The Effects of Housing Density on Social Interactions and Their Correlations with Serotonin in Rodents and Primates.

Population density has been suggested to affect social interactions of individuals, but the underlying neural mechanisms remain unclear. In contrast, neurotransmission of monoamines such as serotonin (5-HT) and dopamine (DA) has been demonstrated to play important roles in social behaviors. Here, we investigated whether housing density affected social interactions of rodents and non-human primates housed in groups, and its correlations with monoamines. Japanese macaques exhibited higher plasma 5-HT, but not DA, concentrations than rhesus macaques. Similarly, C57BL/6 mice exhibited higher plasma and brain tissue 5-HT concentrations than DBA2 mice. Under crowding, C57BL/6 mice and Japanese macaques exhibited more prominent social avoidance with mates than DBA2 mice and rhesus macaques, respectively. Although DBA2 mice and rhesus macaques in crowding exhibited elevated plasma stress hormones, such stress hormone elevations associated with crowding were absent in C57BL/6 mice and Japanese macaques. Administration of parachlorophenylalanine, which inhibits 5-HT synthesis, increased social interactions and stress hormones in C57BL/6 mice under crowding. These results suggest that, animals with hyperserotonemia may exhibit social avoidance as an adaptive behavioral strategy to mitigate stress associated with crowding environments, which may also be relevant to psychiatric disorder such as autism spectrum disorder.

TRPA1-dependent reversible opening of tight junction by natural compounds with an α,ß-unsaturated moiety and capsaicin.

The delivery of hydrophilic macromolecules runs into difficulties such as penetration of the cell membrane lipid bilayer. Our prior experiment demonstrated that capsaicin induces the reversible opening of tight junctions (TJs) and enhances the delivery of hydrophilic macromolecules through a paracellular route. Herein, we screened paracellular permeability enhancers other than capsaicin. As TJ opening by capsaicin is associated with Ca2+ influx, we first screened the compounds that induce Ca2+ influx in layered MDCK II cells, and then we determined the compounds' abilities to open TJs. Our results identified several natural compounds with α,ß-unsaturated moiety. A structure-activity relationship (SAR) analysis and the results of pretreatment with reducing reagent DTT suggested the importance of α,ß-unsaturated moiety. We also examined the underlying mechanisms, and our findings suggest that the actin reorganization seen in capsaicin treatment is important for the reversibility of TJ opening. Furthermore, our analyses revealed that TRPA1 is involved in the Ca2+ influx and TJ permeability increase not only by an α,ß-unsaturated compound but also by capsaicin. Our results indicate that the α,ß-unsaturated moiety can be a potent pharmacophore for TJ opening.

Dopamine-dependent visual attention preference to social stimuli in nonhuman primates.

RATIONALE: Dopamine (DA) plays a central role in reward processing. Accumulating evidence suggests that social interaction and social stimuli have rewarding properties that activate the DA reward circuits. However, few studies have attempted to investigate how DA is involved in the processing of social stimuli. OBJECTIVES: In this study, we investigated the effects of pharmacological manipulations of DA D1 and D2 receptors on social vs. nonsocial visual attention preference in macaques. METHODS: Japanese macaques were subjected to behavioral tests in which visual attention toward social (monkey faces with and without affective expressions) and nonsocial stimuli was examined, with D1 and D2 antagonist administration. RESULTS: The macaques exhibited significantly longer durations of gazing toward the images with social cues than did those with nonsocial cues. Both D1 and D2 antagonist administration decreased duration of gazing toward the social images with and without affective valences. In addition, although D1 antagonist administration increased the duration of gazing toward the nonsocial images, D2 antagonism had no effect. CONCLUSIONS: These results suggest that both D1 and D2 receptors may have roles in the processing of social signals but through separate mechanisms.

The Roles of Dopamine D2 Receptor in the Social Hierarchy of Rodents and Primates.

Dopamine (DA) plays significant roles in regulation of social behavior. In social groups of humans and other animals, social hierarchy exists, which is determined by several behavioral characteristics such as aggression and impulsivity as well as social affiliations. In this study, we investigated the effects of pharmacological blockade of DA D2 receptor on social hierarchy of Japanese macaque and mouse social groups. We found acute administration of the D2 antagonist, sulpiride, in socially housed Japanese macaques attenuated social dominance when the drug was given to high social class macaques. A similar attenuation of social dominance was observed in high social class mice with D2 antagonist administration. In contrast, D2 antagonist administration in low social class macaque resulted in more stable social hierarchy of the group, whereas such effect was not observed in mouse social group. These results suggest that D2 receptor signaling may play important roles in establishment and maintenance of social hierarchy in social groups of several species of animals.

