Genomic Signatures Among Acanthamoeba polyphaga Entoorganisms Unveil Evidence of Coevolution.

The definition of a genomic signature (GS) is "the total net response to selective pressure". Recent isolation and sequencing of naturally occurring organisms, hereby named entoorganisms, within Acanthamoeba polyphaga, raised the hypothesis of a common genomic signature despite their diverse and unrelated evolutionary origin. Widely accepted and implemented tests for GS detection are oligonucleotide relative frequencies (OnRF) and relative codon usage (RCU) surveys. A common pattern and strong correlations were unveiled from OnRFs among A. polyphaga's Mimivirus and virophage Sputnik. RCU showed a common A-T bias at third codon position. We expanded tests to the amoebal mitochondrial genome and amoeba-resistant bacteria, achieving strikingly coherent results to the aforementioned viral analyses. The GSs in these entoorganisms of diverse evolutionary origin are coevolutionarily conserved within an intracellular environment that provides sanctuary for species of ecological and biomedical relevance.

Origin and Evolution of RNA-Dependent RNA Polymerase.

RNA-dependent RNA polymerases (RdRp) are very ancient enzymes and are essential for all viruses with RNA genomes. We reconstruct the origin and evolution of this polymerase since the initial stages of the origin of life. The origin of the RdRp was traced back from tRNA ancestors. At the origin of the RdRp the most ancient part of the protein is the cofactor-binding site that had the capacity of binding to simple molecules as magnesium, calcium, and ribonucleotides. Our results suggest that RdRp originated from junctions of proto-tRNAs that worked as the first genes at the emergence of the primitive translation system, where the RNA was the informational molecule. The initial domain, worked as a building block for the emergence of the fingers and thumb domains. From the ancestral RdRp, we could establish the evolutionary stages of viral evolution from a rooted ancestor to modern viruses. It was observed that the selective pressure under the RdRp was the organization and functioning of the genome, where RNA double-stranded and RNA single-stranded virus formed a separate group. We propose an evolutionary route to the polymerases and the results suggest an ancient scenario for the origin of RNA viruses.

tRNA Core Hypothesis for the Transition from the RNA World to the Ribonucleoprotein World.

Herein we present the tRNA core hypothesis, which emphasizes the central role of tRNAs molecules in the origin and evolution of fundamental biological processes. tRNAs gave origin to the first genes (mRNA) and the peptidyl transferase center (rRNA), proto-tRNAs were at the core of a proto-translation system, and the anticodon and operational codes then arose in tRNAs molecules. Metabolic pathways emerged from evolutionary pressures of the decoding systems. The transitions from the RNA world to the ribonucleoprotein world to modern biological systems were driven by three kinds of tRNAs transitions, to wit, tRNAs leading to both mRNA and rRNA.

A Novel Method to Predict Genomic Islands Based on Mean Shift Clustering Algorithm.

Genomic Islands (GIs) are regions of bacterial genomes that are acquired from other organisms by the phenomenon of horizontal transfer. These regions are often responsible for many important acquired adaptations of the bacteria, with great impact on their evolution and behavior. Nevertheless, these adaptations are usually associated with pathogenicity, antibiotic resistance, degradation and metabolism. Identification of such regions is of medical and industrial interest. For this reason, different approaches for genomic islands prediction have been proposed. However, none of them are capable of predicting precisely the complete repertory of GIs in a genome. The difficulties arise due to the changes in performance of different algorithms in the face of the variety of nucleotide distribution in different species. In this paper, we present a novel method to predict GIs that is built upon mean shift clustering algorithm. It does not require any information regarding the number of clusters, and the bandwidth parameter is automatically calculated based on a heuristic approach. The method was implemented in a new user-friendly tool named MSGIP--Mean Shift Genomic Island Predictor. Genomes of bacteria with GIs discussed in other papers were used to evaluate the proposed method. The application of this tool revealed the same GIs predicted by other methods and also different novel unpredicted islands. A detailed investigation of the different features related to typical GI elements inserted in these new regions confirmed its effectiveness. Stand-alone and user-friendly versions for this new methodology are available at http://msgip.integrativebioinformatics.me.

Ureaplasma diversum Genome Provides New Insights about the Interaction of the Surface Molecules of This Bacterium with the Host.

