CutLang v2: Advances in a Runtime-Interpreted Analysis Description Language for HEP Data.

We will present the latest developments in CutLang, the runtime interpreter of a recently-developed analysis description language (ADL) for collider data analysis. ADL is a domain-specific, declarative language that describes the contents of an analysis in a standard and unambiguous way, independent of any computing framework. In ADL, analyses are written in human-readable plain text files, separating object, variable and event selection definitions in blocks, with a syntax that includes mathematical and logical operations, comparison and optimisation operators, reducers, four-vector algebra and commonly used functions. Adopting ADLs would bring numerous benefits to the LHC experimental and phenomenological communities, ranging from analysis preservation beyond the lifetimes of experiments or analysis software to facilitating the abstraction, design, visualization, validation, combination, reproduction, interpretation and overall communication of the analysis contents. Since their initial release, ADL and CutLang have been used for implementing and running numerous LHC analyses. In this process, the original syntax from CutLang v1 has been modified for better ADL compatibility, and the interpreter has been adapted to work with that syntax, resulting in the current release v2. Furthermore, CutLang has been enhanced to handle object combinatorics, to include tables and weights, to save events at any analysis stage, to benefit from multi-core/multi-CPU hardware among other improvements. In this contribution, these and other enhancements are discussed in details. In addition, real life examples from LHC analyses are presented together with a user manual.

Early recognition of malnutrition and cachexia in the cancer patient: a position paper of a European School of Oncology Task Force.

BACKGROUND: Weight loss and cachexia are common, reduce tolerance of cancer treatment and the likelihood of response, and independently predict poor outcome. METHODS: A group of experts met under the auspices of the European School of Oncology to review the literature and-on the basis of the limited evidence at present-make recommendations for malnutrition and cachexia management and future research. CONCLUSIONS: Our focus should move from end-stage wasting to supporting patients' nutritional and functional state throughout the increasingly complex and prolonged course of anti-cancer treatment. When inadequate nutrient intake predominates (malnutrition), this can be managed by conventional nutritional support. In the presence of systemic inflammation/altered metabolism (cachexia), a multi-modal approach including novel therapeutic agents is required. For all patients, oncologists should consider three supportive care issues: ensuring sufficient energy and protein intake, maintaining physical activity to maintain muscle mass and (if present) reducing systemic inflammation. The results of phase II/III trials based on novel drug targets (e.g. cytokines, ghrelin receptor, androgen receptor, myostatin) are expected in the next 2 years. If effective therapies emerge, early detection of malnutrition and cachexia will be increasingly important in the hope that timely intervention can improve both patient-centered and oncology outcomes.

fMRI visualization of transient activations in the rat olfactory bulb using short odor stimulations.

Odor-evoked activity in the olfactory bulb displays both spatial and temporal organization. The difficulty when assessing spatio-temporal dynamics of olfactory representation is to find a method that reconciles the appropriate resolution for both dimensions. Imaging methods based on optical recordings can reach high temporal and spatial resolution but are limited to the observation of the accessible dorsal surface. Functional magnetic resonance imaging (fMRI) may be useful to overcome this limitation as it allows recording from the whole brain. In this study, we combined ultra fast imaging sequence and short stimulus duration to improve temporal resolution of odor-evoked BOLD responses. Short odor stimulations evoked high amplitude BOLD responses and patterns of activation were similar to those obtained in previous studies using longer stimulations. Moreover, short odor exposures prevented habituation processes. Analysis of the BOLD signal time course in the different areas of activation revealed that odorant response maps are not static entities but rather are temporally dynamic as reported by recent studies using optical imaging. These data demonstrated that fMRI is a non-invasive method which could represent a powerful tool to study not only the spatial dimension of odor representation but also the temporal dimension of information processing.

Extensive immunolesions of basal forebrain cholinergic system impair offspring recognition in sheep.

