Impact of deep brain stimulation (DBS) on olfaction in Parkinson's disease: Clinical features and functional hypotheses.

Deep brain stimulation (DBS) is a surgical therapy typically applied in Parkinson's disease (PD). The efficacity of DBS on the control of motor symptoms in PD is well grounded while the efficacity on non-motor symptoms is more controversial, especially on olfactory disorders (ODs). The present review shows that DBS does not improve hyposmia but can affect positively identification/discrimination scores in PD. The functional hypotheses suggest complex mechanisms in terms of cerebral connectivity and neurogenesis process which could act indirectly on the olfactory bulb and olfactory pathways related to specific cognitive olfactory tasks. The functional hypotheses also suggest complex mechanisms of cholinergic neurotransmitter interactions involved in these pathways. Finally, the impact of DBS on general cognitive functions in PD could also be beneficial to identification/discrimination tasks in PD.

Characterization of novel human intragenic antimicrobial peptides, incorporation and release studies from ureasil-polyether hybrid matrix.

Intragenic antimicrobial peptides (IAPs) are internal sequences of proteins with physicochemical similarities to Antimicrobial Peptides (AMPs) that, once identified and synthesized as individual entities, present antimicrobial activity. Many mature proteins encoded by the genomes of virtually any organism may be regarded as inner reservoirs of IAPs, conferring them ample biotechnological potential. However, IAPs may also share shortcomings with AMPs, such as low half-life in biological media and non-specific adsorption in eukaryotic cells. The present manuscript reports a translational approach that encompasses the uncovering of two novel IAPs from human proteins as well as the first results concerning the incorporation and sustained release of one of these peptides from ureasil-polyether hybrid polymeric films. For such, the software Kamal was used to scan putative IAPs in the human proteome, and two peptides, named Hs05 and Hs06, were identified, synthesized, and tested as antimicrobials. Biophysical assays were conducted using model phospholipid vesicles and 1H NMR solution structures in phospholipid micelles were obtained for the IAP Hs05. This peptide was incorporated in a polymeric matrix composed of the ureasil/PPO-PEO-PPO triblock copolymer, and the resulting films were evaluated by atomic force microscopy and imaging mass spectrometry. The release rate of Hs05 from the polymeric matrix was assessed and the antimicrobial activity of Hs05-loaded hybrid polymeric films was evaluated against the bacterium Escherichia coli. This study represents the first steps towards the development of polymeric films enriched with IAPs obtained from the human proteome as sustained release devices for topical application.

Relative quantification of plasma N-glycans in type II congenital disorder of glycosylation patients by mass spectrometry.

BACKGROUND: Type II Congenital Disorders of Glycosylation (CDG-II) are a group of diseases with challenging diagnostics characterized by defects in the processing of glycans in the Golgi apparatus. Mass Spectrometry (MS) has been a valuable tool in the definition of CDG-II subtypes. While some CDG-II subtypes are associated with specific N-glycan structures, others only produce changes in relative levels, reinforcing the demand for quantification methods. METHODS: Plasma samples from control individuals were pooled, derivatized with deuterated iodomethane (I-CD3), and used as internal standards for controls and patients whose glycans were derivatized with iodomethane (I-CH3), followed by MALDI MS, LC-MS and -MS/MS analyses. RESULTS: Total N-glycans from fifteen CDG-II patients were evaluated, and 4 cases with molecular diagnosis were considered in detail: 2ATP6V0A2-CDG siblings, and 2 MAN1B1-CDG patients, one of them carrying a previously undescribed p.Gly536Val mutation. CONCLUSIONS: Our methodology offers a feasible alternative to the current methods for CDG-II diagnosis by MS, which quantify glycan structures as fractions of the total summed signal across a mass spectrum, a strategy that lowers the variability of minor components. Moreover, given its sensitivity for less concentrated yet biologically relevant structures, it might assist the uncovering of novel diagnostic glycans in other CDG-II subtypes.

Sustainable intensification through rotations with grain legumes in Sub-Saharan Africa: A review.

