Mitochondrial permeability: dual role for the ADP/ATP translocator?

The ADP/ATP translocator (or adenine nucleotide translocase; ANT) is thought to play a dual role: in the transport of ADP and ATP across the mitochondrial inner membrane and in the formation of the mitochondrial permeability-transition pore (mtPTP), a nonspecific pore that is an important mediator of apoptosis (programmed cell death). However, Kokoszka et al. have shown that mitochondria from livers of 'ANT-knockout' mice, in which the ANT has been genetically inactivated, still possess mtPTP activity. From this, the authors conclude that the ANT is a non-essential component of the mtPTP that may be dispensable for mtPTP-associated cell death. These results, which contradict previous evidence and cast doubt on a widely accepted model for the mtPTP (ref. 1), warrant scrutiny and call for a fundamental reappraisal of the role of the ANT in liver metabolism.     

Bayesian integration in sensorimotor learning

When we learn a new motor skill, such as playing an approaching tennis ball, both our sensors and the task possess variability. Our sensors provide imperfect information about the ball's velocity, so we can only estimate it. Combining information from multiple modalities can reduce the error in this estimate. On a longer time scale, not all velocities are a priori equally probable, and over the course of a match there will be a probability distribution of velocities. According to bayesian theory, an optimal estimate results from combining information about the distribution of velocities-the prior-with evidence from sensory feedback. As uncertainty increases, when playing in fog or at dusk, the system should increasingly rely on prior knowledge. To use a bayesian strategy, the brain would need to represent the prior distribution and the level of uncertainty in the sensory feedback. Here we control the statistical variations of a new sensorimotor task and manipulate the uncertainty of the sensory feedback. We show that subjects internally represent both the statistical distribution of the task and their sensory uncertainty, combining them in a manner consistent with a performance-optimizing bayesian process. The central nervous system therefore employs probabilistic models during sensorimotor learning.     

Acylphosphatase overexpression triggers SH-SY5Y differentiation towards neuronal phenotype

An acylphosphatase (AcPase) overexpression study was carried out on SH-SY5Y neuroblastoma cells, using a green fluorescent fusion protein (AcP-GFP), with GFP acting as a reporter protein. The cellular proliferation rate was significantly reduced by overexpression of AcPase by a factor of ten. In contrast, clones transfected with two inactive AcPase mutants showed a growth rate comparable to control cells. This suggests that AcPase catalyzes the proliferative down-regulation. AcPase-overexpressing clones showed a physiological mortality rate as assessed by an MTT reduction test and by evaluation of necrotic markers. DNA fragmentation analysis and assays of caspase-3 and poly (ADP-ribose) polymerase (PARP)-active fragments showed no evidence of any apoptotic pattern. AcPase overexpression led to a marked increase in PARP activity as well as Bcl-2 content; these are commonly up-regulated during differentiative processes in neuronal cells. In fact, the typical differentiation marker, growth-associated-protein 43, was significantly up-regulated. Microscopic observations also showed a clear increase in the differentiative phenotype in AcPase-overexpressing cells. Our results clearly show that AcPase plays a primary causative role in neuronal differentiation.Received 3 May 2004; accepted 25 May 2004     

Involvement of penaeidins in defense reactions of the shrimp Litopenaeus stylirostris to a pathogenic vibrio

The present study reports for the first time the involvement of an antimicrobial peptide in the defense reactions of a shrimp infected by a pathogenic Vibrio, Vibrio penaeicida. New members of the penaeidin family were characterized in the shrimp Litopenaeus stylirostris by RT-PCR and RACE-PCR from hemocyte total RNAs, and by mass spectrometry detection and immunolocalization of mature peptides in shrimp hemocytes. In infected shrimps, bacteria and penaeidin distribution colocalized in the gills and the lymphoid organ that represented the main infected sites. Moreover, the shrimp immune response to infection involved massive hemocyte recruitment to infection sites where released penaeidin may participate in the isolation and elimination of the bacteria, We show that the ability of the shrimps to circumvent shrimp infections is closely related to a recovery phase based on the hematopoietic process.Received 25 November 2003; received after revision 8 January 2004; accepted 21 January 2004     

Functional investigations of exercising muscle: a noninvasive magnetic resonance spectroscopy-magnetic resonance imaging approach

