Cultural niche construction with application to fertility control: A model for education and social transmission of contraceptive use.

The evolution of a cultural trait may be affected by niche construction, or changes in the selective environment of that trait due to the inheritance of other cultural traits that make up a cultural background. This study investigates the evolution of a cultural trait, such as the acceptance of the idea of contraception, that is both vertically and horizontally transmitted within a homogeneous social network. Individuals may conform to the norm, and adopters of the trait have fewer progeny than others. In addition, adoption of this trait is affected by a vertically transmitted aspect of the cultural background, such as the preference for high or low levels of education. Our model shows that such cultural niche construction can facilitate the spread of traits with low Darwinian fitness while providing an environment that counteracts conformity to norms. In addition, niche construction can facilitate the 'demographic transition' by making reduced fertility socially accepted.

Spatial evolution of human cultures inferred through Bayesian phylogenetic analysis.

Spatial distribution of human culture reflects both descent from the common ancestor and horizontal transmission among neighbouring populations. To analyse empirically documented geographical variations in cultural repertoire, we will describe a framework for Bayesian statistics in a spatially explicit model. To consider both horizontal transmission and mutation of the cultural trait in question, our method employs a network model in which populations are represented by nodes. Using algorithms borrowed from Bayesian phylogenetic analysis, we will perform a Markov chain Monte Carlo (MCMC) method to compute the posterior distributions of parameters, such as the rate of horizontal transmission and the mutation rates among trait variants, as well as the identity of trait variants in unobserved populations. Besides the inference of model parameters, our method enables the reconstruction of the genealogical tree of the focal trait, provided that the mutation rate is sufficiently small. We will also describe a heuristic algorithm to reduce the dimension of the parameter space explored in the MCMC method, where we simulate the coalescent process in the network of populations. Numerical examples show that our algorithms compute the posterior distribution of model parameters within a practical computation time, although the posterior distribution tends to be broad if we use uninformative priors.

Cultural transmission of traditional songs in the Ryukyu Archipelago.

Geographic patterns of cultural variations are affected by how cultural traits are transmitted within and between populations. It has been argued that cultural traits are transmitted in different manners depending on their characteristics; for example, words for basic concepts are less liable to horizontal transmission between populations (i.e., borrowing) than other words. Here we examine the geographic variation of traditional songs in the Ryukyu Archipelago, southwestern islands of Japan, to explore cultural evolution of music with a focus on different social contexts in which songs are sung. Published scores of 1,342 traditional songs are coded using the CantoCore song classification scheme and distances between the songs are calculated from the codings. Neighbor-Net graphs of regions/islands are generated on the basis of the musical distances, and delta scores are obtained to examine the treelikeness of the networks. We also perform analysis of molecular variance (AMOVA) to evaluate the extent of musical diversification among regions/islands. Our results suggest that horizontal transmission between populations has played a greater role in the formation of musical diversity than that of linguistic diversity in the Ryukyu Archipelago and that the social context in which songs are sung has an effect on how they are transmitted within and between populations. In addition, we compare the observed patterns of song diversity among regions/islands with those of lexical and mitochondrial-DNA (mtDNA) diversity, showing that the variation of songs sung in the "work" context are associated with the linguistic variation, whereas no association is found between the musical and genetic variation.

Application of a Markovian ancestral model to the temporal and spatial dynamics of cultural evolution on a population network.

Cultural macroevolution concerns a long-term evolutionary process involving transmission of non-genetic or cultural traits between populations as well as birth and death of populations. To understand the spatial dynamics of cultural macroevolution, we present a one-locus model of cultural diffusion in which a cultural trait is transmitted on a network of populations. Borrowing the method of ancestral backward process from population genetics, our model explores the lineage of a trait variant sampled in the present generation to quantify when and where the variant was invented. Mathematical analysis of the model enables us to predict the distribution of cultural age in each population of the network, estimate the frequencies of trait variants originating from given populations, and discuss the time it takes for a trait variant to diffuse between a given pair of populations. We also perform numerical analysis on random scale-free network of populations to investigate the effect of network topology and innovation rate on the age and origin of variants in each population. The result suggests that trait variants are more likely to derive from a population with higher innovation rate. Our numerical analysis also shows that trait variants invented in populations with higher network-centrality values are likely to be maintained at a higher frequency and transmitted to other populations in a shorter time period.

