Hypothetical novel simulations to explain the evolutionary survival of the hypo-reproductive extreme tail in the complex human diversity.

Hierarchical structures which lie hidden between human complex conditions and reproductivity cannot be simple, and trends of each population component does not necessarily pertain to evolutionary theories. As an illustration, the fitness of individuals with heritable extreme conditions can be low across continuing generations in observational data. Autism and schizophrenia are characterized by such evolutionary paradox of survival and hypo-reproductivity in the complex human diversity. Theoretical mechanisms for the observational fact were evaluated using a simple formula which was established to simulate stochastic epistasis-mediated phenotypic diversity. The survival of the hypo-reproductive extreme tail could be imitated just by the predominant presence of stochastic epistasis mechanism, suggesting that stochastic epistasis might be a genetic prerequisite for the evolutionary paradox. As supplemental cofactors of stochastic epistasis, a random link of the extreme tail to both un- and hyper-reproductivity and group assortative mating were shown to be effective for the paradox. Especially, the mixed localization of un- and hyper-reproductivity in the tail of a generational population evidently induced the continuous survival of outliers and extremes. These hypothetical considerations and mathematical simulations may suggest the significance of stochastic epistasis as the essential genetic background of complex human diversity.

Developmental social vulnerability as the intrinsic origin of psychopathology: A paradigm shift from disease entities to psychiatric derivatives within human diversity.

How a social episode is perceived by a person and how the experience affects her/his subsequent behaviors will inevitably and sometimes accidentally vary in each case on the developmental trajectory from the birth of consciousness to death. Both the preceding developmental conditions and the social impact of the episode become a starting point for the following states of human complex conditions, creating the extraordinary diversity that characterizes our complex society. In this evolutionarily carved landscape, genetic factors including stochastic epistasis, environmental modification, and gene-environment interactions are all active. In these processes, interactions between developmental social vulnerability and environmental influences can lead to the emergence and persistence of some derivative states with social maladaptation. In our model, every psychiatric condition including aberrant paranoid-hallucinatory states is classified as a derivative state. The probability distribution curve for these derivative states has a non-linear relationship with the liability in the population, and there is none with probability 1.0 or zero. Individuals with trivial social vulnerability or high resilience may develop the derivative states in tremendously stressful circumstances, and individuals with huge social vulnerability may not necessarily develop the derivative states in the presence of adequate social supports. Social skillfulness/unskillfulness and behavioral flexibility/inflexibility form the core of the vulnerability-related dimensions. The clinical picture of a derivative manifestation is profiled depending on the individual trait levels in the derivative-related dimensions. Each derivative state has a requisite lineup of dimensions and each dimension can contribute to multiple psychiatric conditions. For example, aberrant paranoid-hallucinatory states and bipolar condition may share some developmental conditions as the derivative-related dimensions. Therefore, multiple derivative states can co-occur or be sequentially comorbid. Although the 'learned strategies' can ostensibly mask the clinical manifestation of developmental deviations, the change of the true dimensional position to the socially skillful direction is efficiently obtained through social experiences in a supportive environment. The liability-probability model makes it impossible to discriminate individuals with psychiatric diagnosis from individuals without the diagnosis and allows all of us to reside in the same human complex diversity.

The origin of complex human diversity: Stochastic epistatic modules and the intrinsic compatibility between distributional robustness and phenotypic changeability

The continuing prevalence of a highly heritable and hypo-reproductive extreme tail of a human neurobehavioral quantitative diversity suggests the reproductive majority retains the genetic mechanisms for extremes. From the perspective of stochastic epistasis, the effect of an epistatic modifier variant can randomly vary in both phenotypic value and effect direction among carriers depending on the genetic identity and the modifier carriers are ubiquitous in the population. The neutrality of the mean genetic effect in carriers ensures the survival of the variant under selection pressures. Functionally or metabolically related modifier variants make an epistatic network module and dozens of modules may be involved in the phenotype. To assess the significance of stochastic epistasis, a simplified module-based model was simulated. The individual repertoire of the modifier variants in a module also contributes in genetic identity, which determines the genetic contribution of each carrier modifier. Because the entire contribution of a module to phenotypic outcome is unpredictable in the model, the module effect represents the total contribution of related modifiers as a stochastic unit in simulations. As a result, the intrinsic compatibility between distributional robustness and quantitative changeability could mathematically be simulated using the model. The artificial normal distribution shape in large-sized simulations was preserved in each generation even if the lowest fitness tail was non-reproductive. The robustness of normality across generations is analogous to the real situation of complex human diversity, including neurodevelopmental conditions. The repeated regeneration of a non-reproductive extreme tail may be essential for survival and change of the reproductive majority, implying extremes for others. Further simulation to illustrate how the fitness of extreme individuals can be low across generations may be necessary to increase the plausibility of this stochastic epistasis model.