We conducted a systematic review of literature on the residual effects of grain legumes in cereal-based systems of sub-Saharan Africa (SSA) to quantify the magnitude and variability of rotational effects, to explore the importance of environmental and management factors in determining variability and to evaluate the evidence of the different mechanisms that explain rotational effects. We retrieved 44 unique publications providing 199 observations comparing continuous cereal performance with that of a grain legume-cereal rotation. The overall mean yield increase of 0.49 t grain ha-1, equal to an increase of 41% of the continuous cereal yield, is highly significant, but the variability in residual effects is large. Effects were more pronounced in southern Africa, the highlands of East Africa and the Guinea savannah, and less in the humid forest/derived savannah of West Africa and the Sudano-Sahelian zone. Maize showed stronger yield responses after a legume than millet and sorghum. Agro-ecological zone and cereal type were however confounded. All grain legume types significantly improved cereal yields, with stronger residual effects observed after soybean and groundnut than after cowpea. Fertiliser N application to cereals reduces the residual effects of legumes, but the response at 60-120 kg N ha-1 still equalled 0.32 t ha-1 or 59% of the response when no N is applied. The sustained benefits with large N applications indicate the importance of non-N effects. While mechanisms for improved soil P availability after grain legumes have been studied in some detail, it remains uncertain how important these are in farmers' fields. Grain legumes are unlikely to have a major influence on the availability of nutrients other than N and P, or on soil pH. Beneficial impacts of grain legumes on soil organic matter content can occur if legumes contribute to a greater overall cropping productivity, but studies generally report no such impacts. Evidence of impacts of grain legumes on weeds is limited to striga. Studies on the impacts on nematode pressure in cereals are inconclusive, probably because legumes act as a host for some of the key nematode genera that harm maize. The impact on the pressure of other pests and diseases in cereals is probably important, but evidence on this from SSA is lacking. Future research on N2-fixation by grain legumes and residual N benefits should focus on explaining the wide variability observed among sites. There is a clear need for more detailed mechanistic studies to assess the occurrence and relevance of non-N effects of grain legumes, particularly in relation to common pests and diseases in cereals.

Towards an experimental classification system for membrane active peptides.

Mature proteins can act as potential sources of encrypted bioactive peptides that, once released from their parent proteins, might interact with diverse biomolecular targets. In recent work we introduced a systematic methodology to uncover encrypted intragenic antimicrobial peptides (IAPs) within large protein sequence libraries. Given that such peptides may interact with membranes in different ways, resulting in distinct observable outcomes, it is desirable to develop a predictive methodology to categorize membrane active peptides and establish a link to their physicochemical properties. Building upon previous work, we explored the interaction of a range of IAPs with model membranes probed by differential scanning calorimetry (DSC) and circular dichroism (CD) techniques. The biophysical data were submitted to multivariate statistical methods and resulting peptide clusters were correlated to peptide structure and to their antimicrobial activity. A re-evaluation of the physicochemical properties of the peptides was conducted based on peptide cluster memberships. Our data indicate that membranolytic peptides produce characteristic thermal transition (DSC) profiles in model vesicles and that this can be used to categorize novel molecules with unknown biological activity. Incremental expansion of the model presented here might result in a unified experimental framework for the prediction of novel classes of membrane active peptides.

Encrypted Antimicrobial Peptides from Plant Proteins.

Examples of bioactive peptides derived from internal sequences of proteins are known for decades. The great majority of these findings appear to be fortuitous rather than the result of a deliberate and methodological-based enterprise. In the present work, we describe the identification and the biological activities of novel antimicrobial peptides unveiled as internal fragments of various plant proteins founded on our hypothesis-driven search strategy. All putative encrypted antimicrobial peptides were selected based upon their physicochemical properties that were iteratively selected by an in-house computer program named Kamal. The selected peptides were chemically synthesized and evaluated for their interaction with model membranes. Sixteen of these peptides showed antimicrobial activity against human and/or plant pathogens, some with a wide spectrum of activity presenting similar or superior inhibition efficacy when compared to classical antimicrobial peptides (AMPs). These original and previously unforeseen molecules constitute a broader and undisputable set of evidences produced by our group that illustrate how the intragenic concept is a workable reality and should be carefully explored not only for microbicidal agents but also for many other biological functions.

