The Effects of Altered Prenatal Melatonin Signaling on Adult Behavior and Hippocampal Gene Expression of the Male Rat: A Circadioneuroendocrine-Axis Hypothesis of Psychopathology

Disturbances in melatonin - the neurohormone that signals environmental darkness as part of the circadian circuit of mammals - have been implicated in various psychopathologies in humans. At present, experimental evidence linking prenatal melatonin signaling to adult physiology, behavior, and gene expression is lacking. We hypothesized that administration of melatonin (5 mg/kg) or the melatonin receptor antagonist luzindole (5 mg/kg) to rats in utero would permanently alter the circadian circuit to produce differential growth, adult behavior, and hippocampal gene expressionin the male rat. Prenatal treatment was found to increase growth in melatonin-treated animals. In addition, subjects exposed to melatonin prenatally displayed increased rearing in the open field test and an increased right turn preference in the elevated plusmaze. Rats administered luzindole prenatally, however, displayed greater freezing and grooming behavior in the open field test and improved learning in the Morris water maze. Analysis of relative adult hippocampal gene expression with RT-PCR revealed increasedexpression of brain-derived neurotrophic factor (BDNF) with a trend toward increased expression of melatonin 1A (MEL1A) receptors in melatonin-exposed animals whereas overall prenatal treatment had a significant effect on microtubule-associated protein 2(MAP2) expression. Our data support the conclusion that the manipulation of maternal melatonin levels alters brain development and leads to physiological and behavioral abnormalities in adult offspring. We designate the term circadioneuroendocrine (CNE)axis and propose the CNE-axis hypothesis of psychopathology.

Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis.

Ogawa Mimei's Children's Stories: A Case Study of the Rise of Childhood in the Context of Westernization and Japanese Modernization

In this thesis, I examine the influences of westernization, the tension between Japanese modernity and tradition, and the stories of Hans Christian Andersen on Ogawa Mimei’s children’s stories. I begin the body of my thesis with a brief historical background of Japan, beginning with the start of the Meiji period in 1868. Within the historical section, I focus on societal and cultural elements and changes that pertain to my thesis. I also include the introduction of Hans Christian Andersen in Japan. I wrap up the historical section by a description of Ogawa’s involvement in the Japanese proletarian literature movement and the rise of the Japanese proletarian children’s literature movement. Then, I launch into an analysis of Ogawa’s works categorized by thematic elements. These elements include westernization, class conflict, nature and civilization, religion and morals, and children and childhood. When relevant, I also compare and contrast Ogawa’s stories with Andersen’s. In the westernization section, I show how some of Ogawa’s stories demonstrate contact between Japan and the West. In the Class Conflict section, I discuss how Ogawa views class through a socialist lens, whereas Andersen does not dispute class distinctions, but encourages his readers to attempt an upward social climb. In the nature and civilization section, I show how Ogawa and Andersen share common opinions on the impact of civilization on nature. In the religion and morals section, I show how Ogawa incorporates religion, including Christianity, into vii his works. Andersen utilizes religion in a more overt manner in order to convey morals to his audience. Both authors address religious topics like the concept of the afterlife. Finally, in children and childhood, I demonstrate how both Ogawa and Andersen treat their child protagonists and use them and their situations to instruct their readers. Through this case study, I show how westernization and the tensions between Japanese modernization and tradition led to the rise of the proletarian children’s literature movement, which is exemplified by Ogawa’s stories. The emergence of the proletarian children’s literature movement is an indication of the establishment of a new concept of childhood in Japan. Writers like Ogawa Mimei attempted to write children’s stories that represented the new Japanese culture that was a result of adapting Western ideals to fit Japanese society. Some of Ogawa’s stories are a direct commentary on his opinion of Japanese interaction with the West. By comparing Ogawa’s and Andersen’s stories, I demonstrate how Ogawa borrows certain Western elements and possibly responds directly to Andersen. Ogawa also addresses some of the same topics as Andersen, yet their reactions are not always the same. What I find in my analysis supports my thesis that Ogawa is able to maintain Japanese tradition while infusing his children’s stories with Western and modern elements. In doing so, he reflects a largely popular social and cultural practice of his time.

Testing the TICT State Hypothesis: an Investigation into the Solvatochromic Behavior of 2-Naphthalenylmethylene Malononitrile

Towards the goal of investigating the possible Twisted Intramolecular Charge Transfer (TICT) state mechanism of fluorescence emission, two aromatic dicyanovinyl compounds, 2-(naphthalene-2-ylmethylene) malononitrile (DCN) and a rigidified analogue, 3,4-dihydrophenanthren-1(2H)-ylidene)malononitrile (RDCN) were synthesized and their absorption and steady-state fluorescence emission spectra characterized. The spectral characterization was divided into two studies: first, DCN and RDCN were characterized in liquid solvents of increasing polarity; second, DCN and RDCN were characterized in viscous solvents and rigid glass media. The absorption spectra for both DCN and RDCN in all solvents demonstrated little to no solvatochromism. Emission results for DCN and RDCN in liquid solvents of increasing polarity showed DCN possessing strong solvatochromism while RDCN showed much less solvatochromism. Using the Lippert-Mataga equation, the difference between the ground and excited state dipole moment for DCN was estimated to be 8.4 + 0.4 Debye and between ~3.0 to 5.0 Debye for RDCN. Quantum yield measurements for DCN and RDCN in hexane, diethyl ether and acetonitrile were less than 0.01 and independent of polarity for both both solvents, with DCN generally possessing a quantum yield 3-4 times greater than RDCN. Experiments in glass media for DCN and RDCN showed a lessening of their solvatochromic character in both polar and non-polar glasses. These data provide strong evidence for a link between molecular flexibility and solvatochromism. However, while these data are consistent with a TICT state hypothesis for the emission mechanism, an alternative mechanism proposed by Maroncelli et al.10 involving rotation about the dicyanovinyl double bond in the excited state remains a possibility as well.