The involvement of the basal forebrain cholinergic system has been extensively investigated in instrumental learning but little is known of its participation in social memory, especially in the memorization of individual traits of a conspecific. The present study tested in sheep its contribution to both instrumental learning and individual offspring recognition. Six weeks before parturition, ewes received injections of a specific cholinergic immunotoxin (ME20.4 IgG-saporin) into the lateral ventricles (150 microg) and in some cases additional immunotoxin injections into the nucleus basalis (11 microg/side). After 3 weeks of recovery, ewes were trained on a classical instrumental visual discrimination task known to be sensitive to cholinergic deficits. The formation of memory of offspring was assessed through both olfactory and visual/auditory recognition tasks. Olfactory recognition was tested by presenting at suckling successively an alien and the familiar lamb at 2 and 4 h after parturition. Visual/auditory recognition of the lamb was performed using a non-olfactory discrimination test between the familiar and an alien lamb after 12 h of mother-young contact. The lesion extent was assessed by counting choline acetyltransferase-immunopositive neurons in the basal forebrain and measuring the density of acetylcholinesterase fibers in different target areas. Results showed that immunotoxic lesions delayed acquisition of the instrumental visual discrimination. Moreover, olfactory recognition of the lamb was severely impaired while visual/auditory lamb recognition was marginally altered. There was no evidence for sensorimotor or motivational deficits. Importantly, impairment was observed in animals for which loss of basal forebrain cholinergic neurons and their efferent fibers was higher than 75%, while striatal cholinergic neurons and Purkinje cells were unaffected. This study provides evidence that the basal forebrain cholinergic system contributes not only to instrumental but also to social learning. In addition, the cholinergic modulation seems of importance for processing visual and olfactory modalities. However, since only extensive lesions affect performance, this indicates that the basal forebrain cholinergic system possesses substantial reserve capacity to sustain cognitive functions.

Exposure to behaviourally relevant odour reveals differential characteristics in rat central olfactory pathways as studied through oscillatory activities.

This study investigated how changes in nutritional motivation modulate odour-related oscillatory activities at several levels of the olfactory pathway in non-trained rats. Local field potential recordings were obtained in freely moving animals in the olfactory bulb (OB), anterior and posterior parts of the piriform cortex (APC and PPC respectively) and lateral entorhinal cortex (EC). Dynamic signal analysis detected changes in power during odour presentation for several frequency bands The results showed that in most cases odour presentation was associated with changes in a wide 15-90 Hz frequency band of activity in each olfactory structure. However, nutritional state modulated initial responses to food odour (FO) in the OB and EC selectively in the 15-30 Hz frequency band. Changes in nutritional state also modulated responses to repeated FO stimuli. Habituation was expressed differentially across structures with a clear dissociation between the two parts of the piriform cortex. Finally, systemic injections of scopolamine (0.125 mg/kg) selectively blocked expression of the nutritional modulation in the OB found in the beta band. These results suggest that internal state can differentially modulate odour processing among different olfactory areas and point to a cholinergic-sensitive beta band oscillation during presentation of a behaviourally meaningful odorant.

Functional coupling in rat central olfactory pathways: a coherence analysis.

This experiment determined the importance of functional coupling between structures of central olfactory pathways: the olfactory bulb (OB), anterior (APC), posterior (PPC) parts of the piriform cortex and lateral entorhinal cortex (EC). From local field potential signals obtained in awake rats, coupling during spontaneous activity was estimated with variables reflecting level of coherence computed with a dynamical method. Results revealed a clear hierarchy in the strength of coupling between structures with dissociation within the piriform cortex: PPC was more tightly coupled with the EC than with APC. Systemic injection of a cholinergic antagonist, scopolamine, suggested that tonic coupling is strongly mediated by cortico-cortical connections and not by an external synchronizer, except between OB and APC.

Spatiotemporal distribution of a late synchronized activity in olfactory pathways following stimulation of the olfactory bulb in rats.