Switched Aß43 generation in familial Alzheimer's disease with presenilin 1 mutation.

Presenilin (PS) with a genetic mutation generates abundant ß-amyloid protein (Aß) 43. Senile plaques are formed by Aß43 in the cerebral parenchyma together with Aß42 at middle ages. These brains cause the early onset of Alzheimer's disease (AD), which is known as familial Alzheimer's disease (FAD). Based on the stepwise processing model of Aß generation by γ-secretase, we reassessed the levels of Aßs in the cerebrospinal fluid (CSF) of FAD participants. While low levels of Aß38, Aß40, and Aß42 were generated in the CSF of FAD participants, the levels of Aß43 were unchanged in some of them compared with other participants. We sought to investigate why the level of Aß43 was unchanged in FAD participants. These characteristics of Aß generation were observed in the γ-secretase assay in vitro using cells, which express FAD mutations in PS1. Aß38 and Aß40 generation from their precursors, Aß42 and Aß43, was decreased in PS1 mutants compared with wild-type (WT) PS1, as observed in the CSF. Both the ratios of Aß38/Aß42 and Aß40/Aß43 in PS1 mutants were lower than those in the WT. However, the ratio of Aß43/amyloid precursor protein intracellular domain (AICD) increased in the PS1 mutants in an onset age dependency, while other Aß/AICD ratios were decreased or unchanged. Importantly, liquid chromatography-mass spectrometry found that the generation of Aß43 was stimulated from Aß48 in PS1 mutants. This result indicates that PS1 mutants switched the Aß43 generating line, which reflects the level of Aß43 in the CSF and forming senile plaques.

Childcare support and child social development in Japan: investigating the mediating role of parental psychological condition and parenting style.

In humans, support from partners and alloparents is crucial for successful child-rearing and optimal child development. However, the complex relationships among childcare support, children's outcomes and parental characteristics have not been fully examined. We investigate how three sources of partner and alloparental support-partner's childcare participation, support from children's grandparents and support from non-kin-can be associated with child social development. We hypothesize that the associations between childcare support from partners/alloparents and child social development are partly mediated by parental psychological condition and parenting style. To test this, we conducted path analyses on online survey data collected in 2016 from parents of 3- to 5-year-old children in Japan. We found no evidence that childcare support had direct positive effects on child social development. Rather, the benefit of childcare support was mediated by its effects on parental psychological condition and parenting style, which in turn improved children's outcomes. At the same time, we found some evidence that greater availability of childcare support was directly associated with more behavioural difficulties in children. Our findings reveal the complex pathways between childcare support, parental characteristics and children's outcomes in Japan, showing potential mechanisms behind parental and alloparental effects in industrialized populations. This article is part of the theme issue 'Multidisciplinary perspectives on social support and maternal-child health'.

A demographic test of accidental versus intentional island colonization by Pleistocene humans.

