finally (iv) ‘What are the consequences of pathological [Ca2+]c signalling for mitochondrial function?’ These will be addressed in turn. Thus: (i) accumulation of Ca2+ into mitochondria regulates mitochondrial metabolism and causes a transient depolarisation of mitochondrial membrane potential. (ii) Mitochondria may act as a spatial Ca2+ buffer in many cells, regulating the local Ca2+ concentration in cellular microdomains. This process regulates processes dependent on local cytoplasmic Ca2+ concentration ([Ca2+]c), particularly the flux of Ca2+ through IP3-gated channels of the endoplasmic reticulum (ER) and the channels mediating capacitative Ca2+ influx through the plasma membrane. Consequently, mitochondrial Ca2+ uptake plays a substantial role in shaping [Ca2+]c signals in many cell types. (iii) Impaired mitochondrial Ca2+ uptake alters the spatiotemporal characteristics of cellular [Ca2+]c signalling and downregulates mitochondrial metabolism. (iv) Under pathological conditions of cellular [Ca2+]c overload, particularly in association with oxidative stress, mitochondrial Ca2+ uptake may trigger pathological states that lead to cell death. In the model of glutamate excitotoxicity, microdomains of [Ca2+]c are apparently central, as the pathway to cell death seems to require the local activation of neuronal nitric oxide synthase (nNOS), itself held by scaffolding proteins in close association with the NMDA receptor. Mitochondrial Ca2+ uptake in combination with NO production triggers the collapse of mitochondrial membrane potential, culminating in delayed cell death.

Identification of a pathway for intelligible speech in the left temporal lobe

Abstract: It has been proposed that the identification of sounds, including species-specific vocalizations, by primates depends on anterior projections from the primary auditory cortex, an auditory pathway analogous to the ventral route proposed for the visual identification of objects. We have identified a similar route in the human for understanding intelligible speech. Using PET imaging to identify separable neural subsystems within the human auditory cortex, we used a variety of speech and speech-like stimuli with equivalent acoustic complexity but varying intelligibility. We have demonstrated that the left superior temporal sulcus responds to the presence of phonetic information, but its anterior part only responds if the stimulus is also intelligible. This novel observation demonstrates a left anterior temporal pathway for speech comprehension.

Glutamate release in severe brain ischaemia is mainly by reversed uptake

Abstract: The release of glutamate during brain anoxia or ischaemia triggers the death of neurons, causing mental or physical handicap. The mechanism of glutamate release is controversial, however. Four release mechanisms have been postulated: vesicular release dependent on external calcium or Ca2+ released from intracellular stores; release through swelling-activated anion channels; an indomethacin-sensitive process in astrocytes; and reversed operation of glutamate transporters. Here we have mimicked severe ischaemia in hippocampal slices and monitored glutamate release as a receptor-gated current in the CA1 pyramidal cells that are killed preferentially in ischaemic hippocampus. Using blockers of the different release mechanisms, we demonstrate that glutamate release is largely by reversed operation of neuronal glutamate transporters, and that it plays a key role in generating the anoxic depolarization that abolishes information processing in the central nervous system a few minutes after the start of ischaemia. A mathematical model incorporating K+ channels, reversible uptake carriers and NMDA (N-methyl-D-aspartate) receptor channels reproduces the main features of the response to ischaemia. Thus, transporter-mediated glutamate homeostasis fails dramatically in ischaemia: instead of removing extracellular glutamate to protect neurons, transporters release glutamate, triggering neuronal death.

Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation.

Abstract: Vertebrate gastrulation involves the specification and coordinated movement of large populations of cells that give rise to the ectodermal, mesodermal and endodermal germ layers. Although many of the genes involved in the specification of cell identity during this process have been identified, little is known of the genes that coordinate cell movement. Here we show that the zebrafish silberblick (slb) locus1 encodes Wnt11 and that Slb/Wnt11 activity is required for cells to undergo correct convergent extension movements during gastrulation. In the absence of Slb/Wnt11 function, abnormal extension of axial tissue results in cyclopia and other midline defects in the head2. The requirement for Slb/Wnt11 is cell non-autonomous, and our results indicate that the correct extension of axial tissue is at least partly dependent on medio-lateral cell intercalation in paraxial tissue. We also show that the slb phenotype is rescued by a truncated form of Dishevelled that does not signal through the canonical Wnt pathway3, suggesting that, as in flies4, Wnt signalling might mediate morphogenetic events through a divergent signal transduction cascade. Our results provide genetic and experimental evidence that Wnt activity in lateral tissues has a crucial role in driving the convergent extension movements underlying vertebrate gastrulation.

Abnormalities in the awareness and control of action.

Abstract: Much of the functioning of the motor system occurs without awareness. Nevertheless, we are aware of some aspects of the current state of the system and we can prepare and make movements in the imagination. These mental representations of the actual and possible states of the system are based on two sources: sensory signals from skin and muscles, and the stream of motor commands that have been issued to the system. Damage to the neural substrates of the motor system can lead to abnormalities in the awareness of action as well as defects in the control of action. We provide a framework for understanding how these various abnormalities of awareness can arise. Patients with phantom limbs or with anosognosia experience the illusion that they can move their limbs. We suggest that these representations of movement are based on streams of motor commands rather than sensory signals. Patients with utilization behaviour or with delusions of control can no longer properly link their intentions to their actions. In these cases the impairment lies in the representation of intended movements. The location of the neural damage associated with these disorders suggests that representations of the current and predicted state of the motor system are in parietal cortex, while representations of intended actions are found in prefrontal and premotor cortex.

Hepatocytes from non-hepatic adult stem cells

Abstract: Stem cells are undifferentiated long-lived cells that are capable of many rounds of division. Here we show that adult human liver cells can be derived from stem cells originating in the bone marrow or circulating outside the liver, raising the possibility that blood-system stem cells could be used clinically to generate hepatocytes for replacing damaged tissue.

Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice.

Abstract: Extracellular ATP is implicated in numerous sensory processes ranging from the response to pain to the regulation of motility in visceral organs. The ATP receptor P2X3 is selectively expressed on small diameter sensory neurons, supporting this hypothesis. Here we show that mice deficient in P2X3 lose the rapidly desensitizing ATP-induced currents in dorsal root ganglion neurons. P2X3 deficiency also causes a reduction in the sustained ATP-induced currents in nodose ganglion neurons. P2X3-null mice have reduced pain-related behaviour in response to injection of ATP and formalin. Significantly, P2X3-null mice exhibit a marked urinary bladder hyporeflexia, characterized by decreased voiding frequency and increased bladder capacity, but normal bladder pressures. Immunohistochemical studies localize P2X3 to nerve fibres innervating the urinary bladder of wild-type mice, and show that loss of P2X3 does not alter sensory neuron innervation density. Thus, P2X3 is critical for peripheral pain responses and afferent pathways controlling urinary bladder volume reflexes. Antagonists to P2X3 may therefore have therapeutic potential in the treatment of disorders of urine storage and voiding such as overactive bladder.