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The interplay of fold recognition and experimental structure determination in structural genomics.

Achieving the goals of structural genomics initiatives depends on the outcomes of two groups of factors: the number and distribution of experimentally determined protein structures, and our ability to assign novel proteins to known structures (fold recognition) and use them to build models (modeling). The quality of the tools used for fold recognition defines the scope of experimental effort - the more distant the templates that can be recognized, the smaller the number of proteins that have to be solved. Recent improvements in fold recognition may have suggested that the goals of structural genomics initiatives are getting closer. However, problems that surfaced during the first few years of active work have put many of the early estimates in doubt and new ones are still slow in coming.

Animals↗

DC-virus interplay: a double edged sword.

Myeloid and plasmacytoid dendritic cells, a family of professional antigen presenting cells, are crucial in generating and maintaining anti-viral immunity. Many viruses have evolved to avoid, subvert, and even counterattack them. In this article, we focus on the tuning of innate and adaptive responses induced by human dendritic cells, and on the inhibition of their functions by viruses of medical significance. A constant "tug of war" goes on between dendritic cells and viruses and a main dendritic cell countermeasure is cross-presentation/priming.

Dendritic Cells↗

Aging and T cell development: interplay between progenitors and their environment.

Thymic involution is the hallmark of hematopoietic aging. Because T cell differentiation is a multistep process that occurs non-cell autonomously, aging defects can occur at multiple points along the developmental pathway, both in the T progenitors themselves and in the thymic stromal cells that support their development. Here we review the evidence for age-related thymopoiesis defects at key steps in the production of naïve mature T cells, highlighting the importance of the interaction between stromal aging and progenitor aging.

Aging↗

The interplay between circadian misalignment or sleep disturbances and cognition and brain function in individuals with different degrees of insulin resistance - a systematic review.

Disruption of sleep increases the risk of type 2 diabetes and worsens cognitive outcomes, yet few studies have evaluated the interaction between insulin resistance and sleep parameters in relation to cognitive outcomes or the risk of dementia. This systematic review examines how circadian misalignment and sleep disturbances affect cognition and neuroimaging findings in individuals with varying degrees of insulin resistance. Across 27 studies, disrupted circadian rhythmicity and sleep disturbances were negatively associated with brain health, possibly through its effects on insulin sensitivity, whereas the impact of sleep duration and quality were inconclusive. Methodological heterogeneity, reliance on cross-sectional designs, and limited control for confounders restricted definitive conclusions and highlighted the need for longitudinal and interventional studies with objective measurements. Nonetheless, the findings support circadian rhythmicity as a potentially modifiable risk factor for preserving cognition in insulin-resistant populations. Future research should prioritise prospective and interventional studies and focus on biological markers rather than self-reported outcomes.

Humans↗

Gender inequalities in US adult health: the interplay of race and ethnicity.

Gender differences in adult health are well documented, but only recently has research begun to investigate how race and ethnicity condition gendered health disparities. This paper contributes to this line of inquiry by assessing gender differences in morbidity across five major US racial and ethnic populations. Using data from the 1997-2001 waves of the National Health Interview Survey, the analysis examines differences in men and women's self-rated health, functional limitations, and life-threatening medical conditions for whites, blacks, Mexicans, Puerto Ricans, and Cubans. For each health outcome, we investigate the utility of socioeconomic factors in accounting for observed disparities. Contrary to finding universal excess in female morbidity, the results show that the magnitude of gender difference varies considerably by racial/ethnic group, health outcome, and comparison category. The most striking findings are the consistently higher levels of functional limitations for all women compared to men in their same racial/ethnic group and the poorer health of black women relative to both white and black men for all health measures, after adjustment for socioeconomic and background factors. The gender gap for all other health measures is more variable, and for Mexican women a difference is only evident for functional limitations and only when compared to Mexican men. Our results underscore the need for more research on the role of race and ethnicity in shaping gendered health inequalities and the mechanisms that lead to such variable patterns of difference across and within US racial and ethnic populations.

Adult↗

Folding studies of Cox17 reveal an important interplay of cysteine oxidation and copper binding.