The evoked potential recorded in the rat piriform cortex in response to electrical stimulation of the olfactory bulb is composed of an early component occasionally followed by a late component (60-70 ms). We previously showed that the late component occurrence was enhanced following an olfactory learning. In the present study carried out in naive rats, we investigated the precise conditions of induction of this late component, and its spatiotemporal distribution along the olfactory pathways. In the anaesthetized rat, a stimulating electrode was implanted in the olfactory bulb. Four recording electrodes were positioned, respectively, in the olfactory bulb, the anterior and posterior parts of the piriform cortex, and the entorhinal cortex. Simultaneous recording of signals evoked in the four sampled structures in response to stimulation of the olfactory bulb revealed that the late component was detected in anterior and posterior piriform cortex as well as in entorhinal cortex, but not in the olfactory bulb. The late component occurred reliably for a narrow range of low intensities of stimulation delivered at frequencies not exceeding 1 Hz. Comparison of late component amplitude and latency across the different recorded sites showed that this component appeared first and with the greatest amplitude in the posterior piriform cortex. In addition to showing a functional dissociation between anterior and posterior parts of the piriform cortex, these data suggest that the posterior piriform cortex could be the locus of generation of this late high amplitude synchronized activity, which would then propagate to the neighbouring regions.

Scopolamine impairs the ability of parturient ewes to learn to recognise their lambs.

Within a 4-h period after parturition, the ewe learns the odor of her lamb that will later allow recognition of her offspring from an alien lamb. This study investigated the involvement of the cholinergic system in this olfactory learning. At parturition and 2 h later, ewes received IM injections of saline (C group, n = 21), scopolamine methylbromide (METSCOP group, 100 micrograms/kg, n = 14) a peripherally acting muscarinic antagonist, a low dose of scopolamine hydrobromide (SCOP32 group, 32 micrograms/kg, n = 15) or a higher dose of scopolamine hydrobromide (SCOP100 group, 100 micrograms/kg, n = 18). Maternal behavior was observed at parturition and selective behavior was tested after 4 h of mother-young contact. No differences in maternal behavior at parturition were found between groups. By contrast, the proportion of ewes showing selectivity was significantly lower in the SCOP100 group (7/18) than in the METSCOP group (12/14, P = 0.01), SCOP32 group (12/15, P = 0.03), or C group (17/21, P = 0.01). In addition, saline-treated ewes, after having established their selective bond, received 100 micrograms/kg scopolamine and were again tested for selectivity 20 min later. Only one out of the 17 tested ewes failed to recognize their lambs after this treatment. These results indicate that intact central muscarinic transmission of the brain is required for the learning of individual lamb odor at parturition but not for the recall of this information.

A study of the effects of noradrenaline in the rat olfactory bulb using evoked field potential response.

In the rat, the main olfactory bulb receives a strong noradrenergic (NA) input from the locus coeruleus which is critical for different types of olfactory learning. However, the resulting effect of NA modulation on on the olfactory bulb electrical activity and its pharmacology are not well understood. In this study, we investigated the action of NA on the bulbar neuronal population using evoked field potentials (EFP) elicited antidromically in the olfactory bulb of anesthetized rats, by stimulation of the lateral olfactory tract (LOT). EFPs in response to single and paired-pulse stimulation of the LOT were collected before, during and until 2 h after a 10 min perfusion of pharmacological agents through a push-pull cannula. Four concentrations of NA were tested ranging from 10(-5) M to 10(-2) M. NA induced a reversible dose-dependent effect. The major effect was observed at 10(-3) M. It consisted of an increase in Component 2 amplitude (depolarization of granules cell dendrites) and a decrease in Component 3 amplitude (depolarization of granule cell bodies). In parallel, paired-pulse inhibition of mitral cells by granule cells was increased. The alpha 1 agonist phenylephrine (10(-3) M) mimicked most of the effects of NA whereas the alpha 1 antagonist prazosin (10(-3) M) blocked its main action. Isoproterenol (beta agonist, 10(-3) M) and clonidine (alpha 2 agonist, 10(-3) M) could not reproduce the effects of NA. Thus mainly through the activation of alpha 1 receptors, NA enhances synaptic activation of granule cells and increases feed-back inhibition of mitral cells. Consequences of such effects in the context of learning and memory are discussed.