The Permanent Income Hypothesis: A Test on Czech Privatisation

Since the late eighties, economists have been regarding the transition from command to market economies in Central and Eastern Europe with intense interest. In addition to studying the transition per se, they have begun using the region as a testing ground on which to investigate the validity of certain classic economic propositions. In his research, comprising three articles written in English and totalling 40 pages, Mr. Hanousek uses the so-called "Czech national experiment" (voucher privatisation scheme) to test the permanent income hypothesis (PIH). He took as his inspiration Kreinin's recommendation: "Since data concerning the behaviour of windfall income recipients is relatively scanty, and since such data can constitute an important test of the permanent income hypothesis, it is of interest to bring to bear on the hypothesis whatever information is available". Mr. Hanousek argues that, since the transfer of property to Czech citizens from 1992 to 1994 through the voucher scheme was not anticipated, it can be regarded as windfall income. The average size of the windfall was more than three month's salary and over 60 percent of the Czech population received this unexpected income. Furthermore, there are other reasons for conducting such an analysis in the Czech Republic. Firstly, the privatisation process took place quickly. Secondly, both the economy and consumer behaviour have been very stable. Thirdly, out of a total population of 10 million Czech citizens, an astonishing 6 million, that is, virtually every household, participated in the scheme. Thus Czech voucher privatisation provides a sample for testing the PIH almost equivalent to a full population, thus avoiding problems with the distribution of windfalls. Compare this, for instance with the fact that only 4% of the Israeli urban population received personal restitution from Germany, while the number of veterans who received the National Service Life Insurance Dividends amounted to less than 9% of the US population and were concentrated in certain age groups. But to begin with, Mr. Hanousek considers the question of whether the public percieves the transfer from the state to individual as an increase in net wealth. It can be argued that the state is only divesting itself of assets that would otherwise provide a future source of transfers. According to this argument, assigning these assets to individuals creates an offsetting change in the present value of potential future transfers so that individuals are no better off after the transfer. Mr. Hanousek disagrees with this approach. He points out that a change in the ownership of inefficient state-owned enterprises should lead to higher efficiency, which alone increases the value of enterprises and creates a windfall increase in citizens' portfolios. More importantly, the state and individuals had very different preferences during the transition. Despite government propaganda, it is doubtful that citizens of former communist countries viewed government-owned enterprises as being operated in the citizens' best interest. Moreover, it is unlikely that the public fully comprehended the sophisticated links between the state budget, state-owned enterprises, and transfers to individuals. Finally, the transfers were not equal across the population. Mr. Hanousek conducted a survey on 1263 individuals, dividing them into four monthly earnings categories. After determining whether the respondent had participated in the voucher process, he asked those who had how much of what they received from voucher privatisation had been (a) spent on goods and services, (b) invested elsewhere, (c) transferred to newly emerging pension funds, (d) given to a family member, and (e) retained in their original form as an investment. Both the mean and the variance of the windfall rise with income. He obtained similar results with respect to education, where the mean (median) windfall for those with a basic school education was 13,600 Czech Crowns (CZK), a figure that increased to 15,000 CZK for those with a high school education without exams, 19,900 CZK for high school graduates with exams, and 24,600 CZK for university graduates. Mr. Hanousek concludes that it can be argued that higher income (and better educated) groups allocated their vouchers or timed the disposition of their shares better. He turns next to an analysis of how respondents reported using their windfalls. The key result is that only a relatively small number of individuals reported spending on goods. Overall, the results provide strong support for the permanent income hypothesis, the only apparent deviation being the fact that both men and women aged 26 to 35 apparently consume more than they should if the windfall were annuitised. This finding is still fully consistent with the PIH, however, if this group is at a stage in their life-cycle where, without the windfall, they would be borrowing to finance consumption associated with family formation etc. Indeed, the PIH predicts that individuals who would otherwise borrow to finance consumption would consume the windfall up to the level equal to the annuitised fraction of the increase in lifetime income plus the full amount of the previously planned borrowing for consumption. Greater consumption would then be financed, not from investing the windfall, but from avoidance of future repayment obligations for debts that would have been incurred without the windfall.

Impaired 11 beta-hydroxysteroid dehydrogenase contributes to renal sodium avidity in cirrhosis: hypothesis or fact?

Exaggerated renal sodium retention with concomitant potassium loss is a hallmark of cirrhosis and contributes to the accumulation of fluid as ascites, pleural effusion, or edema. This apparent mineralocorticoid effect is only partially explained by increased aldosterone concentrations. I present evidence supporting the hypothesis that cortisol confers mineralocorticoid action in cirrhosis. The underlying molecular pathology for this mineralocorticoid receptor (MR) activation by cortisol is a reduced activity of the 11 beta-hydroxysteroid dehydrogenase type 2, an enzyme protecting the MR from promiscuous activation by cortisol in healthy mammalians.

Power Calculations for Preclinical Studies Using a K-Sample Rank Test and the Lehmann Alternative Hypothesis

Power calculations in a small sample comparative study, with a continuous outcome measure, are typically undertaken using the asymptotic distribution of the test statistic. When the sample size is small, this asymptotic result can be a poor approximation. An alternative approach, using a rank based test statistic, is an exact power calculation. When the number of groups is greater than two, the number of calculations required to perform an exact power calculation is prohibitive. To reduce the computational burden, a Monte Carlo resampling procedure is used to approximate the exact power function of a k-sample rank test statistic under the family of Lehmann alternative hypotheses. The motivating example for this approach is the design of animal studies, where the number of animals per group is typically small.