Construction and analysis of a human testis/sperm-enriched interaction network: Unraveling the PPP1CC2 interactome.

BACKGROUND: Phosphoprotein phosphatase 1 catalytic subunit gamma 2 (PPP1CC2), a PPP1CC tissue-specific alternative splice restricted to testicular germ cells and spermatozoa, is essential for spermatogenesis and spermatozoa motility. The key to understand PPP1CC2 regulation lies on the characterization of its interacting partners. METHODS: We construct a testis/sperm-enriched protein interaction network and analyzed the topological properties and biological context of the network. Further the interaction of a potential target for pharmacological intervention was validated in human spermatozoa. RESULTS: A total of 1778 proteins and 32,187 interactions between them were identified in the testis/sperm-enriched network. The network analysis revealed the members of functional modules that interact more tightly with each other. In the network, PPP1CC was located in the fourth maximum core part (k=41) and had 106 direct interactors. Sixteen PPP1CC interactors were involved in spermatogenesis-related categories. Also, PPP1CC had 50 direct interactors, highly interconnected and many of them part of the network maximum core (k=44), associated with motility-related annotations, including several previously uncharacterized interactors, such as, LMNA, JAK2 and RIPK3. CONCLUSIONS: In this study we integrated tissue-specific protein expression and protein-protein interaction data in order to identify key PPP1CC2 complexes for male reproductive functions. One of the most intriguing interactors was A-kinase anchor protein 4 (AKAP4), a testis-specific protein related to infertility phenotypes and involved in all major motility-related annotations. GENERAL SIGNIFICANCE: We demonstrated for the first time the interaction between PPP1CC2 and AKAP4 in human spermatozoa and the potential of the complex as contraceptive target.

Amyloid precursor protein interaction network in human testis: sentinel proteins for male reproduction.

BACKGROUND: Amyloid precursor protein (APP) is widely recognized for playing a central role in Alzheimer's disease pathogenesis. Although APP is expressed in several tissues outside the human central nervous system, the functions of APP and its family members in other tissues are still poorly understood. APP is involved in several biological functions which might be potentially important for male fertility, such as cell adhesion, cell motility, signaling, and apoptosis. Furthermore, APP superfamily members are known to be associated with fertility. Knowledge on the protein networks of APP in human testis and spermatozoa will shed light on the function of APP in the male reproductive system. RESULTS: We performed a Yeast Two-Hybrid screen and a database search to study the interaction network of APP in human testis and sperm. To gain insights into the role of APP superfamily members in fertility, the study was extended to APP-like protein 2 (APLP2). We analyzed several topological properties of the APP interaction network and the biological and physiological properties of the proteins in the APP interaction network were also specified by gene ontologyand pathways analyses. We classified significant features related to the human male reproduction for the APP interacting proteins and identified modules of proteins with similar functional roles which may show cooperative behavior for male fertility. CONCLUSIONS: The present work provides the first report on the APP interactome in human testis. Our approach allowed the identification of novel interactions and recognition of key APP interacting proteins for male reproduction, particularly in sperm-oocyte interaction.

Generation and Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus: A Core-Shell Model.

We focus our research on how the core-shell organization controls behavior of the suprachiasmatic nucleus (SCN), how the core and shell are synchronized to the environment, what impact they have on the behavior of the SCN under different lighting conditions, and what mechanisms disrupt synchronization. To this end, we use a reduced Kuramoto model, with parameters inferred from experimental observations and calibrated for mice, and perform a detailed comparison between the model and experimental data under light-dark (LD), dark-dark (DD), and light-light (LL) conditions. The operating limits of free-running and entrained SCN activity under symmetric LD cycles are analyzed, with particular focus on the phenomena of anticipation and dissociation. Results reveal that the core-shell organization of the SCN enables anticipation of future events over circadian cycles. The model predicts the emergence of a second (dissociated) rhythm for large and small LD periods. Our results are in good qualitative and quantitative agreement with experimental observations of circadian dissociation. We further describe SCN activity under LL conditions and show that our model satisfies Aschoff's first rule, according to which the endogenous free-running circadian period observed under complete darkness will shorten in diurnal animals and lengthen in nocturnal animals under constant light. Our results strongly suggest that the Kuramoto model captures essential features of synchronization and entrainment in the SCN. Moreover, our approach is easily extendible to an arbitrary number of groups, with dynamics described by explicit equations for the group phase and synchronization index. Viewed together, the reduced Kuramoto model presents itself as a useful tool for exploring open problems in the study of circadian rhythms, one that can account for evolving views of the circadian system's organization, including peripheral clocks and inter-hemispheric interaction, and can be translated to other nocturnal and diurnal animals, including humans.

Systems biology of microbial communities.

Microbes exist naturally in a wide range of environments in communities where their interactions are significant, spanning the extremes of high acidity and high temperature environments to soil and the ocean. We present a practical discussion of three different approaches for modeling microbial communities: rate equations, individual-based modeling, and population dynamics. We illustrate the approaches with detailed examples. Each approach is best fit to different levels of system representation, and they have different needs for detailed biological input. Thus, this set of approaches is able to address the operation and function of microbial communities on a wide range of organizational levels.

