Daily cycling of nitric oxide synthase (NOS) in the hippocampus of pigeons (C. livia)

Background: Nitric oxide synthase (NOS) is essential for the synthesis of nitric oxide (NO), a non-conventional neurotransmitter with an important role in synaptic plasticity underlying processes of hippocampus-dependent memory and in the regulation of biological clocks and circadian rhythms. Many studies have shown that both the NOS cytosolic protein content and its enzymatic activity present a circadian variation in different regions of the rodent brain, including the hippocampus. The present study investigated the daily variation of NOS enzymatic activity and the cytosolic content of nNOS in the hippocampus of pigeons. Results: Adult pigeons kept under a skeleton photoperiod were assigned to six different groups. Homogenates of the hippocampus obtained at six different times-of-day were used for NOS analyses. Both iNOS activity and nNOS cytosolic protein concentrations were highest during the subjective light phase and lowest in the subjective dark phase of the circadian period. ANOVA showed significant time differences for iNOS enzymatic activity (p < 0.05) and for nNOS protein content (p < 0.05) in the hippocampus. A significant daily rhythm for both iNOS and nNOS was confirmed by analysis with the Cosinor method (p < 0.05). The present findings indicate that the enzymatic activity of iNOS and content of nNOS protein in the hippocampus of pigeons exhibit a daily rhythm, with acrophase values occurring during the behavioral activity phase. Conclusions: The data corroborate the reports on circadian variation of NOS in the mammalian hippocampus and can be considered indicative of a dynamic interaction between hippocampus-dependent processes and circadian clock mechanisms.

The role of wake stiffness on the wake-induced vibration of the downstream cylinder of a tandem pair

When a pair of tandem cylinders is immersed in a flow the downstream cylinder can be excited into wake-induced vibrations (WIV) due to the interaction with vortices coming from the upstream cylinder. Assi, Bearman & Meneghini ( J. Fluid Mech. , vol. 661, 2010, pp. 365–401) concluded that the WIV excitation mechanism has its origin in the unsteady vortex–structure interaction encountered by the cylinder as it oscillates across the wake. In the present paper we investigate how the cylinder responds to that excitation, characterising the amplitude and frequency of response and its dependency on other parameters of the system. We introduce the concept of wake stiffness , a fluid dynamic effect that can be associated, to a first approximation, with a linear spring with stiffness proportional to Re and to the steady lift force occurring for staggered cylinders. By a series of experiments with a cylinder mounted on a base without springs we verify that such wake stiffness is not only strong enough to sustain oscillatory motion, but can also dominate over the structural stiffness of the system. We conclude that while unsteady vortex–structure interactions provide the energy input to sustain the vibrations, it is the wake stiffness phenomenon that defines the character of the WIV response

Design and synthesis of novel non peptidomimtic beta-secretase inhibitors in the treatment of Alzheimer's disease