This study evaluates the hypothesis that some documented cases of long-distance sea crossing by the Late Pleistocene Homo sapiens occurred as a result of accidental drifting, rather than by intentional seafaring. For that purpose, we use an existing computer simulation framework, with some modifications, to investigate the likelihood that a planned or unplanned island colonization by a small group of individuals will persist to establish a viable population. Within the original framework, planned colonization was operationally characterized as being initiated by equal numbers of unrelated young men and women, whereas for unplanned colonization, those who migrate inadvertently were regarded in effect as a random sample of the whole population. Here, we consider a different scenario for unplanned colonization, which we believe is more relevant to sea crossing by the Late Pleistocene humans, that is, we assume that unplanned colonization occurs when members of households on watercrafts with limited voyaging capabilities are drifted away by ocean currents and washed up on a distant island. We also extend the previous analysis by considering a broader range of combinations of fertility and mortality schedules that individuals are assumed to follow. Our simulations suggest the following: (1) colonization of an island by ten or fewer unrelated young men and women can be successful within the feasible range of fertility and mortality levels; (2) in comparison, the likelihood of success for unplanned colonization is considerably smaller for the same range of fertility and mortality levels; and (3) there exists a small range of parameter combinations for which unplanned colonization has a non-negligible prospect of success even without assuming recurrent accidental drifts to the same island, and thus, the accidental colonization scenario cannot be totally excluded. In addition, we find that the minimum founding population required for successful colonization varies substantially depending on the fertility and mortality levels.

Quantifying the spatial pattern of dialect words spreading from a central population.

Some dialect words are shared among geographically distant groups of people without close interaction. Such a pattern may indicate the current or past presence of a cultural centre exerting a strong influence on peripheries. For example, concentric distributions of dialect variants in Japan may be explicable by repeated inventions of new variants at Kyoto, the ancient capital, with subsequent outward diffusion. Here we develop a model of linguistic diffusion within a population network to quantify the distribution of variants created at the central population. Equilibrium distributions of word ages are obtained for idealized networks and for a realistic network of Japanese prefectures. Our model successfully replicates the observed pattern, supporting the notion that a centre-periphery social structure underlies the emergence of concentric patterns. Unlike what has previously been claimed, our model indicates that a novelty bias in linguistic transmission is not always necessary to account for the concentric pattern, whereas some bias in the direction of transmission between populations is needed to be consistent with the observed absence of old words near the central population. Our analysis on the realistic network also suggests that the process of linguistic transmission was not much affected by between-prefecture differences in population size.

γ-Secretase Activity Is Associated with Braak Senile Plaque Stages.

Amyloid ß-proteins (Aßs) Aß1-42 and Aß1-43 are converted via two product lines of γ-secretase to Aß1-38 and Aß1-40. This parallel stepwise processing model of γ-secretase predicts that Aß1-42 and Aß1-43, and Aß1-38 and Aß1-40 are proportional to each other, respectively. To obtain further insight into the mechanisms of parenchymal Aß deposition, these four Aß species were quantified in insoluble fractions of human brains (Brodmann areas 9 to 11) at various Braak senile plaque (SP) stages, using specific enzyme-linked immunosorbent assays. With advancing SP stages, the amounts of deposited Aß1-43 in the brain increased proportionally to those of Aß1-42. Similarly, the amounts of deposited Aß1-38 correlated with those of Aß1-40. Surprisingly, the ratios of deposited Aß1-38/Aß1-42 and Aß1-40/Aß1-43 were proportional and discriminated the Braak SP stages accurately. This result indicates that the generation of Aß1-38 and Aß1-40 decreased and the generation of Aß1-42 and Aß1-43 increased with advancing SP stages. Thus, Aßs deposition might depend on γ-secretase activity, as it does in the cerebrospinal fluid. Here, the extracted γ-secretase from Alzheimer disease brains generates an amount of Aß1-42 and Aß1-43 compared with cognitively normal brains. This refractory γ-secretase localized in detergent-solubilized fractions from brain cortices. But activity modulated γ-secretase, which decreases Aß1-42 and Aß1-43 in the cerebrospinal fluid, localized in detergent-insoluble fractions. These drastic alterations reflect Aß situation in Alzheimer disease brains.

Ectopic Expression Induces Abnormal Somatodendritic Distribution of Tau in the Mouse Brain.