Associations of acute and chronic stress hormones with cognitive functions in autism spectrum disorder.

Extensive studies have reported cognitive abnormalities in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Another line of evidence suggests that stress also affects cognitive functions. In this study, we investigated whether there were associations between stress hormones and cognitive functions in ASD and typically developing (TD) children. Cognitive functions in ASD and TD children were evaluated with a battery of psychological tests for working memory, behavioral flexibility, and social cognition for emotional assessments of others. ASD children exhibited higher hair and salivary cortisol, which reflects chronic and acute stress hormone levels of subjects, respectively, than TD children. Autism-spectrum quotient (AQ) was positively correlated with hair cortisol and the scores of Spence Children's Anxiety Scale in ASD children. In addition, a negative correlation was present between spatial working memory performance and hair cortisol in ASD, but not in TD, children. These results suggest that chronic stress hormone elevation may have relationships with some aspects of cognitive dysfunction in ASD subjects.

The Roles of Dopamine D1 Receptor on the Social Hierarchy of Rodents and Nonhuman Primates.

Background: Although dopamine has been suggested to play a role in mediating social behaviors of individual animals, it is not clear whether such dopamine signaling contributes to attributes of social groups such as social hierarchy. Methods: In this study, the effects of the pharmacological manipulation of dopamine D1 receptor function on the social hierarchy and behavior of group-housed mice and macaques were investigated using a battery of behavioral tests. Results: D1 receptor blockade facilitated social dominance in mice at the middle, but not high or low, social rank in the groups without altering social preference among mates. In contrast, the administration of a D1 receptor antagonist in a macaque did not affect social dominance of the drug-treated animal; however, relative social dominance relationships between the drug-treated and nontreated subjects were altered indirectly through alterations of social affiliative relationships within the social group. Conclusions: These results suggest that dopamine D1 receptor signaling may be involved in social hierarchy and social relationships within a group, which may differ between rodents and primates.

Biological mechanisms underlying evolutionary origins of psychotic and mood disorders.

Psychotic and mood disorders are brain dysfunctions that are caused by gene environment interactions. Although these disorders are disadvantageous and involve behavioral phenotypes that decrease the reproductive success of afflicted individuals in the modern human society, the prevalence of these disorders have remained constant in the population. Here, we propose several biological mechanisms by which the genes associated with psychotic and mood disorders could be selected for in specific environmental conditions that provide evolutionary bases for explanations of when, why, and where these disorders emerged and have been maintained in humans. We discuss the evolutionary origins of psychotic and mood disorders with specific focuses on the roles of dopamine and serotonin in the conditions of social competitiveness/hierarchy and maternal care and other potential mechanisms, such as social network homophily and symbiosis.

Combination of aspartic acid and glutamic acid inhibits tumor cell proliferation.

Placental extract contains several biologically active compounds, and pharmacological induction of placental extract has therapeutic effects, such as improving liver function in patients with hepatitis or cirrhosis. Here, we searched for novel molecules with an anti-tumor activity in placental extracts. Active molecules were separated by chromatographic analysis, and their antiproliferative activities were determined by a colorimetric assay. We identified aspartic acid and glutamic acid to possess the antiproliferative activity against human hepatoma cells. Furthermore, we showed that the combination of aspartic acid and glutamic acid exhibited enhanced antiproliferative activity, and inhibited Akt phosphorylation. We also examined in vivo tumor inhibition activity using the rabbit VX2 liver tumor model. The treatment mixture (emulsion of the amino acids with Lipiodol) administered by hepatic artery injection inhibited tumor cell growth of the rabbit VX2 liver. These results suggest that the combination of aspartic acid and glutamic acid may be useful for induction of tumor cell death, and has the potential for clinical use as a cancer therapeutic agent.

Dopamine in socioecological and evolutionary perspectives: implications for psychiatric disorders.

Dopamine (DA) transmission in brain areas such as the prefrontal cortex (PFC) and nucleus accumbens (NAcc) plays important roles in cognitive and affective function. As such, DA deficits have been implicated in a number of psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder (ADHD). Accumulating evidence suggests that DA is also involved in social behavior of animals and humans. Although most animals organize and live in social groups, how the DA system functions in such social groups of animals, and its dysfunction causes compromises in the groups has remained less understood. Here we propose that alterations of DA signaling and associated genetic variants and behavioral phenotypes, which have been normally considered as "deficits" in investigation at an individual level, may not necessarily yield disadvantages, but even work advantageously, depending on social contexts in groups. This hypothesis could provide a novel insight into our understanding of the biological mechanisms of psychiatric disorders, and a potential explanation that disadvantageous phenotypes associated with DA deficits in psychiatric disorders have remained in humans through evolution.