Whole genome sequencing and analyses of Ureaplasma diversum ATCC 49782 was undertaken as a step towards understanding U. diversum biology and pathogenicity. The complete genome showed 973,501 bp in a single circular chromosome, with 28.2% of G+C content. A total of 782 coding DNA sequences (CDSs), and 6 rRNA and 32 tRNA genes were predicted and annotated. The metabolic pathways are identical to other human ureaplasmas, including the production of ATP via hydrolysis of the urea. Genes related to pathogenicity, such as urease, phospholipase, hemolysin, and a Mycoplasma Ig binding protein (MIB)-Mycoplasma Ig protease (MIP) system were identified. More interestingly, a large number of genes (n = 40) encoding surface molecules were annotated in the genome (lipoproteins, multiple-banded antigen like protein, membrane nuclease lipoprotein and variable surface antigens lipoprotein). In addition, a gene encoding glycosyltransferase was also found. This enzyme has been associated with the production of capsule in mycoplasmas and ureaplasma. We then sought to detect the presence of a capsule in this organism. A polysaccharide capsule from 11 to 17 nm of U. diversum was observed trough electron microscopy and using specific dyes. This structure contained arabinose, xylose, mannose, galactose and glucose. In order to understand the inflammatory response against these surface molecules, we evaluated the response of murine macrophages J774 against viable and non-viable U. diversum. As with viable bacteria, non-viable bacteria were capable of promoting a significant inflammatory response by activation of Toll like receptor 2 (TLR2), indicating that surface molecules are important for the activation of inflammatory response. Furthermore, a cascade of genes related to the inflammasome pathway of macrophages was also up-regulated during infection with viable organisms when compared to non-infected cells. In conclusion, U. diversum has a typical ureaplasma genome and metabolism, and its surface molecules, including the identified capsular material, represent major components of the organism immunopathogenesis.

NADPH-diaphorase activity in brain macrophages during postnatal development in the rat.

NADPH-diaphorase histochemistry, that allows the visualization of cells producing the gaseous intercellular messenger nitric oxide, was used in the study of the forebrain during the first three postnatal weeks in the rat. Subpopulations of NADPH-diaphorase positive neurons were observed at all ages studied. In addition, non-neuronal NADPH-diaphorase-stained cells were detected in the subcortical white matter, and were very numerous in the supraventricular portion of the corpus callosum, and in the internal and external capsules. These cells were present during the first two postnatal weeks, and were especially prominent at the end of the first postnatal week. They were round-shaped and morphologically similar to the brain macrophages, whose phagocytic activity has been shown in previous studies to play a role in naturally occurring cell death and elimination of exhuberant axons. Series of sections adjacent to those stained with NADPH-diaphorase were processed with immunohistochemistry, using two different antibodies (OX-42 and ED-1) that detect macrophagic and microglial markers, and antibodies that recognize the neuronal form of nitric oxide synthase. Furthermore, brain sections from rats at postnatal day 7 were sequentially processed for either OX-42 or nitric oxide synthase immunohistochemistry followed by NADPH-diaphorase histochemistry. The morphological features and distribution of the non-neuronal NADPH-diaphorase-positive cells were superimposable to those obtained with OX-42 and ED-1 immunohistochemistry. In addition, these cells did not display nitric oxide synthase immunoreactivity. Double-labelled NADPH-diaphorase-positive and OX-42-immunoreactive cells were detected at postnatal day 7. The present results show that brain macrophages express NADPH-diaphorase activity during the early stages of the normal postnatal maturation and suggest that nitric oxide produced by brain macrophages could be involved in the development reshaping of the central nervous system.

Intrinsic properties and environmental factors in the regeneration of adult cerebellar axons.