The aspartic protease BACE1 (β-amyloid precursor protein cleaving enzyme, β-secretase) is recognized as one of the most promising targets in the treatment of Alzheimer's disease (AD). The accumulation of β-amyloid peptide (Aβ) in the brain is a major factor in the pathogenesis of AD. Aβ is formed by initial cleavage of β-amyloid precursor protein (APP) by β-secretase, therefore BACE1 inhibition represents one of the therapeutic approaches to control progression of AD, by preventing the abnormal generation of Aβ. For this reason, in the last decade, many research efforts have focused at the identification of new BACE1 inhibitors as drug candidates. Generally, BACE1 inhibitors are grouped into two families: substrate-based inhibitors, designed as peptidomimetic inhibitors, and non-peptidomimetic ones. The research on non-peptidomimetic small molecules BACE1 inhibitors remains the most interesting approach, since these compounds hold an improved bioavailability after systemic administration, due to a good blood-brain barrier permeability in comparison to peptidomimetic inhibitors. Very recently, our research group discovered a new promising lead compound for the treatment of AD, named lipocrine, a hybrid derivative between lipoic acid and the AChE inhibitor (AChEI) tacrine, characterized by a tetrahydroacridinic moiety. Lipocrine is one of the first compounds able to inhibit the catalytic activity of AChE and AChE-induced amyloid-β aggregation and to protect against reactive oxygen species. Due to this interesting profile, lipocrine was also evaluated for BACE1 inhibitory activity, resulting in a potent lead compound for BACE1 inhibition. Starting from this interesting profile, a series of tetrahydroacridine analogues were synthesised varying the chain length between the two fragments. Moreover, following the approach of combining in a single molecule two different pharmacophores, we designed and synthesised different compounds bearing the moieties of known AChEIs (rivastigmine and caproctamine) coupled with lipoic acid, since it was shown that dithiolane group is an important structural feature of lipocrine for the optimal inhibition of BACE1. All the tetrahydroacridines, rivastigmine and caproctamine-based compounds, were evaluated for BACE1 inhibitory activity in a FRET (fluorescence resonance energy transfer) enzymatic assay (test A). With the aim to enhancing the biological activity of the lead compound, we applied the molecular simplification approach to design and synthesize novel heterocyclic compounds related to lipocrine, in which the tetrahydroacridine moiety was replaced by 4-amino-quinoline or 4-amino-quinazoline rings. All the synthesized compounds were also evaluated in a modified FRET enzymatic assay (test B), changing the fluorescent substrate for enzymatic BACE1 cleavage. This test method guided deep structure-activity relationships for BACE1 inhibition on the most promising quinazoline-based derivatives. By varying the substituent on the 2-position of the quinazoline ring and by replacing the lipoic acid residue in lateral chain with different moieties (i.e. trans-ferulic acid, a known antioxidant molecule), a series of quinazoline derivatives were obtained. In order to confirm inhibitory activity of the most active compounds, they were evaluated with a third FRET assay (test C) which, surprisingly, did not confirm the previous good activity profiles. An evaluation study of kinetic parameters of the three assays revealed that method C is endowed with the best specificity and enzymatic efficiency. Biological evaluation of the modified 2,4-diamino-quinazoline derivatives measured through the method C, allow to obtain a new lead compound bearing the trans-ferulic acid residue coupled to 2,4-diamino-quinazoline core endowed with a good BACE1 inhibitory activity (IC50 = 0.8 mM). We reported on the variability of the results in the three different FRET assays that are known to have some disadvantages in term of interference rates that are strongly dependent on compound properties. The observed results variability could be also ascribed to different enzyme origin, varied substrate and different fluorescent groups. The inhibitors should be tested on a parallel screening in order to have a more reliable data prior to be tested into cellular assay. With this aim, preliminary cellular BACE1 inhibition assay carried out on lipocrine confirmed a good cellular activity profile (EC50 = 3.7 mM) strengthening the idea to find a small molecule non-peptidomimetic compound as BACE1 inhibitor. In conclusion, the present study allowed to identify a new lead compound endowed with BACE1 inhibitory activity in submicromolar range. Further lead optimization to the obtained derivative is needed in order to obtain a more potent and a selective BACE1 inhibitor based on 2,4-diamino-quinazoline scaffold. A side project related to the synthesis of novel enzymatic inhibitors of BACE1 in order to explore the pseudopeptidic transition-state isosteres chemistry was carried out during research stage at Università de Montrèal (Canada) in Hanessian's group. The aim of this work has been the synthesis of the δ-aminocyclohexane carboxylic acid motif with stereochemically defined substitution to incorporating such a constrained core in potential BACE1 inhibitors. This fragment, endowed with reduced peptidic character, is not known in the context of peptidomimetic design. In particular, we envisioned an alternative route based on an organocatalytic asymmetric conjugate addition of nitroalkanes to cyclohexenone in presence of D-proline and trans-2,5-dimethylpiperazine. The enantioenriched obtained 3-(α-nitroalkyl)-cyclohexanones were further functionalized to give the corresponding δ-nitroalkyl cyclohexane carboxylic acids. These intermediates were elaborated to the target structures 3-(α-aminoalkyl)-1-cyclohexane carboxylic acids in a new readily accessible way.