Cox17 is a key mitochondrial copper chaperone involved in the assembly of cytochrome c oxidase (COX). The NMR solution structure of the oxidized apoCox17 isoform consists of a coiled-coil conformation stabilized by two disulfide bonds involving Cys(26)/Cys(57) and Cys(36)/Cys(47). This appears to be a conserved tertiary fold of a class of proteins, localized within the mitochondrial intermembrane space, that contain a twin Cys-x(9)-Cys sequence motif. An isomerization of one disulfide bond from Cys(26)/Cys(57) to Cys(24)/Cys(57) is required prior to Cu(I) binding to form the Cu(1)Cox17 complex. Upon further oxidation of the apo-protein, a form with three disulfide bonds is obtained. The reduction of all disulfide bonds provides a molten globule form that can convert to an additional conformer capable of binding up to four Cu(I) ions in a polycopper cluster. This form of the protein is oligomeric. These properties are framed within a complete model of mitochondrial import and COX assembly.

Amino Acid Sequence↗

A nutritive view on the host-pathogen interplay.

The interaction between pathogenic microbes and their host is determined by survival strategies on both sides, including competition for essential nutrients. During evolution, pathogenic microbes developed ways to access certain nutrients from the host, which, by contrast, can be exploited by the host for defence by restricting the availability of these nutrients. In this article, we review ecological aspects of the host-pathogen relationship and describe examples for competitive nutrient usage. We also discuss the beneficial probiotic microbes of the mammalian gut, which influence their environment including inflammatory host responses, and how they might be supported by prebiotic diets.

Amino Acids↗

Permeation in ion channels: the interplay of structure and theory.

Combined with high-resolution atomic-level crystal structures of channel forming peptides, theory has become a powerful tool for illuminating factors influencing permeation. Here, advantages and limitations of the more familiar continuum and molecular modeling techniques are briefly outlined. These methods are applied to issues of permeation in two different channel families: gramicidin and K(+) channels. Using structural data, theory provides verifiable atomic-level insights into permeation dynamics, channel conductance and molecular selectivity mechanisms. Not only can theory confirm experimental inference, it can also sometimes provide structural perspectives in advance of experiment.

Amino Acid Sequence↗

Nucleotide excision repair and its interplay with transcription.

Nucleotide excision repair (NER) is a multistep process capable to remove a variety of DNA distorting lesions from prokaryotic and eukaryotic genomes. In eukaryotic cells, the process requires more than 30 proteins to perform the different steps, i.e. recognition of DNA damage, single strand incisions and excision of the lesion-containing DNA fragment and DNA repair synthesis/ligation. NER can operate via two subpathways: global genome repair (GGR) and a specialized pathway coupled to active transcription (transcription-coupled repair, TCR) and directed to DNA lesions in the transcribed strand of active genes. Both in vivo as well as in cultured cells the fast removal of transcription blocking lesions by TCR is crucial to escape from lethal effects of inhibited transcription inhibition The most delicate step in NER is the recognition of the DNA lesions in their different chromatin context and the mechanism of damage recognition in GGR and TCR is principally different and requires specific proteins. In GGR, the XPC-HR23B is essential for the formation of the incision complex. In TCR the Cockayne syndrome (CS) gene products are key players in the recognition of a stalled RNA polymerase the presumed signaling structure for repair of transcribed strands. In this study, we show that the extent of recovery of UV-inhibited transcription and TCR strictly depends on the amount of CSB protein as well as the amount of DNA damage present in the cell. This indicates that the ratio between DNA damage frequency and CSB protein concentration in the cell is rather critical for acute cellular response, i.e. recovery of inhibited transcription upon DNA damage infliction, and hence cellular survival.

Animals↗

Interplay of Darwinian and frequency-dependent selection in the host-associated microbial populations.