Tau is a microtubule (MT)-associated protein that is localized to the axon. In Alzheimer's disease, the distribution of tau undergoes a remarkable alteration, leading to the formation of tau inclusions in the somatodendritic compartment. To investigate how this mislocalization occurs, we recently developed immunohistochemical tools that can separately detect endogenous mouse and exogenous human tau with high sensitivity, which allows us to visualize not only the pathological but also the pre-aggregated tau in mouse brain tissues of both sexes. Using these antibodies, we found that in tau-transgenic mouse brains, exogenous human tau was abundant in dendrites and somata even in the presymptomatic period, whereas the axonal localization of endogenous mouse tau was unaffected. In stark contrast, exogenous tau was properly localized to the axon in human tau knock-in mice. We tracked this difference to the temporal expression patterns of tau. Endogenous mouse tau and exogenous human tau in human tau knock-in mice exhibited high expression levels during the neonatal period and strong suppression into the adulthood. However, human tau in transgenic mice was expressed continuously and at high levels in adult animals. These results indicated the uncontrolled expression of exogenous tau beyond the developmental period as a cause of mislocalization in the transgenic mice. Superresolution microscopic and biochemical analyses also indicated that the interaction between MTs and exogenous tau was impaired only in the tau-transgenic mice, but not in knock-in mice. Thus, the ectopic expression of tau may be critical for its somatodendritic mislocalization, a key step of the tauopathy.SIGNIFICANCE STATEMENT Somatodendritic localization of tau may be an early step leading to the neuronal degeneration in tauopathies. However, the mechanisms of the normal axonal distribution of tau and the mislocalization of pathological tau remain obscure. Our immunohistochemical and biochemical analyses demonstrated that the endogenous mouse tau is transiently expressed in neonatal brains, that exogenous human tau expressed corresponding to such tau expression profile can distribute into the axon, and that the constitutive expression of tau into adulthood (e.g., human tau in transgenic mice) results in abnormal somatodendritic localization. Thus, the expression profile of tau is tightly associated with the localization of tau, and the ectopic expression of tau in matured neurons may be involved in the pathogenesis of tauopathy.

Cultural and evolutionary dynamics with best-of-k learning when payoffs are uncertain.

Social learning not only takes the form of random copying of other individuals, but also involves learners' choice of what to learn or from whom to learn. Best-of-k learning refers to a kind of success-biased social learning strategy in which a learner randomly samples k exemplars from the population and imitates the most "successful" one, or the one gaining the highest payoff. While it is intuitive that best-of-k learning can promote the spread of superior variants and thereby enable cumulative cultural evolution, a previous mathematical analysis has shown that it may sometimes result in maladaptive cultural evolution when the payoffs associated with cultural variants vary stochastically. If so, best-of-k learners may be selectively disfavored and in the long run replaced by unbiased learners, who simply copy someone chosen at random. Here we develop new mathematical models that are more simplified and mathematically tractable than the previous model to achieve a fuller analysis of cultural and evolutionary dynamics involving best-of-k learning and stochastic payoffs. We find that best-of-k learning, unlike unbiased learning, can facilitate the invasion of an on average inferior variant that sometimes gives a very high payoff, destabilize a population fixed with a variant that is on average superior but occasionally results in a very low payoff, and maintain cultural polymorphism at equilibrium. Considering gene-culture coevolution of learning rules and cultural variants, under the assumption that social learning is always faithful, it is shown that a population of best-of-k learners at the culturally polymorphic state can always be invaded by unbiased learners and eventually converges to a culturally monomorphic state. Nonetheless, we show that best-of-k learning can be stable against invasion by unbiased learning if social learning is sometimes combined with individual learning.

Visualization of Amyloid ß Deposits in the Human Brain with Matrix-assisted Laser Desorption/Ionization Imaging Mass Spectrometry.