'A Distortion in the mirror of being': verso un modello liquido di personaggio. Da Nabokov alle sperimentazioni contemporanee in ambito slavo

La tesi mira a ridefinire lo statuto del personaggio nell’ambito del self-conscious novel postmoderno, alla luce delle più recenti tendenze narratologiche, con particolare riferimento all’unnatural narratology. Per poter presentare un modello scientificamente valido si è fatto ricorso alla comparazione della produzione letteraria di due macro-aree: quella britannica e quella slava (Russia - Unione Sovietica - e Polonia). Come figura di mediazione tra queste due culture si pone senza dubbio Vladimir V. Nabokov, cardine e personalità di spicco della ricerca. Tra le analisi testuali proposte sono stati presi in considerazione i seguenti autori: Julian Barnes, Vladimir Nabokov, Daniil Charms, Konstantin Vaginov, Andrej Bitov, Saša Sokolov, Bruno Schulz e Tadeusz Kantor.

Towards a new test of time dilation: Laser spectroscopy on lithium ions stored at a velocity of 33.8 % of the speed of light

The subject of the presented thesis is the accurate measurement of time dilation, aiming at a quantitative test of special relativity. By means of laser spectroscopy, the relativistic Doppler shifts of a clock transition in the metastable triplet spectrum of ^7Li^+ are simultaneously measured with and against the direction of motion of the ions. By employing saturation or optical double resonance spectroscopy, the Doppler broadening as caused by the ions' velocity distribution is eliminated. From these shifts both time dilation as well as the ion velocity can be extracted with high accuracy allowing for a test of the predictions of special relativity. A diode laser and a frequency-doubled titanium sapphire laser were set up for antiparallel and parallel excitation of the ions, respectively. To achieve a robust control of the laser frequencies required for the beam times, a redundant system of frequency standards consisting of a rubidium spectrometer, an iodine spectrometer, and a frequency comb was developed. At the experimental section of the ESR, an automated laser beam guiding system for exact control of polarisation, beam profile, and overlap with the ion beam, as well as a fluorescence detection system were built up. During the first experiments, the production, acceleration and lifetime of the metastable ions at the GSI heavy ion facility were investigated for the first time. The characterisation of the ion beam allowed for the first time to measure its velocity directly via the Doppler effect, which resulted in a new improved calibration of the electron cooler. In the following step the first sub-Doppler spectroscopy signals from an ion beam at 33.8 %c could be recorded. The unprecedented accuracy in such experiments allowed to derive a new upper bound for possible higher-order deviations from special relativity. Moreover future measurements with the experimental setup developed in this thesis have the potential to improve the sensitivity to low-order deviations by at least one order of magnitude compared to previous experiments; and will thus lead to a further contribution to the test of the standard model.

Study of the effect of minor compounds on the oxidative stability and physical properties of bulk oil, oil-in-water emulsion, and food emulsions

Minor components are of particular interest due to their antioxidant and biological properties. Various classes of lipophilic minor components (plant sterols (PS) and α-tocopherol) were selected as they are widely used in the food industry. A Fast GC-MS method for PS analysis in functional dairy products was set up. The analytical performance and significant reduction of the analysis time and consumables, demonstrated that Fast GC-MS could be suitable for the PS analysis in functional dairy products. Due to their chemical structure, PS can undergo oxidation, which could be greatly impacted by matrix nature/composition and thermal treatments. The oxidative stability of PS during microwave heating was evaluated. Two different model systems (PS alone and in combination) were heated up to 30 min at 1000 W. PS degraded faster when they were alone than in presence of TAG. The extent of PS degradation depends on both heating time and the surrounding medium, which can impact the quality and safety of the food product destined to microwave heating/cooking. Many minor lipid components are included in emulsion systems and can affect the rate of lipid oxidation. The oxidative stability of oil-in-water (O/W) emulsions containing PS esters, ω-3 FA and phenolic compounds, were evaluated after a 14-day storage at room temperature. Due to their surface active character, PS could be particularly prone to oxidation when they are incorporated in emulsions, as they are more exposed to water-soluble prooxidants. Finally, some minor lipophilic components may increase oxidative stability of food systems due to their antioxidant activity. á-tocopherol partitioning and antioxidant activity was determined in the presence of excess SDS in stripped soybean O/W emulsions. Results showed that surfactant micelles could play a key role as an antioxidant carrier, by potentially increasing the accessibility of hydrophobic antioxidant to the interface.