Quantitative Nature of Social Vulnerability and Autism: An Important Paradigm Shift in the DSM-5 for Autism Spectrum Disorder.

In the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), autistic characteristics in social interaction and communication are described as qualitative impairments. However, the difference between autistics and nonautistics in the draft of the 5th edition (DSM-5 draft) is quantitative rather than qualitative. The word "qualitative" is deleted in the draft text, and it is specified that the relation between social demands and individual limited capacities is critical for symptom manifestation (criterion C). Because the proposed levels of support requirement in the draft are mere observable outcomes of social vulnerability, the boundary between level 1 and nonautistic condition is determined by the relation between social demands and individual capacities. In addition to the introduction of the single category (autism spectrum disorder (ASD)) to cover the entire case spectrum, the DSM-5 draft is clearly based on a conviction that ASD is indistinguishable from the normal behavioral range. This concise review provides an explanation for this implicit paradigm shift from qualitative to quantitative. Importantly, the conditional role of social demands for symptom manifestation in the draft can be plausibly interpreted using a unique liability-probability model.

Enhancement of antitumor activity of OK-432 (picibanil) by Triton X-114 phase partitioning.

OK-432 (Picibanil), a Streptococcal immunotherapeutic agent, has been used for immunotherapy of various cancers as a biological response modifier (BRM). However, OK-432 contains multiple components consisting of immunotherapeutic ones and contaminants which may weaken the effects or exert side-effects. In this study, we investigated extraction of contaminants from OK-432 using Triton X-114 (TX-114)-water phase partitioning and examined an antitumor effect of the resulting preparation. OK-432 was subjected to TX-114 partitioning to give residual precipitate designated as OK-TX-ppt. OK-TX-ppt exerted no TLR2-mediated activity, but induced interleukin (IL)-6 in human PBMC. OK-TX-ppt also induced tumor necrosis factor (TNF)-alpha, IL-10, IL-12, and interferon (IFN)-gamma in PBMC. Moreover, IFN-gamma-inducing activity of OK-TX-ppt was significantly higher and IL-10 production was lower than that of OK-432. In tumor-bearing mice model, administration of OK-TX-ppt i.p. extended the survival time of Meth-A-bearing mice compared to OK-432. OK-TX-ppt also increased the levels of IL-12 and IFN-gamma in mouse spleen cells in vitro. These results indicated that TX-114 partitioning removed some contaminants, which attenuates the antitumor effect, from OK-432 and increase the immunotherapeutic effects of OK-432.

For others: epistasis and the evolutionary survival of an extreme tail of the quantitative distribution of autistic assets.

The ongoing paradigm shift from the traditional qualitative dichotomy concept to the quantitative framework increases the necessity of an evolutionary implication and interpretation of the presence of a hypo-reproductive behavioral extreme (autism) with strong genetic contribution. As a theoretical challenge to explain the survival of the dimensional distribution of autistic traits, an epistasis-associated oscillation of fitness outcomes is proposed. In this hypothesis, an allele could contribute to the existence of both phenotypic extreme tails and the hypothesized genetic machinery (quantitative trait loci) for autism would necessarily be common in the entire human population. The postulated autism genes would allow autistics to enjoy autistic traits and assets and all of the residual non-autistic individuals could owe their social skills and reproductive advantages to the same autism genes. Importantly, the reported modest correlations between core autistic dimensions can be illustrated using unsynchronized epistatic pleiotropy.

Evidence of immunostimulating lipoprotein existing in the natural lipoteichoic acid fraction.

Lipoteichoic acid (LTA) is a cell surface glycoconjugate of gram-positive bacteria and is reported to activate the innate immune system. We previously reported that purified LTA obtained from Enterococcus hirae has no immunostimulating activity, but a subfraction (Eh-AF) in an LTA fraction possesses activity. In this study, we established a mouse monoclonal antibody neutralizing the activity of Eh-AF and investigated its inhibitory effects. Monoclonal antibody (MAbEh1) was established by the immunization of BALB/c mice with Eh-AF, followed by hybridoma screening based on its inhibitory effect for the production of interleukin-6 (IL-6) induced by Eh-AF. MAbEh1 neutralized the production of IL-6 by LTA fraction from not only E. hirae but also Staphylococcus aureus, while it failed to block that of lipopolysaccharide, suggesting that the antibody recognized a common active structure(s) in LTA fractions. Synthetic glycolipids in these LTAs did not induce cytokine production, at least in our system. Interestingly, the antibody was found to inhibit the activity of immunostimulating synthetic lipopeptides, Pam(3)CSK(4) and FSL-1. These results suggest that MAbEh1 neutralizes the activity of lipoprotein-like compounds which is responsible for the activity of the LTA fraction of E. hirae and S. aureus.

