This study tried to differentiate the consequences of chronic hypoxia on the electrophysiological and physiological properties and the histological characteristics of slow and fast muscles in rats. Animals inhaled a 10% O₂ concentration for a 1-month period. Then, slow [soleus (SOL)] and fast [extensor digitorum longus (EDL)] muscles were analyzed in vitro by physiological and electrophysiological measurements and histological analyses. The results were compared to those obtained in corresponding muscles of an age-matched normoxic group. After exposure to hypoxia: (1) in SOL, there was a tendency to elevated F_max, a significant increase in twitch force and tetanic frequency and a shortening of M-wave duration, and a reduced percentage of type I fibres, whereas the proportion of type IIa fibres doubled; (2) in EDL, F_max and tetanic frequency were lowered, the muscle became less resistant to fatigue, and the proportion of type IId/x fibres was halved. Then, after 1 month of hypoxia, in the SOL muscle, both the contractile and histological properties resemble those of a fast muscle. By contrast, the EDL became slower, despite its histology was modestly affected. Reduced muscle use in hypoxia could explain the tendency for deteriorating adaptations in EDL, and the faster properties of SOL could result from hypoxia-induced inhibition of the growth-related fast-to-slow shift in muscle fibre types.

The margination of a particle circulating in the blood stream has been analyzed. The contribution of buoyancy, hemodynamic forces, van der Waals, electrostatic and steric interactions between the circulating particle and the endothelium lining the vasculature has been considered. For practical applications, the contribution of buoyancy, hemodynamic forces and van der Waals interactions should be only taken into account, whilst the effect of electrostatic and steric repulsion becomes important only at very short distances from the endothelium (1–10 nm). The margination speed and the time for margination t_s have been estimated as a function of the density of the particle relative to blood Δ ρ, the Hamaker constant A and radius R of the particle. A critical radius R_c exists for which the margination time t_s has a maximum, which is influenced by both Δ ρ and A: the critical radius decreases as the relative density increases and the Hamaker constant decreases. Therefore, particles used for drug delivery should have a radius smaller than the critical value (in the range of 100 nm) to facilitate margination and interaction with the endothelium. While particles used as nanoharvesting agents in proteomics or genomics analysis should have a radius close to the critical value to minimize margination and increase their circulation time.

Brain cancer accounts for approx 1.4% of all cancers and 2.3% of all cancer-related deaths. The incidence of primary cerebral malignancies varies between 4 and 10/100,000 in the general population. This incidence tends to increase with age (4/100,000 up to the age of 12 yr; 6/100,000 up to the age of 35 yr; 18/100,000 up to the age of 55 yr; 70/100,000 up to the age of 75 yr).

Here we show that a new class of antibiotics—acyldepsipeptides—has antibacterial activity against Gram-positive bacteria in vitro and in several rodent models of bacterial infection. The acyldepsipeptides are active against isolates that are resistant to antibiotics in clinical application, implying a new target, which we identify as ClpP, the core unit of a major bacterial protease complex. ClpP is usually tightly regulated and strictly requires a member of the family of Clp-ATPases and often further accessory proteins for proteolytic activation. Binding of acyldepsipeptides to ClpP eliminates these safeguards. The acyldepsipeptide-activated ClpP core is capable of proteolytic degradation in the absence of the regulatory Clp-ATPases. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death.

Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia. We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome. We hypothesize that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors.

In this study, we have applied high-density oligonucleotide microarray technology to characterize biologic changes associated with adenoviral vector-mediated target cell infection. We infected a human melanoma cell line, M21, with the tropism-modified vectors, Ad5lucRGD and Ad5/3luc1. In addition, we infected the M21 cell line with the Ad5luc1, a vector which primarily exploits the coxsackie and adenovirus receptor, as its primary native receptor. We found significant changes in gene expression of 5492 genes induced by Ad5luc1 infection, 2439 genes induced by Ad5/3luc1 infection, and 1251 genes induced by Ad5lucRGD infection, compared to unifected cells. Among these changes in gene expression, 783 changes were common to Ad5/3luc1 and Ad5luc1 infections, 266 were common to Ad5lucRGD and Ad5luc1 infections, and 185 changes in gene expression were common to Ad5/3luc1 and Ad5lucRGD infections. Interestingly, 89 changes in gene expression were common to all the three groups, suggesting a commonly affected pathway. This analysis represents a unique application of microarray to study vector-related issues. Furthermore, these studies demonstrate the utility of microarray for characterizing the biologic sequelae of host–vector interaction.

Key Points

The remarkable processing capabilities of the brain rely on efficient communication between the huge number of neurons and neuronal assemblies that constitute functionally specialized units. Abundant anatomical connections form the structural basis of communication. Functionally, the synchronization of oscillatory neuronal activity has increasingly been recognized as a mechanism for long-range communication.

Studies of the insect olfactory system provide the most direct evidence that oscillatory communication is behaviourally relevant. These and other studies point towards several mechanisms that funtion on different spatial scales to support interneuronal communication. Filtering and resonance phenomena indicate the dependence of neuronal activity on the frequency content of the input. Specific structural connectivity underlies the emergence of particular network properties that facilitate specific computations by spatiotemporal patterns of excitation and inhibition.

New analytical methods have allowed the non-invasive investigation of frequency-specific long-range communication in the human brain with magnetoencephalographic (MEG) recordings.

Recent studies in humans and monkeys have provided new evidence for the physiological relevance of oscillatory synchronization in motor and cognitive functions. Synchronization in the beta frequency band seems to have a particularly important role in long-range communication. The functional relevance of desynchronization processes is also being increasingly recognized, and specific spatiotemporal patterns of synchronization desynchronization have been directly related to attentional processes and behavioural performance.

In the human motor system, oscillations in the primary motor cortex modulate the firing rate of spinal motor neurons. This modulation is evident as oscillatory coupling between motor cortex activity and muscle activity.

Electrophysiological recordings of basal ganglia-thalamocortical circuits in healthy monkeys, a monkey model of Parkinson's disease and patients with Parkinson's disease have provided new insights into the functional roles of oscillations and oscillatory synchronization in normal and disturbed motor behaviour. Specifically, enhanced beta and reduced gamma oscillations are associated with the poverty and slowness of movement that is characteristic of Parkinson's disease. In addition, tremor seems to arise from abnormal synchronization of oscillations in several cortical and subcortical brain areas.

Chronic high-frequency deep brain stimulation, which can be delivered through electrodes that have been implanted in specific basal ganglia target structures, greatly improves motor symptoms in patients with Parkinson's disease, probably through desynchronizing effects.

Pathological changes in long-range synchronization are also evident in other movement disorders, as well as in neuropsychiatric diseases. Further work is needed to better understand the mechanisms that govern oscillatory communication and the consequences of disturbed communication. Hopefully, these studies will lead to the development of new therapeutic approaches.