Oligomerization affects the kinetics and thermodynamics of the interaction of a Bowman-Birk inhibitor with proteases.

The black-eyed pea trypsin/chymotrypsin inhibitor (BTCI) forms concentration dependent homomultimers, as previously demonstrated by Light scattering and Atomic Force Microscopy. Considering that these self-aggregates might influence their binding to cognate enzymes, we investigated the interaction of BTCI at picomolar concentrations using surface immobilized Chymotrypsin (α-CT) and Trypsin (T) by Surface Plasmon Resonance. Our results indicate that BTCI has subnanomolar affinity to both immobilized enzymes, which is approximately two orders of magnitude higher than previously reported. Moreover, we probed the influence of temperature on protein binding equilibria in order to investigate their interaction energetics. While the BTCI/T interaction concurs with the canonical entropy-driven mechanism described for BBI interactions with serine proteinases, the BTCI/α-CT interaction does not. Our measurements indicate that bimolecular BTCI/α-CT complexes form with a negative enthalpy change and a moderate entropic increase. Direct calorimetric evaluation is in accord with the van't Hoff approximation obtained by SPR. We demonstrate that as protein concentrations increase to the micromolar range, secondary endothermic events become prevalent and affect both the kinetics and thermodynamics of protein associations. Our study reinforces that BBI interactions with serine proteinases should be studied in dilute solutions to abridge often neglected secondary interactions.

[Olfaction in depressive disorders: Issues and perspectives]. / L'olfaction dans les troubles dépressifs : intérêts et perspectives.

Research on sensorial interactions with psychiatric diseases and particularly with the depressive syndrome has mainly focused on visual or auditory processes and much less on olfaction. The depressive illness is one of the most frequent psychiatric diagnoses in the community, with approximately one in five women and one in eight men experiencing a major depressive episode during their lifetime. Although genetic, epigenetic, neuroanatomical, neurochemical, neuroendocrinological and neuroimmunological changes can be detected during depression, the etiology of depression remains partly unclear. The current explanatory models are based on two main factors, i.e. pharmacological dysfunctions and stress effects. In this way and because of strong connections between olfactory pathways and cerebral areas implied in mood regulation and emotions (i.e. the limbic system and prefrontal areas), the interactions between olfaction and depression could constitute a relevant way of research at three different levels. First, olfactory dysfunction observed in depression could serve the diagnosis and contribute to a better understanding of mechanisms implied in thymic pathologies. Published papers show a decrease of olfactory sensitivity in major depression which does not occur in bipolar or saisonal depression. Second, it has been shown that olfactory deficits could induce depressive symptoms. In this context, an animal model (olfactory bulbectomized rat) reinforces the hypothesis of the important role of olfaction in depression based on neuroanatomical and neurochemical observations. Third, several publications have demonstrated that odors can positively impact the depressive mood. Thus, a remediation by odors in depression appears to be a promising way. From several decades, the olfaction/depression interactions have been covered by a broad literature. Thus, the present review will not propose an exhaustive examination but aims to point out the most recently published papers and highlight their contributions to the understanding of olfactory processes implied in depression.

Impact of olfactory and auditory priming on the attraction to foods with high energy density.

\]\Recent research suggests that non-attentively perceived stimuli may significantly influence consumers' food choices. The main objective of the present study was to determine whether an olfactory prime (a sweet-fatty odour) and a semantic auditory prime (a nutritional prevention message), both presented incidentally, either alone or in combination can influence subsequent food choices. The experiment included 147 participants who were assigned to four different conditions: a control condition, a scented condition, an auditory condition or an auditory-scented condition. All participants remained in the waiting room during15 min while they performed a 'lure' task. For the scented condition, the participants were unobtrusively exposed to a 'pain au chocolat' odour. Those in the auditory condition were exposed to an audiotape including radio podcasts and a nutritional message. A third group of participants was exposed to both olfactory and auditory stimuli simultaneously. In the control condition, no stimulation was given. Following this waiting period, all participants moved into a non-odorised test room where they were asked to choose, from dishes served buffet-style, the starter, main course and dessert that they would actually eat for lunch. The results showed that the participants primed with the odour of 'pain au chocolat' tended to choose more desserts with high energy density (i.e., a waffle) than the participants in the control condition (p = 0.06). Unexpectedly, the participants primed with the nutritional auditory message chose to consume more desserts with high energy density than the participants in the control condition (p = 0.03). In the last condition (odour and nutritional message), they chose to consume more desserts with high energy density than the participants in the control condition (p = 0.01), and the data reveal an additive effect of the two primes.