Muscle unloading potentiates the effects of acetyl-L-carnitine on the slow oxidative muscle phenotype

The effect of acetyl-L-carnitine (ALCAR) supplementation to 3-month-old rats in normal-loading and unloading conditions has been here investigated by a combined morphological, biochemical and transcriptional approach to test whether ALCAR might cause a remodeling of the metabolic/contractile phenotype of soleus muscle. Morphological assessment demonstrated an increase of type I oxidative fiber content and cross-sectional area in ALCAR-treated animals both in normal-loading and in unloading conditions. ALCAR prevented loss of mitochondrial mass in unloaded animals whereas no ALCAR-dependent increase of mitochondrial mass occurred in normal-loaded muscle. Validated microarray analysis delineated an ALCAR-induced maintenance of a slow-oxidative expression program only in unloaded soleus muscle. Indeed, the muscle adjustment of the expression profile of factors underlying mitochondrial oxidative metabolism, protein turnover, fiber type differentiation and an adaptation of voltage-gated ion channel expression was distinguishable with respect to the loading status. This selectivity may suggest a key role of muscle loading status in the manifestation of ALCAR effects. The results extend to a broader level of biological informations the previous notion on ALCAR positive effect in rat soleus muscle during unloading and point to a role of ALCAR for the maintenance of its slow-oxidative fiber character.

The evolution of antennal courtship in diplazontine parasitoid wasps (Hymenoptera, Ichneumonidae, Diplazontinae)

Background As predicted by theory, traits associated with reproduction often evolve at a comparatively high speed. This is especially the case for courtship behaviour which plays a central role in reproductive isolation. On the other hand, courtship behavioural traits often involve morphological and behavioural adaptations in both sexes; this suggests that their evolution might be under severe constraints, for instance irreversibility of character loss. Here, we use a recently proposed method to retrieve data on a peculiar courtship behavioural trait, i.e. antennal coiling, for 56 species of diplazontine parasitoid wasps. On the basis of a well-resolved phylogeny, we reconstruct the evolutionary history of antennal coiling and associated morphological modifications to study the mode of evolution of this complex character system. Results Our study reveals a large variation in shape, location and ultra-structure of male-specific modifications on the antennae. As for antennal coiling, we find either single-coiling, double-coiling or the absence of coiling; each state is present in multiple genera. Using a model comparison approach, we show that the possession of antennal modifications is highly correlated with antennal coiling behaviour. Ancestral state reconstruction shows that both antennal modifications and antennal coiling are highly congruent with the molecular phylogeny, implying low levels of homoplasy and a comparatively low speed of evolution. Antennal coiling is lost on two independent occasions, and never reacquired. A zero rate of regaining antennal coiling is supported by maximum parsimony, maximum likelihood and Bayesian approaches. Conclusions Our study provides the first comparative evidence for a tight correlation between male-specific antennal modifications and the use of the antennae during courtship. Antennal coiling in Diplazontinae evolved at a comparatively low rate, and was never reacquired in any of the studied taxa. This suggests that the loss of antennal coiling is irreversible on the timescale examined here, and therefore that evolutionary constraints have greatly influenced the evolution of antennal courtship in this group of parasitoid wasps. Further studies are needed to ascertain whether the loss of antennal coiling is irreversible on larger timescales, and whether evolutionary constraints have influenced courtship behavioural traits in a similar way in other groups.

"Flirts and Other "Voluptuous Tyrants":Wollstonecraft, Rousseau and the Politics of Desire"

For the 18th and 19th centuries, flirtation was largely understood to be the symptom of a woman’s uncontrollable (and innate) sexual appetite. Any woman who questioned its cultural operations, such as Mary Wollstonecraft, was accused of being simultaneously sexually inappropriate in her interests, as well as prudish in her denial of feminine desire as a legitimate expression of a woman’s character. What this talk will argue, however, is that, for Wollstonecraft, the flirt is a fundamentally masculine figure who engages not in a struggle over desire, but rather in a struggle for power based on monarchical politics of the Ancien Regime.