Scopolamine injection into the olfactory bulb impairs short-term olfactory memory in rats.

A previous experiment showed that systemic administration of the muscarinic antagonist scopolamine altered delayed matching in an olfactory task in rats. The present experiment tested whether the impairment could result from blockade of the cholinergic transmission in the first relay structure of the olfactory system, the olfactory bulb. Drug was infused directly into both olfactory bulbs before test sessions. Results showed that the intrabulbar infusion reproduced the effect of the systemic administration. With a 4-s delay between target odor and choice test, performances of treated rats remained unchanged; but with a 30-s delay, rats performed randomly. Results from a complementary electrophysiological experiment in anesthetized rats support the idea that scopolamine injected into the olfactory bulb was unlikely to have reached more central structures. Further evidence for the involvement of pure sensory areas in short-term memory is concluded.

Scopolamine impairs delayed matching in an olfactory task in rats.

The action of the cerebral cholinergic system seems to be important for remembering events over short time intervals. We decided to test this hypothesis in the rat by developing an original model of short term memory based on the olfactory sensory modality which is a major determinant in the animal behaviour. The principle of the experiment was a "delayed match-to-sample" test performed in a classical T maze divided into two compartments. In the first compartment, rats received an odorant stimulation, then, in the second, they had to discriminate between the two arms odorized differently. To receive a food reinforcement, the animals had to enter the arm signaled by the odor presented in the first part of the maze. The test was performed with (Short-term memory condition) or without (Immediate memory condition) a variable delay between the first odor sampling and the discrimination task. Both tests were performed with control and scopolamine-treated animals (0.5, 0.125 and 0.0625 mg/kg IP). An injection of scopolamine (0.5 mg/kg) impaired performances, even when no retention of the odor was required. However, lower doses (0.125, 0.0625 mg/kg) selectively altered performances in the short term memory condition. These results suggest that intact muscarinic transmission is required for an olfactory cue to be used over a short time after its presentation.

Cholinergic modulation of excitability in the rat olfactory bulb: effect of local application of cholinergic agents on evoked field potentials.

The effect of exogenously applied cholinergic agents upon mitral-granule cell complex activity of the olfactory bulb was studied in anesthetized rats. Output neurons were activated by electrical paired-pulse stimulation (40-80 ms time interval) applied either to the olfactory nerve (orthodromic stimulation) or to the lateral olfactory tract (antidromic stimulation). Evoked field potentials were recorded in the granule cell layer. Cholinergic agents were introduced close to the mitral cell body layer through a push-pull cannula. With both orthodromic and antidromic stimulations, acetylcholine in the presence of eserine (an acetylcholinesterase blocker), did not alter the conditioning volley, while it induced a significant increase in the amplitude of the test volley. This effect could be replicated using the cholinergic agonist carbachol. This attenuation of the paired-pulse inhibition is due to a reduction of the dendrodendritic inhibitory action of granule cells upon relay cells. Muscarinic and nicotinic transmission were studied using antidromic and orthodromic stimulations, respectively. The selective effect of acetylcholine on the test volley was totally abolished by the blockade of the muscarinic transmission (by atropine). The blockade of the GABAergic transmission (by picrotoxin), could also prevent the acetylcholine-induced effect. The results lead us to propose that in deep bulbar layers, acetylcholine may activate muscarinic receptors situated on second-order GABAergic interneurons. These interneurons could in turn inhibit granule cells (first-order interneurons). The nicotinic antagonist d-tubocurarine selectively enhanced the duration of the late component and did not appear to modify early components when stimulation was applied to the olfactory nerve. This effect related to both the conditioning and the test volleys and the enhancement in the duration of depolarization of granule cell dendrites suggests that normal activation of nicotinic receptors contributes to a faster repolarization of granule cells. Since nicotinic receptors belong to the outer glomerular layer, this result points to the existence of interneurons belonging to the periglomerular region where they receive nicotinic input and project to deep layers where they modulate granule cell activity. Taken together, our results suggest the presence of a phasic muscarinic and a tonic nicotinic modulation of bulbar interneuronal activity. Since both could finally reduce the inhibitory action of granule cells, the action of cholinergic afferents would facilitate transmission of bulbar output neurons to central structures.