Classification of antipsychotic drugs by gene expression in the frontal cortex of mice.

Antipsychotic drugs are classified as typical and atypical based on extrapyramidal effects. However, since the frontal cortex is one of the most important regions for antipsychotic actions, this study attempted to classify antipsychotic drugs based on gene expression in the frontal cortex. Chlorpromazine and thioridazine were selected as typical antipsychotics, and olanzapine and quetiapine as atypical antipsychotics. Since these drugs have similar chemical structures, the effect of the basic structure on gene expression can be eliminated. Cluster analysis of microarray experiments separated 4-drug-administered mice into chlorpromazine-quetiapine and thioridazine-olanzapine groups. This classification scheme is different from that which is based on criteria currently used to group the typical and atypical drugs and suggests that antipsychotic drugs can be further separated into multiple groups.

Administration of haloperidol with biperiden reduces mRNAs related to the ubiquitin-proteasome system in mice.

In order to find molecules affected by administration of an antipsychotic drug with an antimuscarinic drug, which is a common prescription used to prevent extrapyramidal adverse effects caused by the antipsychotic drugs, gene expression profiling in the frontal cortex was studied in mice. After 14 days of administration with 2 mg/kg haloperidol, a typical antipsychotic drug, and 2 mg/kg biperiden, a high-affinity antagonist for muscarinic receptors in the brain, approximately 500 mRNAs related to synaptic function were investigated. The levels of the mRNAs related to the ubiquitin-related systems were significantly reduced after the combined administration. However, the separate administration of either haloperidol or biperiden had little effect on the levels of the mRNAs. This result suggests that coadministration of haloperidol and biperiden specifically affects the ubiquitin-related system.

Antinociceptive mechanism of L-DOPA.

The mechanism of L-DOPA for antinociception was investigated. Nociceptive behaviors in mice after an intrathecal (i.t.) administration of substance P were evaluated. L-DOPA (i.t.) dose-dependently attenuated the substance P-induced nociceptive behaviors. Co-administration of benserazide (i.t.), a DOPA decarboxylase inhibitor, abolished the antinociceptive effect of L-DOPA. The L-DOPA-induced antinociception was antagonized by sulpiride, a D2 blocker, but not by SCH 23390, a D1 blocker. These results suggest that L-DOPA relieves pain after conversion to dopamine, with the dopamine sedating pain transmission by way of the dopamine D2 receptor.

Gene expression profiling in the midbrain of striatal 6-hydroxydopamine-injected mice.

In order to clarify mechanisms underlying dopaminergic neuronal death in Parkinson's disease (PD), a gene expression profiling study was performed in a rodent model of PD. In this model, mice are intrastriatally injected with 6-hydroxydopamine (6-OHDA) and dopaminergic neurons in the substantia nigra (SN) gradually die by retrograde degeneration. The SN were removed 2 h, 24 h, or 14 days after 6-OHDA administration. Levels of mRNAs related to cell death or survival were quantified using adaptor-tagged competitive PCR (ATAC-PCR). The cyclin D1 gene showed an immediate increase in mRNA expression. After 24 h, when dopaminergic neurons were under intense degeneration, levels of caspase 8 mRNA and p53 apoptosis effecter related to pmp 22 (PERP) mRNA increased and, conversely, FAS mRNA decreased. After 14 days, when the degeneration was attenuated, levels of PERP mRNA and serum- and glucocorticoid-regulated kinase (SGK) mRNA still increased. SGK has a similarity to AKT, which is an important molecule involved in nerve growth factor signal transduction. AKT mRNA levels are low in dopaminergic neurons. These results suggest that an increase in cyclin D1 mRNA triggers dopaminergic neurons to enter an abnormal cell cycle, which leads to neuronal degeneration and cell death, possibly induced by PERP and caspase 8. In addition to cell death-related genes, several survival-related genes are activated. SGK might function as a key enzyme for the survival of dopaminergic neurons.