Neurodevelopmental Plasticity in Pre- and Postnatal Environmental Interactions: Implications for Psychiatric Disorders from an Evolutionary Perspective.

Psychiatric disorders are disadvantageous behavioral phenotypes in humans. Accordingly, a recent epidemiological study has reported decreased fecundity in patients with psychiatric disorders, such as schizophrenia and autism spectrum disorders. Moreover, the fecundity of the relatives of these patients is not exceedingly higher compared to the fecundity of the relatives of normal subjects. Collectively, the prevalence of psychiatric disorders among humans is expected to decrease over generations. Nevertheless, in reality, the prevalence rates of psychiatric disorders in humans either have been constant over a long period of time or have even increased more recently. Several attempts to explain this fact have been made using biological mechanisms, such as de novo gene mutations or variants, although none of these explanations is fully comprehensive. Here, we propose a hypothesis towards understanding the biological mechanisms of psychiatric disorders from evolutionary perspectives. This hypothesis considers that behavioral phenotypes associated with psychiatric disorders might have emerged in the evolution of organisms as a neurodevelopmental adaptation against adverse environmental conditions associated with stress.

Silicate fiber-based 3D cell culture system for anticancer drug screening.

BACKGROUND: Three-dimensional (3D) in vitro cultures can recapitulate the physiological in vivo microenvironment. 3D Modeling techniques have been investigated and applied in anticancer drug screening. MATERIALS AND METHODS: A silicate fiber scaffold was used for 3D cell cultures, and used to model the efficacy of anticancer drugs, such as mytomicin C and doxorubicin. RESULTS: A unique 3D structure was observed in 13 human tumor cell lines on scaffold, and these cells exhibited higher drug resistance than cells in two-dimensional (2D) cultures. Furthermore, the production of lactate and expression of the nuclear factor-kappa B (NF-κB)-regulated genes B cell lymphoma-2 (BCL2), cyclooxygenase-2 (COX2), and vascular endothelial growth factor (VEGF) were higher in 3D cultures than in 2D cultures. CONCLUSION: These findings suggest that a 3D model using a silicate fiber scaffold can mimic features of cancer, and is also a suitable model for the evaluation of anticancer drugs in vitro.

Contribution of the Japan International Cooperation Agency health-related projects to health system strengthening.

BACKGROUND: The Japan International Cooperation Agency (JICA) has focused its attention on appraising health development assistance projects and redirecting efforts towards health system strengthening. This study aimed to describe the type of project and targets of interest, and assess the contribution of JICA health-related projects to strengthening health systems worldwide. METHODS: We collected a web-based Project Design Matrix (PDM) of 105 JICA projects implemented between January 2005 and December 2009. We developed an analytical matrix based on the World Health Organization (WHO) health system framework to examine the PDM data and thereby assess the projects' contributions to health system strengthening. RESULTS: The majority of JICA projects had prioritized workforce development, and improvements in governance and service delivery. Conversely, there was little assistance for finance or medical product development. The vast majority (87.6%) of JICA projects addressed public health issues, for example programs to improve maternal and child health, and the prevention and treatment of infectious diseases such as AIDS, tuberculosis and malaria. Nearly 90% of JICA technical healthcare assistance directly focused on improving governance as the most critical means of accomplishing its goals. CONCLUSIONS: Our study confirmed that JICA projects met the goals of bilateral cooperation by developing workforce capacity and governance. Nevertheless, our findings suggest that JICA assistance could be used to support financial aspects of healthcare systems, which is an area of increasing concern. We also showed that the analytical matrix methodology is an effective means of examining the component of health system strengthening to which the activity and output of a project contributes. This may help policy makers and practitioners focus future projects on priority areas.

Specific recognition of cytosine by hypoxanthine in pyrrolidinyl peptide nucleic acid.

Hypoxanthine is an unnatural base that can potentially pair with all natural nucleobases. While hypoxanthine in DNA exhibits marginal preference for pairing with cytosine (C), little is known about its pairing behavior in other DNA analogues. In this study, we synthesized a hypoxanthine-containing monomer and incorporated it into pyrrolidinyl peptide nucleic acid with α/ß-peptide backbone derived from D-prolyl-(1S,2S)-2-aminocyclopentanecarboxylic acid (acpcPNA). DNA binding studies clearly revealed that hypoxanthine in acpcPNA behaves like G-analogue because it can specifically form a stable base pair with dC in DNA. The ability to replace G by hypoxanthine without affecting the base pairing properties of acpcPNA can solve a number of problems associated with G-rich acpcPNA including difficult synthesis, formation of secondary structures and fluorescence quenching.