The central role of peripheral nodes in directed network dynamics.

Many social, technological, and biological systems with asymmetric interactions display a variety of collective phenomena, such as opinion formation and synchronization. This has motivated much research on the dynamical impact of local and mesoscopic structure in directed networks. However, the unique constraints imposed by the global organization of directed networks remain largely undiscussed. Here, we control the global organization of directed Erdos-Rényi networks, and study its impact on the emergence of synchronization and ferromagnetic ordering, using Kuramoto and Ising dynamics. In doing so, we demonstrate that source nodes - peripheral nodes without incoming links - can disrupt or entirely suppress the emergence of collective states in directed networks. This effect is imposed by the bow-tie organization of directed networks, where a large connected core does not uniquely ensure the emergence of collective states, as it does for undirected networks.

Condensation phenomena of a conserved-mass aggregation model on weighted complex networks.

We investigate the condensation phase transitions of the conserved-mass aggregation (CA) model on weighted scale-free networks (WSFNs). In WSFNs, the weight w_{ij} is assigned to the link between the nodes i and j . We consider the symmetric weight given by w_{ij}=(k_{i}k_{j});{alpha} . On WSFNs, we numerically show that a certain critical alpha_{c} exists below which the CA model undergoes the same type of condensation transitions as those of the CA model on regular lattices. However, for alpha > or = alpha_{c} , the condensation always occurs for any density rho and omega . We analytically find alpha_{c}=(gamma-3)/2 on the WSFN with the degree exponent gamma . To obtain alpha_{c} , we analytically derive the scaling behavior of the stationary probability distribution P_{k};{infinity} of finding a walker at nodes with degree k , and the probability D(k) of finding two walkers simultaneously at the same node with degree k . We find P_{k};{infinity} approximately k;{alpha+1-gamma} and D(k) approximately k;{2(alpha+1)-gamma} , respectively. With P_{k};{infinity} , we also show analytically and numerically that the average mass m(k) on a node with degree k scales as k;{alpha+1} without any jumps at the maximal degree of the network for any rho as in SFNs with alpha=0 .

Association between socioeconomic attainments and suicidal ideation by age groups in Korea.

BACKGROUND:: Suicidal ideation is a strong antecedent of suicidal behavior, associated with increased likelihood of suicide. Thus, suicidal ideation serves to identify which groups are at more risk of suicide and has policy implications for targeting groups to prevent suicide. AIMS:: A substantial body of research has addressed potential determinants of suicide ideation in Korea. Little attention has been paid, however, to analyzing the extent to which socioeconomic attainments (education, household income, and employment status) are associated with risk of suicidal ideation, drawing on nationally representative data. METHODS:: Data were drawn from the 2012 Korea Welfare Panel Study (KOWEPS). Among the 12,606 respondents, the findings are based on 1,500 young adults (age 18-35) and 3,469 middle-aged adults (age 36-55) who answered a question about suicidal ideation. RESULTS:: For young adults, respondents from 2-year and 4-year colleges and higher had lower probabilities of suicidal ideation compared with respondents from high school. People out of the labor force also exhibited an elevated risk of suicidal ideation compared with those in waged employment. Middle-aged adults displayed different patterns. Middle-aged respondents from 4-year colleges or higher had an increased likelihood of suicidal ideation. The likelihood of reporting suicidal ideation was predicted to decrease as household income increased only for middle-aged adults. CONCLUSIONS:: The information about suicidal ideation was obtained from only one question of self-response, which limits the validity of the suicidal ideation measurement. The cross-sectional setting of the data prevents us from estimating causal relationships. Nevertheless, the findings imply that age-specific policy should be implemented to ameliorate differential risk for suicidal ideation and benefit public mental health in the long run.

Scaling property of flux fluctuations from random walks.

We study dynamical scaling of flux fluctuation sigma(t) from the one-random-walker model on regular lattices and complex networks and compare it to the surface width W(t) of a corresponding growth model. On the regular lattices, we analytically show that sigma(t) undergoes a crossover from the nontrivial scaling regime to the trivial one by increasing time t, and we verify the results by numerical simulations. In contrast to the results on the regular lattices, sigma(t) does not show any crossover behavior on complex networks and satisfies the scaling relation sigma(t) approximately t(1/2) for any t. On the other hand, we show that W(t) of the corresponding model on complex networks has two different scaling regimes, W approximately t(1/2) for t<>N .

Statistical properties of sampled networks by random walks.

We study the statistical properties of the sampled networks by a random walker. We compare topological properties of the sampled networks such as degree distribution, degree-degree correlation, and clustering coefficient with those of the original networks. From the numerical results, we find that most of topological properties of the sampled networks are almost the same as those of the original networks for gamma les approximately <3. In contrast, we find that the degree distribution exponent of the sampled networks for gamma>3 somewhat deviates from that of the original networks when the ratio of the sampled network size to the original network size becomes smaller. We also apply the sampling method to various real networks such as collaboration of movie actor, Worldwide Web, and peer-to-peer networks. All topological properties of the sampled networks are essentially the same as those of the original real networks.