8 research outputs found
Electrophysiology of the Olivo-Cerebellar Loop
In animals, motor function and muscle control are critical for an organisms ability
to interact with and react to its environment. This behavior can have many different
functions, from finding food to defending themselves against enemies. In general,
we can subdivide movements into two categories: 1) involuntary movements, like
reflexes, and 2) voluntary movements. From an evolutionary point of view, the more
efficient these movements are, the higher the chance of survival. In vertebrates, the
cerebellum controls movement and monitors its efficiency by collecting sensory information,
such as limb position, balance information and vision. All this information
is evaluated to control and correct our intended movements . The cerebellum
is located just above the brainstem at the lower back of the brain. In humans, it is
the size of a fist and has a very high nerve cell (neuron) density. The outer layer of
the cerebellum, also known as the cerebellar cortex, consists of grey matter and the
inner layer consists of white matter. The neurons in the cerebellum are arranged in
remarkably homogeneous and repetitive structural patterns with little variation in
organization across species
Prognostically useful gene-expression profiles in acute myeloid leukemia
BACKGROUND: In patients with acute myeloid leukemia (AML) a combination of
methods must be used to classify the disease, make therapeutic decisions,
and determine the prognosis. However, this combined approach provides
correct therapeutic and prognostic information in only 50 percent of
cases. METHODS: We determined the gene-expression profiles in samples of
peripheral blood or bone marrow from 285 patients with AML using
Affymetrix U133A GeneChips containing approximately 13,000 unique genes or
expression-signature tags. Data analyses were carried out with Omniviz,
significance analysis of microarrays, and prediction analysis of
microarrays software. Statistical analyses were performed to determine the
prognostic significance of cases of AML with specific molecular
signatures. RESULTS: Unsupervised cluster analyses identified 16 groups of
patients with AML on the basis of molecular signatures. We identified the
genes that defined these clusters and determined the minimal numbers of
genes needed to identify prognostically important clusters with a high
degree of accuracy. The clustering was driven by the presence of
chromosomal lesions (e.g., t(8;21), t(15;17), and inv(16)), particular
genetic mutations (CEBPA), and abnormal oncogene expression (EVI1). We
identified several novel clusters, some consisting of specimens with
normal karyotypes. A unique cluster with a distinctive gene-expression
signature included cases of AML with a poor treatment outcome.
CONCLUSIONS: Gene-expression profiling allows a comprehensive
classification of AML that includes previously identified genetically
defined subgroups and a novel cluster with an adverse prognosis
Purkinje cell input to cerebellar nuclei in tottering: Ultrastructure and physiology
Homozygous tottering mice are spontaneous ataxic mutants, which carry a mutation in the gene encoding the ion pore of the P/Q-type voltage-gated calcium channels. P/Q-type calcium channels are prominently expressed in Purkinje cell terminals, but it is unknown to what extent these inhibitory terminals in tottering mice are affected at the morphological and electrophysiological level. Here, we investigated the distribution and ultrastructure of their Purkinje cell terminals in the cerebellar nuclei as well as the activities of their target neurons. The densities of Purkinje cell terminals and their synapses were not significantly affected in the mutants. However, the Purkinje cell terminals were enlarged and had an increased number of vacuoles, whorled bodies, and mitochondria. These differences started to occur between 3 and 5 weeks of age and persisted throughout adulthood. Stimulation of Purkinje cells in adult tottering mice resulted in inhibition at normal latencies, but the activities of their postsynaptic neurons in the cerebellar nuclei were abnormal in that the frequency and irregularity of their spiking patterns were enhanced. Thus, although the number of their terminals and their synaptic contacts appear quantitatively intact, Purkinje cells in tottering mice show several signs of axonal damage that may contribute to altered postsynaptic activities in the cerebellar nuclei
High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients
The proto-oncogene EVI1 encodes a DNA binding protein and is located on
chromosome 3q26. The gene is aberrantly expressed in acute myeloid
leukemia (AML) patients carrying 3q26 abnormalities. Two mRNAs are
transcribed from this locus: EVI1 and a fusion of EVI1 with MDS1
(MDS1-EVI1), a gene located 5' of EVI1. The purpose of this study was to
investigate which of the 2 gene products is involved in transformation in
human AML. To discriminate between EVI1 and MDS1-EVI1 transcripts,
distinct real-time quantitative polymerase chain reaction (PCR) assays
were developed. Patients with 3q26 abnormalities often showed high EVI1
and MDS1-EVI1 expression. In a cohort of 319 AML patients, 4 subgroups
could be distinguished: EVI1(+) and MDS1-EVI1(-) (6 patients; group I),
EVI1(+) and MDS1-EVI1(+) (26 patients; group II), EVI1(-) and MDS1-EVI1(+)
(12 patients; group III), and EVI1(-) and MDS1-EVI1(-) (275 patients;
group IV). The only 4 patients with a 3q26 aberration belonged to groups I
and II. Interestingly, high EVI1 and not MDS1-EVI1 expression was
associated with unfavorable karyotypes (eg, -7/7q-) or complex karyotypes.
Moreover, a significant correlation was observed between EVI1 expression
and 11q23 aberrations (mixed lineage leukemia [MLL] gene involvement).
Patients from groups I and II had significantly shorter overall and
event-free survival than patients in groups III and IV. Our data
demonstrate that high EVI1 expression is an independent poor prognostic
marker within the intermediate- risk karyotypic group
Encoding of Oscillations by Axonal Bursts in Inferior Olive Neurons
Inferior olive neurons regulate plasticity and timing in the cerebellar cortex via the climbing fiber pathway, but direct characterization of the output of this nucleus has remained elusive. We show that single somatic action potentials in olivary neurons are translated into a burst of axonal spikes. The number of spikes in the burst depends on the phase of subthreshold oscillations and, therefore, encodes the state of the olivary network. These bursts can be successfully transmitted to the cerebellar cortex in vivo, having a significant impact on Purkinje cells. They enhance dendritic spikes, modulate the complex spike pattern, and promote short-term and long-term plasticity at parallel fiber synapses in a manner dependent on the number of spikes in the burst. Our results challenge the view that the climbing fiber conveys an all-or-none signal to the cerebellar cortex and help to link learning and timing theories of olivocerebellar function