Effects of pyridine inhalation exposure on olfactory epithelium in mice.

Olfactory neurons in the nasal mucosa have the capacity to regenerate continuously along the lifespan by neurogenesis processes starting with progenitor cells close to the basal lamina. The cellular turnover into olfactory neuroepithelium may be modified by environmental stimuli insofar as nasal mucosa is directly in contact with airborne chemicals. However, few studies have been focused on selective changes, especially those concerning mature olfactory neurons and basal cells during specific inhalation exposure. Among chemicals, solvents are known to induce changes in smell abilities and concomitant histological and cellular modifications related to the type of molecule, concentration and time of exposure. This study was designed to characterize smell sensitivity (using behavioral tests) and immunohistochemical effects on olfactory neuroepithelium induced by pyridine exposure in mice. Olfactory marker protein (OMP) and proliferating cell nuclear antigen (PCNA) were used to characterize respectively mature olfactory neurons and basal cells. Results showed that inhalation exposure to pyridine had no impact on smell sensitivity whatever the concentration used and the time of exposure. These findings were in agreement with immunohistochemical measurements showing the same cellular kinetic whatever the condition of exposition to pyridine. Indeed, OMP-positive cells increased and PCNA-positive cells decreased as early as the beginning of exposure and cell amounts remained stable at this level until the end of exposure. These findings suggest that pyridine could have the property to rapidly activate a cellular turnover from basal cell progenitors. Rather than toxic effects, the present findings suggest that the metabolites of pyridine might have cell cycle activation properties.

Comparison between low doses of TMT and cat odor exposure in anxiety- and fear-related behaviors in mice.

Few comparisons were made between cat odor and synthetic fox odor (TMT) to study fear and anxiety in rodents. TMT is frequently used are at high concentration while the stimulus should be as possible closer to natural conditions. The aim of this work was to compare behavioral responses of mice exposed to cat odor and low doses of TMT (i.e. 10 µl of a solution containing 1%, 0.1% or 0.01% TMT). Behavioral parameters were recorded in elevated plus-maze and in open field. Results showed that 1% TMT and 0.1% TMT induced similar responses to cat odor, contrary to water and 0.01% TMT which failed to elicit fear or anxiety-related behaviors. Additionally, behavioral changes were more marked in EPM - e.g. time spent in open arms - than in open field - e.g. freezing. These findings are discussed in terms of a possible continuum of mild anxiety-like behaviors to strong fear-like behaviors linked to predator odor intensity.

Lateralisation in wine olfactory threshold detection: comparison between experts and novices.

The study of olfactory lateralisation in humans has given rise to many publications, but few studies have been focused on possible differences in relation to the experience towards specific odorants. The aim of the present study was to compare unilateral detection thresholds for three wines between expert and novice judges. Additionally, irritation and hedonic valence were also evaluated using monorhinal stimulations. Results showed that the novices had lower detection thresholds with the left nostril--whatever the wine--compared to the experts. Concerning hedonic rating, no nostril difference existed in the expert group contrary to the novice group, which evaluated wines as more pleasant with the left than with the right nostril. Irritation rating appeared not to be lateralised in both groups. However, the novices rated the three wines as more irritant than the experts with the right as well as with the left nostril. These findings suggest that the level of experience induced specific differences in terms of lateralisation between wine experts and novices.

Postnatal exposure to predator odor (TMT) enhances spatial learning in mice adulthood.