'Listen, Rama’s Wife!’: Maithil Women’s Perspectives and Practices in the Festival of Sāmā-Cakevā

As a female-only festival in a significantly gender-segregated society, sāmā cakevā provides a window into Maithil women’s understandings of their society and the sacred, cultural subjectivities, moral frameworks, and projects of self-construction. The festival reminds us that to read male-female relations under patriarchal social formations as a dichotomy between the empowered and the disempowered ignores the porous boundaries between the two in which negotiations and tradeoffs create a symbiotic reliance. Specifically, the festival names two oppositional camps—the male world of law and the female world of relationships—and then creates a male character, the brother, who moves between the two, loyal to each, betraying, in a sense, each, but demonstrating, by his movements, the currents and avenues of power. This article makes available to other scholars of South Asian culture and society an extended description and analysis of this distinctive festival, while also contributing to the scholarly discussion of women’s expressive traditions.

The Blue Of

When I first started my thesis, I intended for my finished project to be a compilation of poems that aims to reflect and reveal several repeating themes of our society's collective unconscious, such as the relationship between the physical and spiritual aspects of being and the representation of women's lives, organized religion,adolescence, and mental illness. I proposed writing a chapbook of poetry that reflects an exploration of, and sensitivity to, the human unconscious mind, fears, and desires. Consulting other works of surreal, lyric, and confessional poetry, I sought to personallydevelop as both a poet and a psychology student. I made a conscious effort to avoid trying to attach a specific 'meaning' to each poem. I understand that, in poetry, the reader is never entirely aware of exactly what the poet is trying to convey. All the reader knows is what he or she sees in a given poem and how he or she responds to that poem. However, through working on my thesis I discovered that, while meaning may not be intentional in the drafting process, developing what the poem meant to me was central to the process of revision. Furthermore, I realized that I unconsciously returned to specific themes across various poems, something that was not apparent to me until I re-read my entire collection ...

Macroevolutionary patterns in the diversification of parrots: effects of climate change, geological events and key innovations

Aim Parrots are thought to have originated on Gondwana during the Cretaceous. The initial split within crown group parrots separated the New Zealand taxa from the remaining extant species and was considered to coincide with the separation of New Zealand from Gondwana 82-85 Ma, assuming that the diversification of parrots was mainly shaped by vicariance. However, the distribution patterns of several extant parrot groups cannot be explained without invoking transoceanic dispersal, challenging this assumption. Here, we present a temporal and spatial framework for the diversification of parrots using external avian fossils as calibration points in order to evaluate the relative importance of the influences of past climate change, plate tectonics and ecological opportunity. Location Australasian, African, Indo-Malayan and Neotropical regions. Methods Phylogenetic relationships were investigated using partial sequences of the nuclear genes c-mos, RAG-1 and Zenk of 75 parrot and 21 other avian taxa. Divergence dates and confidence intervals were estimated using a Bayesian relaxed molecular clock approach. Biogeographic patterns were evaluated taking temporal connectivity between areas into account. We tested whether diversification remained constant over time and if some parrot groups were more species-rich than expected given their age. Results Crown group diversification of parrots started only about 58 Ma, in the Palaeogene, significantly later than previously thought. The Australasian lories and possibly also the Neotropical Arini were found to be unexpectedly species-rich. Diversification rates probably increased around the Eocene/Oligocene boundary and in the middle Miocene, during two periods of major global climatic aberrations characterized by global cooling. Main conclusions The diversification of parrots was shaped by climatic and geological events as well as by key innovations. Initial vicariance events caused by continental break-up were followed by transoceanic dispersal and local radiations. Habitat shifts caused by climate change and mountain orogenesis may have acted as a catalyst to the diversification by providing new ecological opportunities and challenges as well as by causing isolation as a result of habitat fragmentation. The lories constitute the only highly nectarivorous parrot clade, and their diet shift, associated with morphological innovation, may have acted as an evolutionary key innovation, allowing them to explore underutilized niches and promoting their diversification.