The success of axon regeneration in the adult mammalian brain depends on the presence of growth-permissive environmental conditions as well as on specific properties of the affected neurons. To investigate the relative contribution of extrinsic cues and intrinsic determinants to reparative processes we have investigated the regenerative properties of olivocerebellar and Purkinje cell axons. When these axon populations are severed in the cerebellar white matter and confronted with embryonic neural grafts of cerebellar or extracerebellar origin, the former vigorously regenerate into the transplant, whereas the latter invariably fail to do so (Rossi et al., 1995). The same response occurs when dissociated Schwann cells are implanted in the lesion site: Purkinje cell axons fail to regrow, whereas olivocerebellar fibres regenerate for considerable distances. Within the graft, regenerating fibres follow tortuous courses along Schwann cell bundles and sometimes end with poorly developed terminal plexuses. Some of them, however, succeed in crossing the graft and grow further into the host cortex, where they break into fine terminal branches confined to the granular layer. The remarkable regenerative response of olivocerebellar axons revealed by these experiments might be an intrinsic reaction of the affected neurons to axon injury or it might be elicited by growth promoting cues derived from the grafts. To elucidate this point we have undertaken the investigation of cellular changes occurring in adult inferior olivary neurons following the transection of the inferior cerebellar peduncle. Our results show that axotomy induces a series of cellular changes, or reparative and regressive character, which ultimately lead to cell death. Interestingly, however, these modifications are not uniformly distributed throughout the whole inferior olive. (i) Neuronal atrophy and degeneration progress more rapidly in the PO and DAO than in the MAO. (ii) A subpopulation of inferior olivary neurons become reactive for NADPH-diaphorase histochemistry, and their preferential localisation in the MAO suggests that this modification is related to the longer survival of these cells after axotomy. (iii) The developmentally regulated calcitonin gene-related peptide (CGRP) is reexpressed by a subset of neurons in the caudal nuclear compartments. These results further emphasise the conclusion that the dissimilar regenerative response of Purkinje cell and olivocerebellar axons confronted with permissive environmental conditions is due to different intrinsic properties of these neuronal populations. The reexpression of developmentally regulated substances by axotomised inferior olivary neurons suggests that their reparative reaction is triggered by axon injury. However, the pattern of growth of regenerating olivocerebellar axons is strongly conditioned by environmental constraints, which, in the present experimental conditions, do not allow them to reattain denervated Purkinje cells.

Inferior olive lesion induces long-term modifications of cerebellar inhibition on Deiters nuclei.

The frequency of discharge of cerebellar Purkinje cells and lateral vestibular nuclear cells were recorded at different intervals of time after injection of 3-acetylpyridine (3AP), which destroys the inferior olivary nucleus. During the first few days, Purkinje cells showed an increase of simple spike firing, while Deiters cells showed a strong depression of their discharge. Recordings up to 3 months demonstrated, for both groups of cells, a recovery, whose time course is faster for Deiters cells than for Purkinje cells. A reduced inhibitory efficacy of Purkinje cells, as a consequence of climbing fibre deprivation, is suggested.

Schwann cell-derived factors support serotoninergic neuron survival and promote neurite outgrowth.

During embryogenesis and the postnatal period, neurons and glia interact in the development and differentiation of specific populations of nerve cells. Both in the peripheral (PNS) and in the central nervous system (CNS), glial cells have been shown in various experimental conditions to constitute a favorable substrate for neural adhesion, neural polarity, shape and axonal extension, while numerous soluble molecules secreted by neurons influence the survival and differentiation of the glial cells themselves. The aim of the present work was to investigate the influence of postnatal Schwann cells (SC) on embryonic serotoninergic (5-HT) neurons of the raphe, in order to study the possible influence of the peripheral glia on the CNS neurons. Cultures of SC from sciatic nerve of postnatal rats and neurons from rat embryonic rhombencephalon were successfully established and cells were immunocytochemically characterized. The number of 5-HT neurons, and the number and length of their branches were quantified in the cultures of 5-HT neurons, in cultures added with Nerve Growth Factor (NGF) and Insulin-like Growth Factor I (IGF-I), in co-cultures with SC and in cultures added with conditioned medium obtained from SC cultures. The results indicated that SC have the capacity to promote the survival and growth of 5-HT neurons in culture, and that this activity is mediated by soluble factors. Although the precise nature and mechanism of action of the growth factor or factors produced by SC in the presence of 5-HT neurons was not identified, our results add more data on the possible activity of the peripheral glia in promoting and enhancing the survival and outgrowth of the CNS neurons.

Preferred amino acids and thermostability.