Muscle fatigue, which is defined as the decline in muscle performance during exercise, may occur at different sites along the pathway from the central nervous system through to the intramuscular contractile machinery. Historically, both impairment of neuromuscular transmission and peripheral alterations within the muscle have been proposed as causative factors of fatigue development. However, according to more recent studies, muscle energetics play a key role in this process. Intramyoplasmic accumulation of inorganic phosphate (P_i) and limitation in ATP availability have been frequently evoked as the main mechanisms leading to fatigue. Although attractive, these hypotheses have been elaborated on the basis of experimental results obtained in vitro, and their physiological relevance has never been clearly demonstrated in vivo. In that context, noninvasive methods such as 31-phosphorus magnetic resonance spectroscopy and surface electromyography have been employed to understand both metabolic and electrical aspects of muscle fatigue under physiological conditions. Mapping of muscles activated during exercise is another interesting issue which can be addressed using magnetic resonance imaging (MRI). Exercise-induced T2 changes have been used in order to locate activated muscles and also as a quantitative index of exercise intensity. The main results related to both issues, i.e. the metabolic and electrical aspects of fatigue and the MRI functional investigation of exercising muscle, are discussed in the present review.Received 4 September 2003; received after revision 4 December 2003; accepted 22 December 2003     

Differential distribution of TASK-1, TASK-2 and TASK-3 immunoreactivities in the rat and human cerebellum

In this work, the distributions of some acid-sensitive two-pore-domain K⁺ channels (TASK-1, TASK-2 and TASK-3) were investigated in the rat and human cerebellum. Astrocytes situated in rat cerebellar tissue sections were positive for TASK-2 channels. Purkinje cells were strongly stained and granule cells and astrocytes were moderately positive for TASK-3. Astrocytes isolated from the hippocampus, cerebellum and cochlear nucleus expressed TASK channels in a primary tissue culture. Our results suggest that TASK channel expression may be significant in the endoplasmic reticulum of the astrocytes. The human cerebellum showed weak TASK-2 immunolabelling. The pia mater, astrocytes, Purkinje and granule cells demonstrated strong TASK-1 and TASK-3 positivities. The TASK-3 labelling was stronger in general, but it was particularly intense in the Purkinje cells and pia mater.Received 25 February 2004; received after revision 19 April 2004; accepted 28 April 2004     

Diversity of structures and properties among catalases

More than 300 catalase sequences are now available, divided among monofunctional catalases (> 225), bifunctional catalase-peroxidases (> 50) and manganese-containing catalases (> 25). When combined with the recent appearance of crystal structures from at least two representatives from each of these groups (nine from the monofunctional catalases), valuable insights into the catalatic reaction mechanism in its various forms and into catalase evolution have been gained. The structures have revealed an unusually large number of modifications unique to catalases, a result of interacting with reactive oxygen species. Biochemical and physiological characterization of catalases from many different organisms has revealed a surprisingly wide range of catalatic efficiencies, despite similar sequences. Catalase gene expression in micro-organisms generally is controlled either by sensors of reactive oxygen species or by growth phase regulons, although the detailed mechanisms vary considerably.Received 2 June 2003; received after revision 24 June 2003; accepted 1 July 2003     

The molecular mechanisms of congenital hypofibrinogenaemia

Congenital hypofibrinogenaemia is characterized by abnormally low levels of fibrinogen and is usually caused by heterozygous mutations in the fibrinogen chain genes (, and ). However, it does not usually result in a clinically significant condition unless inherited in a homozygous or compound heterozygous state, where it results in a severe bleeding disorder, afibrinogenaemia. Various protein and expression studies have improved our understanding of how mutations causing hypo- and afibrinogenaemia affect secretion of the mature fibrinogen molecule from the hepatocyte. Some mutations can perturb chain assembly as in the 153 Cys Arg case, while others such as the B Leu Arg and the B414 Gly Ser mutations allow intracellular hexamer assembly but inhibit protein secretion. An interesting group of mutations, such as 284 Gly Arg and 375 Arg Trp, not only cause hypofibrinogenaemia but are also associated with liver disease. The nonexpression of these variant chains in plasma fibrinogen is due to retention in the endoplasmic reticulum, which in turn leads to hypofibrinogenaemia.Received 17 December 2003; received after revision 19 January 2004; accepted 21 January 2004     

Neurobiology and neuroimmunology of Tourette’s syndrome: an update

Tourettes syndrome is a childhood-onset neuropsychiatric disorder characterized by the presence of both multiple motor and vocal tics. While the pathogenesis at a molecular and cellular level remains unknown, structural and functional neuroimaging studies point to the involvement of the basal ganglia and related cortico-striato-thalamo-cortical circuits as the neuroanatomical site for Tourettes syndrome. Moreover, Tourettes syndrome has a strong genetic component, and considerable progress has been made in understanding the mode of transmission and in identifying potential genomic loci. Summaries of recent findings in these areas will be reviewed, followed by a critical overview of findings both supporting and challenging the proposed autoimmune hypothesis of Tourettes syndrome. We conclude that Tourettes syndrome is a heterogeneous disorder, and that immune factors may indeed be involved in some patients.Received 12 August 2003; received after revision 8 October 2003; accepted 31 October 2003