In order to analyze the microevolutionary processes in host-associated microorganisms, we simulated the dynamics of rhizobia populations composed of a parental strain and its mutants possessing the altered fitness within "plant-soil" system. The population dynamics was presented as a series of cycles (each one involves "soil-->rhizosphere-->nodules-->soil" succession) described using recurrent equations. For representing the selection and mutation pressures, we used a universal approach based on calculating the shifts in the genetic ratios of competing bacterial genotypes within the particular habitats and across several habitats. Analysis of the model demonstrated that a balanced polymorphism may be established in rhizobia population: mutants with an improved fitness do not supplant completely the parental strain while mutants with a decreased fitness may be maintained stably. This polymorphism is caused by a rescue of low-fitted genotypes via negative frequency-dependent selection (FDS) that is implemented during inoculation of nodules and balances the Darwinian selection that occurs during multiplication or extinction of bacteria at different habitats. The most diverse populations are formed if the rhizobia are equally successful in soil and nodules, while a marked preference for any of these habitats results in the decrease of diversity. Our simulation suggests that FDS can maintain the mutualistic rhizobia-legume interactions under the stress conditions deleterious for surviving the bacterial strains capable for intensive N2 fixation. Genetic consequences of releasing the modified rhizobia strains may be addressed using the presented model.

Colony Count, Microbial↗

Intriguing interplay between viral proteins during herpesvirus assembly or: the herpesvirus assembly puzzle.

Herpes virions are complex particles that consist of more than 30 different virally encoded proteins. The molecular basis of how this complicated structure is assembled is only recently beginning to emerge. After replication in the host cell nucleus viral DNA is incorporated into preformed capsids which leave the nucleus by budding at the inner nuclear membrane resulting in the formation of primary enveloped virions in the perinuclear space. The primary envelope then fuses with the outer leaflet of the nuclear membrane, thereby releasing nucleocapsids into the cytoplasm. Final envelopment including the acquisition of more than 15 tegument and more than 10 envelope (glyco)proteins occurs by budding into Golgi-derived vesicles. Mature virions are released after fusion of the vesicle membrane with the plasma membrane of the cell. Thus, herpesvirus morphogenesis requires a sequence of envelopment--de-envelopment--re-envelopment processes which are distinct not only in the subcellular compartments in which they occur but also in the viral proteins involved. This review summarizes recent advances in our understanding of the complex protein-protein interactions involved in herpesvirus assembly and egress.

Animals↗

Interplay between FGF, one-eyed pinhead, and T-box transcription factors during zebrafish posterior development.

The zebrafish T-box transcription factors spadetail (spt) and the brachyury ortholog no tail (ntl) are together essential for posterior mesoderm formation. In addition to being functionally redundant, spt and ntl also genetically interact with zygotic mutant alleles of one-eyed pinhead (Zoep), leading to synergistic mesodermal defects. Here we have used genetic and pharmacological assays to address the mechanism of these interactions. We show that Zoep and ntl are together required upstream of spt expression, accounting for the severity of the mesodermal defects in Zoep;ntl embryos. Since Xenopus brachyury is proposed to regulate fgf expression, and FGF signaling is required for spt expression, we analyzed the involvement of the FGF signaling pathway in these genetic interactions. Using a specific inhibitor of FGFR activity to indirectly assay the strength of FGF signaling in individual embryos, we found that spt and ntl mutant embryos were both hypersensitive to the FGFR inhibitor. This hypersensitivity is consistent with the possibility that Spt and Ntl function upstream of FGF signaling. Furthermore, we show that minor pharmacological or genetic perturbations in FGF signaling are sufficient to dramatically enhance the Zoep mutant phenotype, providing a plausible explanation for why Zoep genetically interacts with spt and ntl. Finally, we show that Zoep and ace/fgf8 function are essential for the formation of all posterior tissues, including spinal cord. Taken together, our data provide strong in vivo support for the regulation of FGF signaling by T-box transcription factors, and the cooperative activity of Oep and FGF signaling during the formation of posterior structures.

Animals↗

Interplay between activator-inhibitor coupling and cell-matrix adhesion in a cellular automaton model for chondrogenic patterning.