Most organisms grow at temperatures from 20 to 50 degrees C, but some prokaryotes, including Archaea and Bacteria, are capable of withstanding higher temperatures, from 60 to >100 degrees C. Their biomolecules, especially proteins, must be sufficiently stable to function under these extreme conditions; however, the basis for thermostability remains elusive. We investigated the preferential usage of certain groupings of amino acids and codons in thermally adapted organisms, by comparative proteome analysis, using 28 complete genomes from 18 mesophiles (M), 4 thermophiles (T), and 6 hyperthermophiles (HT). Whenever the percent of glutamate (E) and lysine (K) increased in the HT proteomes, the percent of glutamine (Q) and histidine (H) decreased, so that the E + K/Q + H ratio was >4.5; it was <2.5 in the M proteomes, and 3.2 to 4.6 in T. The E + K/Q + H ratios for chaperonins, potentially thermostable proteins, were higher than their proteome ratios, whereas for DNA ligases, which are not necessarily thermostable, they followed the proteome ratios. Analysis of codon usage revealed that HT had more AGR codons for Arg than they did CGN codons, which were more common in mesophiles. The E + K/Q + H ratio may provide a useful marker for distinguishing HT, T and M prokaryotes, and the high percentage of the amino acid couple E + K, consistently associated with a low percentage of the pair Q + H, could contribute to protein thermostability. The preponderance of AGR codons for Arg is a signature of all HT so far analyzed. The E + K/Q + H ratio and the codon bias for Arg are apparently not related to phylogeny. HT members of the Bacteria show the same values as the HT members of the Archaea; the values for T organisms are related to their lifestyle (intermediate temperature) and not to their domain (Archaea) and the values for M are similar in Eukarya, Bacteria and Archaea.

Origin and evolution of the Peptidyl Transferase Center from proto-tRNAs.

We tested the hypothesis of Tamura (2011) [3] that molecules of tRNA gave origin to ribosomes, particularly to the Peptidyl Transferase Center (PTC) of the 23S ribosomal RNA. We reconstructed the ancestral sequences from all types of tRNA and compared them in their sequences with the current PTC of 23S ribosomal RNA from different organisms. We built an ancestral sequence of proto-tRNAs that showed a remarkable overall identity of 50.53% with the catalytic site of PTC. We conclude that the Peptidyl Transferase Center was indeed originated by the fusion of ancestral sequences of proto-tRNA.

Leishmaniose visceral humana: reflexões éticas e jurídicas acerca do controle do reservatório canino no Brasil / Human visceral leishmaniasis: ethical and legal reflections on the canine reservoir control in Brazil

O Brasil enfrenta atualmente dificuldades no combatea leishmaniose visceral humana.De acordo a Organização Mundial da Saúde, a eutanásia dos cães sintomáticos e soropositivos é uma das medidas de controle do agravo, conforme decreto vigente 51.838, de 14 de março de 1963, o que se torna importantediscutir o diálogo entre Saúde e Direito como estratégia para se evitar a expansão da doença, devido à resistência dos proprietários em entregar seus cães, com alto valor afetivo, a zoonoses. Conclui-se que para uma política pública efetiva vários elementos devem levados em consideração, sobretudo a interdisciplinaridade, enfatizando reflexões jurídicas e saúde, envolvendo questões que permeiam as relações humanas no contexto da ética e da legislação (AU)

Brazil currently faces difficulties in combating human visceral leishmaniasis. According to the World Health Organization, euthanasia of symptomatic and seropositive dogs is one of injury control measures, according to current Decree 51838 of March 14, 1963, which becomes important to discuss the dialogue between health and law as a strategy to prevent the spread of the disease, due to the owners ' resistance to deliver their dogs with high emotional value, zoonoses. It is concluded that for effective public policy more elements are taken into consideration, especially interdisciplinary, emphasizing legal and health considerations involving issues that permeate the human relationships in the context of ethics and law (AU)

On the Purkinje cell activity increase induced by suppression of inferior olive activity.

Previous experiments performed in rats under barbiturate anaesthesia have shown a remarkable increase of simple spike firing rate in cerebellar Purkinje cells following inferior olive lesion or inactivation. The increase is due, at least in part, to the withdrawal of the tonic background activity of corticocerebellar interneurones, which have GABA as a chemical transmitter. Since barbiturates potentiate GABAergic inhibition, it is possible that the effect is due to the presence of this type of anaesthesia. In absence of general anaesthesia, we have compared the simple spike firing rate of the Purkinje cells in rats with intact inferior olive and 3-5 days after inferior olive lesion by 3-acetylpyridine. In the latter condition, the firing rate is significantly higher. In other rats, under urethane anaesthesia, which is not known to interfere with GABAergic transmission, the inferior olive has been reversibly inactivated by applying a cooling probe to the ventral surface of the medulla. Following cooling of the inferior olive on one side, a remarkable increase of simple spike activity, parallel to the disappearance of complex spike activity, has been observed in the Purkinje cells of the contralateral side. These results show that the presence of the simple spike firing increase, which follows the removal of the climbing fibre activity, does not depend on an anaesthetic which potentiates GABAergic transmission, although its amplitude is affected by the same anaesthetic. They suggest, therefore, that the tonic inhibition exerted by the olivocerebellar pathway on the Purkinje cells operates also in physiological conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurotoxicity of HIV coat protein gp120, NMDA receptors, and protein kinase C: a study with rat cerebellar granule cell cultures.