The neuropathology of Alzheimer's disease (AD) is characterized by the accumulation and aggregation of amyloid ß (Aß) peptides into extracellular plaques of the brain. The Aß peptides, composed of 40 amino acids, are generated from amyloid precursor proteins (APP) by ß- and γ-secretases. Aß is deposited not only in cerebral parenchyma but also in leptomeningeal and cerebral vessel walls, known as cerebral amyloid angiopathy (CAA). While a variety of Aß peptides were identified, the detailed production and distribution of individual Aß peptides in pathological tissues of AD and CAA have not been fully addressed. Here, we develop a protocol of matrix-assisted laser desorption/ionization-based imaging mass spectrometry (MALDI-IMS) on human autopsy brain tissues to obtain comprehensive protein mapping. For this purpose, human cortical specimens were obtained from the Brain Bank at the Tokyo Metropolitan Institute of Gerontology. Frozen cryosections are cut and transferred to indium-tin-oxide (ITO)-coated glass slides. Spectra are acquired using the MALDI system with a spatial resolution up to 20 µm. Sinapinic acid (SA) is uniformly deposited on the slide using either an automatic or a manual sprayer. With the current technical advantages of MALDI-IMS, a typical data set of various Aß species within the same sections of human autopsied brains can be obtained without specific probes. Furthermore, high-resolution (20 µm) imaging of an AD brain and severe CAA sample clearly shows that Aß1-36 to Aß1-41 were deposited into leptomeningeal vessels, while Aß1-42 and Aß1-43 were deposited in cerebral parenchyma as senile plaque (SP). It is feasible to adopt MALDI-IMS as a standard approach in combination with clinical, genetic, and pathological observations in understanding the pathology of AD, CAA, and other neurological diseases based on the current strategy.

The effect of sexual selection on phenotypic diversification among human populations: A simulation study.

Despite the generally low level of inter-population genetic differentiation in humans as compared with great apes, it has long been acknowledged that there is a considerable amount of geographic variations in human phenotypes, for example, skin pigmentation, cranial morphology, and soft-tissue facial morphology, to name but a few. Indeed, recent studies have suggested that the extent of inter-population diversity in some human phenotypes is greater than expected from random drift alone. Such an excess of phenotypic diversity is often attributed to adaptation to local environment. However, this account is valid only if populations differ in some ecological aspects that elicit differential selection acting on a given phenotypic feature. Another long-standing hypothesis is the sexual selection hypothesis, which claims that phenotypic diversity arises and/or is maintained owing to variations in preference for mating partners. In this paper, we explore the plausibility of the sexual selection hypothesis by means of computer simulations, in which the inter-population diversity of a quantitative trait is evaluated against the expectation from random drift, using the QST-FST comparison. As possible driving factors of sexual selection, we consider two types of mate-choice preference: preference for the population average and preference for a culturally-transmitted arbitrary trend. Our simulations suggest that sexual selection can, under certain circumstances, maintain and/or generate a detectable amount of inter-population phenotypic diversity, even when populations are ecologically identical and loosely connected to each other by mutual migration. Since mating decisions in humans are considerably affected by social learning, human mate-choice preference may be more readily diversified between populations than in other animals. We suggest, therefore, that some of the observed human phenotypic variations may be better understood as a product of cultural, rather than ecological, diversification.

Distribution of endogenous normal tau in the mouse brain.

Tau is a microtubule-associated protein (MAP) that is localized to the axon. In Alzheimer's disease (AD), the distribution of tau undergoes a remarkable alteration, leading to the formation of tau inclusions in the somatodendritic compartment. While the abnormal aggregated tau has been extensively studied in human patient tissues and animal models of AD, how normal tau localizes to the axon, which would be the foundation to understand how the mis-localization occurs, has not been well studied due to the poor detectability of normal unaggregated tau in vivo. Therefore, we developed immunohistochemical techniques that can detect normal mouse and human tau in brain tissues with high sensitivity. Using these techniques, we demonstrate the global distribution of tau in the mouse brain and confirmed that normal tau is exclusively localized to the axonal compartment in vivo. Interestingly, tau antibodies strongly labeled nonmyelinated axons such as hippocampal mossy fibers, while white matters generally exhibited low levels of immunoreactivity. Furthermore, mouse tau is highly expressed not only in neurons but also in oligodendrocytes. With super resolution imaging using the stimulated-depletion microscopy, axonal tau appeared punctate rather than fibrous, indicating that tau decorates microtubules sparsely. Co-labeling with presynaptic and postsynaptic markers revealed that normal tau is not localized to synapses but sparsely distributes in the axon. Taken together, this study reports novel antibodies to investigate the localization and mis-localization of tau in vivo and novel findings of normal tau localization in the mouse brain.