Pyrrolidinyl peptide nucleic acid with α/ß-peptide backbone: A conformationally constrained PNA with unusual hybridization properties.

We describe herein a new conformationally constrained analog of PNA carrying an alternating α/ß amino acid backbone consisting of (2'R,4'R)-nucleobase-subtituted proline and (1S,2S)-2-aminocyclopentanecarboxylic acid (acpcPNA). The acpcPNA has been synthesized and evaluated for DNA, RNA and self-pairing properties by thermal denaturation experiments. It can form antiparallel hybrids with complementary DNA with high affinity and sequence specificity. Unlike other PNA systems, the thermal stability of acpcPNA·DNA hybrid is largely independent of G+C contents, and is generally higher than that of acpcPNA·RNA hybrid with the same sequence. Thermodynamic parameters analysis suggest that the A·T base pairs in the acpcPNA·DNA hybrids are enthalpically stabilized over G·C pairs. The acpcPNA also shows a hitherto unreported behavior, namely the inability to form self-pairing hybrids. These unusual properties should make the new acpcPNA a potentially useful candidate for various applications including microarray probes and antigene agents.

Triplet Analysis That Identifies Unpaired Regions of Functional RNAs.

We developed a novel method for analyzing RNA sequences, deemed triplet analysis, and applied the method in an in vitro RNA selection experiment in which HIV-1 Tat was the target. Aptamers are nucleic acids that bind a desired target (bait), and to date, many aptamers have been identified by in vitro selection from enough concentrated libraries in which many RNAs had an obvious consensus primary sequence after sufficient cycles of the selection. Therefore, the higher-order structural features of the aptamers that are indispensable for interaction with the bait must be determined by additional investigation of the aptamers. In contrast, our triplet analysis enabled us to extract important information on functional primary and secondary structure from minimally concentrated RNA libraries. As a result, by using our method, an important unpaired region that is similar to the bulge of TAR was readily predicted from a partially concentrated library in which no consensus sequence was revealed by a conventional sequence analysis. Moreover, our analysis method may be used to assess a variety of structural motifs with desired function.

Association between the transition from unemployment to re-employment after abrupt bankruptcy and the depressive symptoms.

The study aimed to examine the effects of long-term unemployment and the transition from unemployment to re-employment after abrupt bankruptcy on the mental health of unemployed Japanese. The cases of 96 men and 54 women who were laid off by a large shoemaking company because of sudden bankruptcy in 1998, were examined for one year. The mental health of these individuals was evaluated using a 'self-rating questionnaire for depression (SRQ-D)'. The respondents were categorized by employment transition status into four groups: (1) still employed full-time, (2) unemployment to full-time employment, (3) unemployment to part-time employment, and (4) still unemployed. The prevalence rate of depressive symptoms in the 'still unemployed' group was significantly higher (adjusted odds ratio (OR) = 4.33) than in the still employed group. Moreover, high levels of depressive symptoms were observed in the individuals in the 'unemployment to part-time employment' group (adjusted OR = 4.93). There was no significant risk of depressive tendency among individuals in the 'unemployment to full-time employment' group. The results suggest that the negative effect of re-employment to part-time employment on depressive symptoms is similar to that in long-term unemployment.

[Current status of operations in community general support centers and the correlation of personal traits, work environment and occupational stress].