Respiratory patterning of the rat olfactory bulb unit activity: nasal versus tracheal breathing.

To assess the role of nasal/tracheal (N/T) breathing in the respiratory patterning of the olfactory bulb (OB) neurons, the activity of 21 units was recorded in 6 anesthetized rats set with a cannula enabling reversible tracheotomy: the rats could inhalate either through nasal pathways or through trachea directly. Shift from tracheal to nasal breathing induced respiratory patterning in 7 units. The changes were steady, reversible and reproducible. The present data, matched with previous ones, indicate that tracheotomy and anesthesia decrease the occurrence of respiratory patterning in OB neurons. The experiments also suggest that peripheral as well as central structures may be a source of respiratory modulation in the olfactory bulb.

The effect of acetylcholine on rat olfactory bulb unit activity.

The olfactory bulb (OB) of the rat receives an extrinsic innervation from the most anterior part of the basal forebrain cholinergic complex. The effect of microiontophoretically applied acetylcholine (ACh) on OB unit activity was studied in 16 adult male rats. A total of 80 units was recorded and in 50% of the cases the cell layer where the recording was done was clearly identified. The results provide evidence for a particularly high level of sensitivity to ACh in the outer glomerular layer (73%). Both inhibitory and excitatory responses were found. These results are in agreement with histological studies indicating that this layer presents the highest density of cholinergic terminals. As a whole, present knowledge suggests the existence of a strong cholinergic control of the olfactory input at the level of the first synapse in the system.

Topography of centrifugal acetylcholinesterase-positive fibres in the olfactory bulb of the rat: evidence for original projections in atypical glomeruli.

An original pathway of centrifugal acetylcholinesterase-positive fibres is described in the olfactory bulb of the rat. A dense network of positive fibres spreads out superficially at the boundaries of the lateral olfactory tract and the glomerular layer. These labelled fibres converge towards atypical glomerular structures lying close to the classical olfactory glomeruli. The atypical glomeruli are located dorsally at the medial border of the accessory olfactory bulb, in the area previously described as the "modified glomerular complex", and in the ventrolateral bulbar area. They structurally differ from typical glomeruli, as suggested by observations on semithin sections. The ultrastructural distribution of acetylcholinesterases into axonal and dendritic profiles, around and inside atypical glomeruli, is consistent with the hypothesis of centrifugal modulatory influences at this level. This study illustrates several new aspects of morphofunctional heterogeneity in the olfactory system. The glomerular layer of the main olfactory bulb can no longer be considered as morphologically and functionally uniform. Atypical glomeruli located in the mediodorsal and the ventrolateral boundaries of the glomerular layer are characterized by both structural features and an uncommonly high convergence of acetylcholinesterase-positive centrifugal fibres. Such areas might be involved in the processing of specific olfactory signals as demonstrated elsewhere for the "modified glomerular complex".

A centrifugal respiratory modulation of olfactory bulb unit activity: a study on acute rat preparation.

In behaving rats, unit activity in the mitral and granule cell layers of the olfactory bulb (OB) can be modulated by respiration. In order to determine whether central influences could take part in this phenomenon, respiratory rhythm and the activity of OB units were recorded in the present experiment and analyzed temporally in 18 anaesthetized tracheotomized rats. In spite of the interrupted nasal airflow, 30 of the 80 cells recorded in the mitral and granule cell layers, still displayed a significant respiratory patterning of their activity. Maximal neuronal discharges were time-locked with different phases of the respiratory cycle, most often synchronized with the end of expiration. This is in contrast with previous observations in intact animals. Possible underlying mechanisms are discussed.