Imbalanced Expression of Tau and Tubulin Induces Neuronal Dysfunction in C. elegans Models of Tauopathy.

Tauopathy is a type of dementia defined by the accumulation of filamentous tau inclusions in neural cells. Most types of dementia in the elderly, including Alzheimer's disease, are tauopathies. Although it is believed that tau protein abnormalities and/or the loss of its functions results in neurodegeneration and dementia, the mechanism of tauopathy remains obscure. Loss of microtubules and/or tubulin is a known consequence of tau accumulating in neurons in Alzheimer's disease. In other words, there is an excess level of tau relative to tubulin in tauopathy neurons. To test whether this imbalance of tau and tubulin expression results in the neurotoxicity of tau, we developed several transgenic C. elegans lines that express human tau at various levels in pan-neurons. These worms showed behavioral abnormalities in a tau expression-dependent manner. The knockdown of a tubulin-specific chaperon, or a subset of tubulin, led to enhanced tau toxicity even in low-expressing tau-transgenic worms that showed no abnormal behaviors. In addition, the suppression of tau expression in tubulin knockdown worms rescued neuronal dysfunction. Thus, not only the overexpression of tau but also a reduction in tubulin can trigger the neurotoxicity of tau. Tau expressed in worms was also highly phosphorylated and largely bound to tubulin dimers rather than microtubules. Relative amount of tubulin-unbound tau was increased in high-expressing tau-transgenic worms showing tau toxicity. We further demonstrated that tau aggregation was inhibited by co-incubation of purified tubulin in vitro, meaning sufficient amounts of tubulin can protect against the formation of tau inclusions. These results suggest that the expression ratio of tau to tubulin may be a determinant of the tauopathy cascade.

Semagacestat Is a Pseudo-Inhibitor of γ-Secretase.

γ-secretase inhibitors (GSI) are drugs developed to decrease amyloid-ß peptide (Aß) production by inhibiting intramembranous cleavage of ß-amyloid protein precursor (ßAPP). However, a large phase 3 trial of semagacestat, a potential non-transition state analog (non-TSA) GSI, in patients with Alzheimer's disease (AD) was terminated due to unexpected aggravation of cognitive deficits and side effects. Here, we show that some semagacestat effects are clearly different from a phenotype caused by a loss of function of presenilins, core proteins in the γ-secretase complex. Semagacestat increases intracellular byproduct peptides, produced along with Aß through serial γ-cleavage of ßAPP, as well as intracellular long Aß species, in cell-based and in vivo studies of AD model mice. Other potential non-TSA GSIs, but not L685,458, a TSA GSI, have similar effects. Furthermore, semagacestat inhibits release of de novo intramembranous γ-byproducts to the soluble space. Thus, semagacestat is a pseudo-GSI, and therefore, the semagacestat clinical trial did not truly test the Aß hypothesis.

Distinct deposition of amyloid-ß species in brains with Alzheimer's disease pathology visualized with MALDI imaging mass spectrometry.