OBJECTIVE: The purpose of this study was to identify the current status of operations at community general support centers which provide coordination for elderly care and the correlation of personal traits, work environment and the occupational stress of the staff. METHODS: Subjects of the study were 251 staff members of community general support centers. The current status of operations at the community general support centers and the personal traits, work environment, effort-remuneration imbalance model (ERI) and general health questionnaire (GHQ) were surveyed. The initial analysis involved a comparison by a chi-square test on: The effort-remuneration ratio (E/R ratio) of personal traits and work environment, risk of over-commitment (OC), and GHQ score. To explore the correlation between the E/R ratio of the three GHQ groups (low, middle and high score groups) and the OC value, one-way analysis of variance was performed. RESULTS: Out of the four basic functions of the community general support centers, 22.0% of the respondents noted that "establishment of a regional, comprehensive/multi-tiered service network" was functioning, and 50.4% of respondents noted that "comprehensive and continuous care management" was functioning. The average effort score was 15.5 +/- 5.3, approximately double the average value of preceding studies. Significant differences found in GHQ scores were related to working hours (p<0.001) and anxiety was related to task content (p<0.001). Moreover, a higher GHQ score was accompanied by a higher E/R ratio and as a result of the multiple comparison, a marked difference was observed between the GHQ low score group and the GHQ high score group (p<0.001), and a significant difference was also found between the GHQ low score group and GHQ medium score group (p=0.012). Items observed to have significant correlation with high E/R ratio were: "Weekly working hours of 50 h or more" (OR: 10.38, 95% CI: 2.52-42.70), "Unstable employment" (OR: 2.75, 95% CI: 1.22-6.21) and "Anxiety related to task content" (OR: 17.04, 95% CI: 3.57-81.24). Items observed to have significant correlation with OC value risk factors were: "Weekly working hours of 50 h or more" (OR: 8.04, 95% CI: 1.99-32.41) and "Anxiety related to task content" (OR: 4.60, 95% CI: 2.04-10.37). CONCLUSIONS: We conclude that the basic functions of the community general support centers are not presently very functional. The stress levels of the community general support center staff are high and their health levels are low. This indicates that staff are forced to work with anxiety related to task content under conditions of poor pay and long working hours.

Study of protein-protein binding reaction by whole-column fluorescence-imaged CIEF.

Whole-column fluorescence-imaged CIEF was applied to study protein-protein binding reaction. A homemade whole-column fluorescence-imaged CIEF experimental setup was built, and its CIEF performance was evaluated with native fluorescent protein green fluorescence protein and fluorescently labeled proteins (bovine albumin, human albumin, and BSA). pIs, focusing time, detection limits, and linear quantitative range of the proteins were obtained. Furthermore, the method was used to study FITC-protein A-human IgG binding reaction. Experimental results showed that the apparent binding ratio of the FITC-protein A to human IgG was 1:2, and pI of the binding conjugates were about 6.3-6.5. No binding reaction was found between green fluorescence protein and the fluorescent-labeled proteins.

Effects of short-term exposure to whole-body vibration on wakefulness level.

To investigate the relationships between whole-body vibration and changes in wakefulness, We measured the change of a subjective wakefulness level and electroencephalogram (EEG). Subjects are ten healthy male university students. The subjects were exposed to whole-body vibration with frequency (10 Hz) and acceleration level (0.6 ms(-2) r.m.s.) for 12 min in the seated position. Subjective wakefulness level was evaluated using the questionnaire of VASS (Visual Analog Sleepiness Scale) and KSS (The Kwansei Gakuin Sleepiness Scale). For the electroencephalogram (EEG) measurement, AAT (Alpha Attenuation Test) which repeats three times each opened and closed eye for 1 min was conducted. Wakefulness levels were defined as the ratio of mean alpha-wave power during eyes closed versus eyes opened. VASS and KSS increased and subjective level of wakefulness decreased from pre- to post exposure in all subjects, regardless of vibration exposure. The objective wakefulness levels of AAT were reduced at the post-exposure test in all subjects. In the case with exposure to whole-body vibration was a significant difference from the case without exposure to whole-body vibration. It is suggested that a short-term exposure to whole-body vibration may cause a reduction of wakefulness level.

Effect of a physical activity improvement program using the transtheoretical model at a small-scale company.

The present study aimed to investigate the potential use of the transtheoretical model (TTM) by clarifying the program's effects on workers at a small-scale company. Subjects were 22 male workers at a communication system company. They were divided into two physical activity improvement program groups, the TTM-based assistance group (TTM group, n=12) and the control group (n=10). During the study period each subject was asked to wear a calorie counter and to record daily exercise. Changes in number of steps per day and body weight were measured before, immediately after, and 1 month after the intervention ended. Stage of exercise behavior, health protective behavior, and self-efficacy were also examined by means of self-administered questionnaires. In the control group, the number of steps per day tended to increase immediately after the intervention and then decreased at 1 month after the program ended. In both groups, physical activity peaked during commuting and lunch hours. This peak persisted for 1 month after the intervention in the TTM group, but not in the control group. Moreover, the stage of exercise behavior tended to progress in the TTM group, whereas regression in the stage of exercise behavior was observed in the control group. In the control group, although the exercise self-efficacy score after intervention was higher than that before intervention, the health protective behavior score decreased at 1 month after the program ended. This study suggested that physical activity improvement programs based on TTM may be useful for workers at small-scale companies. However, further study of larger numbers of workers will be needed to confirm the validity and usefulness of these results.