Adult behavioral and physiological responses are partly dependent on neonatal experiences. In several animal species, enriched/aprovished environments and stressful/appeasing events are crucial in the setting of adaptative behaviors. However, little is known about the effects of postnatal exposure to predator odor (as unconditioned fear-related stimulus) on spatial learning at adulthood. Thus, the aim of the present study was to investigate the effects of a postnatal exposure to 2,4,5-trimethylthiazoline (TMT, as a predator odor) on radial arm maze (RAM), Tolman maze (TM) and Morris water maze (MWM) in mice at adulthood. The results showed that a TMT group constituted by mice exposed postnatally during 3 weeks to TMT presented significantly better spatial learning achievements in adulthood compared to a water group, postnatally exposed to water only, as well as compared to a butanol group (butanol used as an odor without ecological significance) exposed postnatally to butanol during 3 weeks.

Just noticeable difference in olfaction: a discriminative tool between healthy elderly and patients with cognitive disorders associated with dementia.

Olfactory dysfunction appears to be one of the earliest signs of several age-related neurodegenerative disorders, including Alzheimer`s disease (AD) or Parkinson`s disease (PD). To rate performance and olfactory deficits in patients with cognitive disorders, various olfactory tasks have been used such as odor detection, discrimination, recognition memory, identification and naming but no study has been focused on just noticeable difference (JND), a sensitive tool of detection. The aim of this study was to investigate and compare variations in JNDs in healthy elderly and in patients with cognitive disorders associated with dementia. The results showed significantly higher olfactory JNDs in a population with cognitive disorders associated with dementia - i.e. a lower olfactory detection performance - compared to a control population paired in age, gender and education level. Additionally, the findings of the present study showed strong correlations between cognitive performances and JND scores in the control population contrary to the patient population. These findings are discussed in relation to the relevance of using olfactory JNDs in the diagnosis of dementias.

Just noticeable difference in olfaction is related to trigeminal component of odorants.

Many studies have dealt with the interrelationships between both olfactory and trigeminal systems but a poorly explored question concerns the role of each system in the detection processes, especially in the just noticeable difference (JND). The aim of this study was to investigate variations in JNDs for three odorants in relation to their trigeminal component, i.e. low, middle, high. The results indicated that the higher the trigeminal component, the lower the JND, suggesting a better capacity to perceive intensity changes for pungent odorants than for relatively pure odorants.

Postnatal exposure to synthetic predator odor (TMT) induces quantitative modification in fear-related behaviors during adulthood without change in corticosterone levels.

Environmental stimuli and adverse experiences in early life may result in behavioral and physiological changes in adulthood. In several animal species, the odors cues are crucial in the setting of adaptive behaviors, especially towards predators. However, little is known about the effects of postnatal exposure to predator odor on the later physiological and behavioral responses to this natural stressor. Thus, the aim of this study was to investigate the effects of a postnatal exposure to synthetic predator odor (TMT) in mice pups on later adult fear-related behaviors and corticosterone levels in response to this specific stimulus. Pups postnatally exposed to only water showed later in adult life behavioral responses when exposed to TMT that were statistically different from mice that were exposed as neonates to TMT. In addition, mice exposed as neonates to TMT showed a decrease of fear-related behaviors while no differences occurred in the corticosterone levels between both groups.

Peripheral and central levels in nasal trigeminal sensitization and desensitization.

In order to investigate the role of central and peripheral mechanisms in nasal trigeminal sensitization/desensitization processes, the present work recorded psychophysical (intensity ratings) and psychophysiological (skin conductance) responses to allyl isothiocyanate volatile nasal stimulation--during normal breathing--in monorhinal condition after a controlateral stimulation of the other nostril. Insofar as both nostrils are anatomically separated, modifications in responses can be interpreted as a central regulation process. Results showed that sensitization was clearly related to central mechanisms contrarily to desensitization which depended only of peripheral level.

Carbon dioxide effects on olfactory functioning: behavioral, histological and immunohistochemical measurements.