The neuronal loss observed in AIDS patients may be partly due to the neurotoxicity of HIV coat protein gp120, whose mechanism of action has been suggested to involve an interaction with voltage-dependent Ca2+ channels and NMDA receptors (Lipton, Trends Neurosci 15:75-79, 1992). In the present investigation we analyzed the acute neurotoxicity of gp120 on a purified neuronal population (rat cerebellar granule cell cultures) amply used for studies on glutamate toxicity. Cultures of 7-8 days were exposed for 15 min to a buffered Locke's solution containing the substances under study, washed, and cultured for another 24 hr in their original medium. The cells were stained with the nuclear dyes propidium iodide (for dead cells) and Hoechst 33258 (for total cells) and counted. Average cell death in controls was 8%. gp120 (1 pM-10 nM) caused an increase of cell death of about 80%. The effect was totally antagonized by NMDA antagonists (1 mM APV and 10 microM MK-801), by 1 microM nifedipine, and by anti-gp120 antibodies. At a concentration of 100 microM glutamate caused an average 130% increase of cell death, which was totally antagonized by APV. The effect of gp120 or glutamate did not appear to be mediated by the secretion of neurotoxins by nonneuronal cells present in a low proportion in the cultures nor to be due to the inactivation of (or competition with) neurotrophic factors present in the medium. The simultaneous administration of gp120 and glutamate (in various combinations of concentrations) had an effect that was less than additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Rat CNS white matter, but not gray matter, is nonpermissive for neuronal cell adhesion and fiber outgrowth.

In adult mammalian CNS, axons mostly fail to regenerate after injury, while in the PNS they often succeed in reaching their previous targets. Crucial differences are present in the local tissue microenvironment of CNS and PNS. To investigate the substrate properties of nervous tissue for neuronal adhesion and fiber growth, we used frozen sections of rat CNS and PNS as culture substrates for neuroblastoma cells and for sympathetic and dorsal root ganglia. The results showed that CNS white matter from adult rat spinal cord, cerebellum, forebrain, or optic nerve did not allow cell adhesion and axonal elongation. In contrast, gray matter areas, sciatic nerve, and also trout CNS white and gray matter were permissive substrates. To delineate the tissue components of white matter involved in this nonpermissive substrate effect, newborn rats were injected for 13 d with the antimitotic agent 5-azacytidine. This treatment strongly reduced the oligodendrocyte population and the myelin content of the spinal cord. The immunoreactivity for specific oligodendrocyte and astrocyte markers confirmed the selective suppression of oligodendroglia in these rats. Neuroblastoma cells plated on spinal cord sections taken from these animals were no longer exclusively localized on the gray matter but were also found on regions normally rich in myelin. A significant reduction of the white matter nonpermissive substrate effect was also obtained by the monoclonal antibody IN-1 directed against 2 defined myelin proteins with inhibitory substrate properties (Caroni and Schwab, 1988b). Our results, therefore, show that, in the adult mammalian CNS, cell adhesion and axonal elongation are prevented by white matter components, which are, at least in part, associated with oligodendrocytes and myelin.

Lesioned corticospinal tract axons regenerate in myelin-free rat spinal cord.

In the adult central nervous system (CNS) of higher vertebrates lesioned axons seemed unable to regenerate and reach their former target regions due to influences of the CNS microenvironment. Evidence from in vitro and biochemical experiments has demonstrated the presence of inhibitory substrate components in CNS tissue, in particular in white matter. These CNS components, which strongly inhibit neurite growth, were identified as minor membrane proteins of defined molecular mass (35 and 250 kDa) in oligodendrocyte membranes and CNS myelin. Oligodendrocyte development and myelin formation can be prevented by x-irradiation of newborn rats. Here we show that in myelin-free spinal cords cortico-spinal tract fibers transected at 2 weeks of age show reelongation of many millimeters within 2-3 weeks after the lesion. In normally myelinated controls, regenerative sprouts grew less than 1.7 mm caudal to the lesion.