The Effects of Prenatal Exposure to Altered Melatonin Levels on Hippocampal Gene Expression in the Male Rat

The stability of the circadian rhythm for mammals depends on the levels of serotonin and melatonin, neurohormones that signal for lightness and darkness, respectively. Disruption in the stability of neurohormones has been shown to be a critical factor in psychopathological disorders in humans. For example, altering levels of melatonin in utero through administration of melatonin or the melatonin receptor antagonist, luzindole, has been shown to cause changes in developmental growth and adult behavior in the male rat. Analysis of relative adult hippocampal gene expression with RT-PCR revealed differences in ARNTL expression that suggested abnormality in clock gene expression of the rats that were prenatally exposed to altered levels of melatonin. Differences in the degree of plasticity as suggested by previous behavior testing did not result in differences in gene expression for GABA receptors or NMDA receptors. Morevoer, growth associated protein 43, GAP-43, a protein that is necessary for neuronal growth cones as well as long term learning has been found to be critical for axon and presynaptic terminal formation and retention in other studies, but hippocampal gene expression in our study showed no significant alteration after exposure to various maternal melatonin levels. However, ARNTL is a key regulatory component of clock genes and the circadian cycle so that alterations in the expression of thi critical gene may lead to critical changes in neuronal growth and plasticity. Our data support the conclusion that the manipulation of maternal melatonin levels alters the brain development and the circadian cycles that may lead to physiological and behavioral abnormalities in adult offspring.

The assessment of cognition in visually impaired older adults

Background: visual and cognitive impairments are common in later life. Yet there are very few cognitive screening tests for the visually impaired. Objective: to screen for cognitive impairment in the visually impaired. Methods: case-control study including 150 elderly participants with visual impairment (n = 74) and a control group without visual impairment (n = 76) using vision-independent cognitive tests and cognitive screening tests (MMSE and clock drawing tests (CDT)) which are in part vision dependent. Results: the scoring of the two groups did not differ in the vision-independent cognitive tests. Visually impaired patients performed poorer than controls in the vision-dependent items of the MMSE (T = 7.3; df: 148; P < 0.001) and in CDT (T = 3.1; df: 145; P = 0.003). No group difference was found when vision-independent items were added to MMSE and CDT. The test score gain by the use of vision-independent items correlated with the severity of visual impairment (P < 0.002). Conclusion: visually impaired patients benefit from cognitive tests, which do not rely on vision. The more visually impaired the greater the benefit.

Bacchus and Civic Order: The Culture of Drink in Early Modern Germany / Bacchus und die bürgerliche Ordnung. Die Kultur des Trinkens im frühneuzeitlichen Augsburg

Lining the streets inside the city's gates, clustered in its center, and thinly scattered among its back quarters were Augsburg's taverns and drinking rooms. These institutions ranged from the poorly lit rooms of backstreet wine sellers to the elaborate marble halls frequented by society's most privileged members. Urban drinking rooms provided more than food, drink, and lodging for their guests. They also conferred upon their visitors a sense of social identity commensurate with their status. Like all German cities, Augsburg during the sixteenth and seventeenth centuries had a history shaped by the political events attending the Reformation, the post-Reformation, and the Thirty Years' War; its social and political character was also reflected and supported by its public and private drinking rooms. In Bacchus and Civic Order: The Culture of Drink in Early Modern Germany, Ann Tlusty examines the social and cultural functions served by drinking and tavern life in Germany between 1500 and 1700, and challenges existing theories about urban identity, sociability, and power. Through her reconstruction of the social history of Augsburg, from beggars to council members, Tlusty also sheds light on such diverse topics as social ritual, gender and household relations, medical practice, and the concerns of civic leaders with public health and poverty. Drunkenness, dueling, and other forms of tavern comportment that may appear "disorderly" to us today turn out to be the inevitable, even desirable result of a society functioning according to its own rules.