Most studies on toxic inhalation focus on solvent effects and few have dealt with gases on olfactory functioning. Among gases, the effects of carbon dioxide on general physiology have been well investigated contrary to the impact on olfactory neuroepithelium. Thus, this work was designed to evaluate in mice the possible effects of 3% CO(2) in two exposure periods: a 5h/day and a 12h/day conditions. Behavioral, histological and immunohistochemical observations were conducted every 2 weeks, i.e. before (W0), during (W2, W4) and after exposure (W6, W8). Firstly, behavioral evaluations of odor sensitivity showed differences in relation to the odor tested, i.e. no effect with congener urine odor and a reinforcement of 2,4,5-trimethythiazoline (TMT) (predator odor) repulsion. Secondly, histological evaluations showed a similar evolution of the epithelium thickness, i.e. a decrease along the exposure as well as during the post-exposure period and an increase of cell number (whatever the phenotype) although the kinetic appeared different in both experimental conditions. Thirdly, immunohistochemical quantification of olfactory marker protein (OMP)- and proliferating cell nuclear antigen (PCNA)-positive cells revealed that the number of mature olfactory neurons increased at the early beginning of exposure period in both conditions. While a decrease was observed in the following weeks (W4-W8) for the 12h/day condition, a stable amount of OMP-positive cells was maintained in the 5h/day condition. In contrast, the number of PCNA-positive cells followed a similar evolution, i.e. a constant decrease along the experiment. These findings indicate that the effects of CO(2) inhalation exposure are selectively dose-dependent.

Inhalation exposure to acetone induces selective damage on olfactory neuroepithelium in mice.

Due to their specific position in the nasal cavity, the cells of olfactory neuroepithelium can be damaged by exposure to environmental airborne chemicals. However, few studies have been focused on selective damage, i.e. olfactory sensory neurons, basal cells, supporting and duct cells. As solvents are known to induce critical effects on olfactory neuroepithelium (OE), this study was designed to characterize histological and immunohistological effects induced by acetone exposure on OE in mice. Behavioral tests were conducted to evaluate olfactory sensitivity. Moreover, olfactory neuroepithelium was examined to evaluate the thickness and the total number of cells. Finally, different markers, olfactory marker protein (OMP) and proliferating cell nuclear antigen (PCNA), were used to characterize respectively olfactory sensory neurons and basal cells, and secondly to evaluate the dynamic of the tissue turnover. Results showed structural modifications, since the thickness and the number of cells in the OE were modified according to the time course of the exposure. Additionally, no changes for OMP-positive cells were observed whereas significant differences appeared for the density of PCNA-positive cells in relation to their location (main-body or basal layer of OE). These findings indicate that acetone exposure induces selective damage in olfactory neuroepithelium.

Regression of aortic valve stenosis by ApoA-I mimetic peptide infusions in rabbits.

BACKGROUND AND PURPOSE: Aortic valve stenosis (AVS) is the most common valvular heart disease, and standard curative therapy remains open heart surgical valve replacement. The aim of our experimental study was to determine if apolipoprotein A-I (ApoA-I) mimetic peptide infusions could induce regression of AVS. EXPERIMENTAL APPROACH: Fifteen New Zealand White male rabbits received a cholesterol-enriched diet and vitamin D(2) until significant AVS was detected by echocardiography. The enriched diet was then stopped to mimic cholesterol-lowering therapy and animals were allocated randomly to receive saline (control group, n=8) or an ApoA-I mimetic peptide (treated group, n=7), three times per week for 2 weeks. Serial echocardiograms and post mortem valve histology were performed. KEY RESULTS: Aortic valve area increased significantly by 25% in the treated group after 14 days of treatment (P=0.012). Likewise, aortic valve thickness decreased by 21% in the treated group, whereas it was unchanged in controls (P=0.0006). Histological analysis revealed that the extent of lesions at the base of valve leaflets and sinuses of Valsalva was smaller in the treated group compared with controls (P=0.032). The treatment also reduced calcification, as revealed by the loss of the positive relationship observed in the control group (r=0.87, P=0.004) between calcification area and aortic valve thickness. CONCLUSIONS AND IMPLICATIONS: Infusions of ApoA-I mimetic peptide lead to regression of experimental AVS. These positive results justify the further testing of high-density lipoprotein (HDL)-based therapies in patients with valvular aortic stenosis. Regression of aortic stenosis, if achieved safely, could transform the clinical treatment of this disease.