Olivocerebellar axon regeneration and target reinnervation following dissociated Schwann cell grafts in surgically injured cerebella of adult rats.

The ability of Schwann cells to induce the regeneration of severed olivocerebellar and Purkinje cell axons across an injury up to their deafferented targets was tested by transplanting freshly dissociated cells from newborn rat sciatic nerves into surgically lesioned adult cerebella. The grafted glial cells consistently filled the lesion gap and migrated into the host parenchyma. Transected olivocerebellar axons vigorously regenerated into the graft, where their growth pattern and direction followed the arrangement of Schwann cell bundles. Although some of these axons terminated within the transplant, many of them rejoined the cerebellar parenchyma beyond the lesion. Here, their fate depended on the territory encountered. No growth occurred in the white matter. Numerous fibres penetrated into the granular layer and formed terminal branches that remained confined within this layer. A few of them, however, regenerated up to the molecular layer and formed climbing fibres on Purkinje cell dendrites. By contrast, the growth of transected Purkinje cell axons into the grafts was very poor. These results underscore the different intrinsic responsiveness of Purkinje cell and olivocerebellar axons to the growth-promoting action of Schwann cells, and show that the development and outcome of the regenerative phenomena is strongly conditioned by the spatial organization and specific features of the environmental cues encountered by the outgrowing axons along the course they follow. However, Schwann cells effectively bridge the lesion gap, induce the regeneration of olivocerebellar axons, and direct their growth up to the deafferented host cortex, where some of them succeed in reinnervating their natural targets.

Dynamic characteristics of optokinetically controlled eye movements following inferior olive lesions in the brown rat.

1. The inferior olive was destroyed by the drug 3-acetylpyridine in brown rats. Spontaneous and optokinetic eye movements in response to constant-velocity rotation (5-80 deg/s) or sinusoidal oscillations (0.05 and 0.1 Hz with 15 deg/s peak velocity and 0.3, 0.5, 1.0 and 2 Hz with 5 deg/s peak velocity) of the visual surround were recorded 4-6 days, 40-50 days and 3-4 months after the lesion using the magnetic search coil technique. 2. Persistent oculomotor deficits were observed in rats with a lesion of more than 97% of inferior olive neurones. In cases with a less complete lesion, no or only transient deficits were observed. In these latter cases the bulk of surviving neurones was located in the caudal half of the inferior olive, which includes the dorsal cap of Kooy. 3. Eye position holding after saccadic gaze shifts in the light was strongly deficient, showing pronounced postsaccadic centripetal drift for several hundred milliseconds. Similar deficits were observed in slow-phase components following quick phases of optokinetic nystagmus. In the dark, eye position holding was also deficient. 4. Closed-loop gains of optokinetic step responses obtained from rats with inferior olive lesions could be as good as those obtained from control animals. There was, however, a trend towards smaller gain values over the range of stimulus velocities tested. The duration of optokinetic after-nystagmus was not changed. 5. The initial fast rise of slow-phase velocity of optokinetic step responses was reduced by about 30-50%, showing no recovery in the follow-up experiments up to 3-4 months after the lesion. 6. Optokinetic responses to sinusoidal oscillations of the visual surround exhibited an increasing drop in gain for frequencies between 0.1 to 0.5 Hz. In the range of 0.5-2.0 Hz gain was only about 0.2 compared to 0.7-0.8 in control animals. Phase lag of sinusoidal responses was shifted to larger values by about 25-35 deg for frequencies increasing from 0.1 to 0.5 Hz. At 1.0 Hz phase shift was reduced to about 15 deg and at 2.0 Hz no significant change in phase was observed. Both gain and phase of sinusoidal responses showed some recovery when tested 3-4 months after inferior olive lesion. 7. The results suggest that inferior olive lesions impair velocity-to-position integration, mainly as a consequence of the missing climbing fibre input to the cerebellar flocculi.(ABSTRACT TRUNCATED AT 400 WORDS)