Amyloid ß (Aß) deposition in the brain is an early and invariable feature of Alzheimer's disease (AD). The Aß peptides are composed of about 40 amino acids and are generated from amyloid precursor proteins (APP), by ß- and γ-secretases. The distribution of individual Aß peptides in the brains of aged people, and those suffering from AD and cerebral amyloid angiopathy (CAA), is not fully characterized. We employed the matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) to illustrate the spatial distribution of a broad range of Aß species in human autopsied brains. With technical advancements such as formic acid pretreatment of frozen autopsied brain samples, we have: i) demonstrated that Aß1-42 and Aß1-43 were selectively deposited in senile plaques while full-length Aß peptides such as Aß1-36, 1-37, 1-38, 1-39, 1-40, and Aß1-41 were deposited in leptomeningeal blood vessels. ii) Visualized distinct depositions of N-terminal truncated Aß40 and Aß42, including pyroglutamate modified at Glu-3 (N3pE), only with IMS for the first time. iii) Demonstrated that one single amino acid alteration at the C-terminus between Aß1-42 and Aß1-41 results in profound changes in their distribution pattern. In vitro, this can be attributed to the difference in the self-aggregation ability amongst Aß1-40, Aß1-41, and Aß1-42. These observations were further confirmed with immunohistochemistry (IHC), using the newly developed anti-Aß1-41 antibody. Here, distinct depositions of truncated and/or modified C- and N-terminal fragments of Aßs in AD and CAA brains with MALDI-IMS were visualized in a spacio-temporal specific manner. Specifically, Aß1-41 was detected both with MALDI-IMS and IHC suggesting that a single amino acid alteration at the C-terminus of Aß results in drastic distribution changes. These results suggest that MALDI-IMS could be used as a standard approach in combination with clinical, genetic, and pathological observations in understanding the pathology of AD and CAA.

Evolution of group-wise cooperation: Is direct reciprocity insufficient?

Group-wise cooperation, or cooperation among three or more individuals, is an integral part of human societies. It is likely that group-wise cooperation also played a crucial role in the survival of early hominins, who were confronted with novel environmental challenges, long before the emergence of Homo sapiens. However, previous theoretical and empirical studies, focusing mainly on modern humans, have tended to suggest that evolution of cooperation in sizable groups cannot be explained by simple direct reciprocity and requires some additional mechanisms (reputation, punishment, etc.), which are cognitively too demanding for early hominins. As a partial resolution of the paradox, our recent analysis of a stochastic evolutionary model, which considers the effect of random drift, has revealed that evolution of group-wise cooperation is more likely to occur in larger groups when an individual's share of the benefit produced by one cooperator does not decrease with increasing group size (i.e., goods are non-rivalrous). In this paper, we further extend our previous analysis to explore possible consequences of introducing rare mistakes in behavior or imperfect information about behavior of others on the model outcome. Analyses of the extended models show that evolution of group-wise cooperation can be facilitated by large group size even when individuals intending to cooperate sometimes fail to do so or when all the information about the past behavior of group members is not available. We argue, therefore, that evolution of cooperation in sizable groups does not necessarily require other mechanisms than direct reciprocity if the goods to be produced via group-wise cooperation are non-rivalrous.

Alanine substitutions in the GXXXG motif alter C99 cleavage by γ-secretase but not its dimerization.

The amyloid ß (Aß) protein is a major component of senile plaques, one of the neuropathological hallmarks of Alzheimer's disease. Amyloidogenic processing of amyloid precursor protein (APP) by ß- and γ-secretases leads to production of Aß. APP contains tandem triple repeats of the GXXXG motif in its extracellular juxtamembrane and transmembrane regions. It is reported that the GXXXG motif is related to protein-protein interactions, but it remains controversial whether the GXXXG motif in APP is involved in substrate dimerization and whether dimerization affects γ-secretase-dependent cleavage. Therefore, the relationship between the GXXXG motifs, substrate dimerization, and γ-secretase-dependent cleavage sites remains unclear. Here, we applied blue native poly acrylamide gel electrophoresis to examine the effect of alanine substitutions within the GXXXG motifs of APP carboxyl terminal fragment (C99) on its dimerization and Aß production. Surprisingly, alanine substitutions in the motif failed to alter C99 dimerization in detergent soluble state. Cell-based and solubilized γ-secretase assays demonstrated that increasing alanine substitutions in the motif tended to decrease long Aß species such as Aß42 and Aß43 and to increase in short Aß species concomitantly. Our data suggest that the GXXXG motif is crucial for Aß production, but not for C99 dimerization.