We present a stochastic cellular automaton model for the behavior of limb bud precartilage mesenchymal cells undergoing chondrogenic patterning. This "agent-oriented" model represents cells by points on a lattice that obey rules motivated by experimental findings. The "cells" follow these rules as autonomous agents, interacting with other cells and with the microenvironments cell activities produce. The rules include random cell motion, production and lateral deposition of a substrate adhesion molecule (SAM, corresponding to fibronectin), production and release of a diffusible growth factor ("activator," corresponding to TGF-beta) that stimulates production of the SAM, and another diffusible factor ("inhibitor") that suppresses the activity of the activator. We implemented the cellular automaton on a two-dimensional (2D) square lattice to emulate the quasi-2D micromass culture extensively used to study patterning in avian limb bud precartilage cells. We identified parameters that produce nodular patterns that resemble, in size and distribution, cell condensations in leg-cell cultures, thus establishing a correspondence between in vitro and in silico results. We then studied the in vitro and in silico micromass cultures experimentally. We altered the standard in vitro micromass culture by diluting the initial cell density, transiently exposing it to exogenous activator, suppressing the inhibitor, and constitutively activating fibronectin production. We altered the standard in silico micromass culture in each case by changing the corresponding parameter. In vitro and in silico experiments agreed well. We also used the model to test hypotheses for differences in the in vitro patterns of cells derived from chick embryo forelimb and hindlimb. We discuss the applicability of this model to limb development in vivo and to other organ development.

Algorithms↗

Reproductive cycle of the Neotropical Crotalus durissus terrificus: I. Seasonal levels and interplay between steroid hormones and vasotocinase.

Crotaline snakes present delayed fertilization and sperm storage because secondary vitellogenesis is not completed by the time of mating. The release of vitellogenesis and synchrony between ovulation and fertilization suggest a steroidal modulation. We investigated changes of sexual steroid levels during reproduction in the Neotropical rattlesnake Crotalus durissus terrificus, analyzing macroscopical variations of reproductive condition (vitellogenesis, pregnancy, and post-partum) and plasma levels of estradiol, progesterone, and vasotocinase cystine aminopeptidase (CAP) activity over 2 years. Data showed 44.4% non-reproductive snakes (40.1% primary vitellogenesis and 4.3% post-partum) and 55.6% reproductive (36.8% secondary vitellogenesis and 18.8% pregnant). Estradiol was low in spring and summer, increasing in autumn till it peaked in winter. Estradiol in secondary vitellogenesis was significantly higher than in primary vitellogenesis, or in pregnant and post-partum females, Progesterone dropped significantly in autumn compared to summer, winter, and spring. Pregnant females showed the highest levels of progesterone compared to primary or secondary vitellogenesis, or post-partum females. CAP activity showed lowest values in reproductive females in autumn and greatest levels in post-partum females. A significant negative linear relationship was obtained between CAP activity and estradiol. The combination of morphological observations, levels of steroids and CAP activity allowed us to suggest a similar morphological reproductive pattern between temperate and tropical rattlesnakes, and to infer the role of estradiol, progesterone and CAP activity on vitellogenesis, gestation and sperm storage, respectively.

Animals↗

Interplay of TNF-alpha and IL-10 in regulating oxidative stress in isolated adult cardiac myocytes.

Oxidative stress and inflammation are considered to be important factors in the pathogenesis of congestive heart failure subsequent to myocardial infarction. Endogenous TNF-alpha plays a central role in initiating and sustaining the inflammatory response. IL-10, an anti-inflammatory cytokine, has been shown to antagonize some of the deleterious effects of TNF-alpha. In this study, we tested whether an imbalance of these two contrasting cytokines leads to increased oxidative stress and cardiac myocyte dysfunction. Isolated adult rat cardiac myocytes were exposed to different concentrations of TNF-alpha and IL-10 (1-20 ng/ml) alone or in combination. As a positive control, cells were also exposed to H2O2 (100 microI) to induce oxidative stress. An exposure to TNF-alpha (10 ng/ml) caused a significant decrease in both protein and mRNA for manganese superoxide dismutase and catalase, decreased glutathione peroxidase protein, increased intracellular reactive oxygen species and lipid peroxidation, and caused cell injury as measured by creatine kinase release. IL-10 treatment (10 ng/ml) by itself had no effect on any of these parameters, but it prevented all the above listed changes caused by TNF-alpha. IL-10/TNF-alpha ratio of lower or higher than 1 was less effective in reducing TNF-alpha generated oxidative stress. H2O2 treatment increased oxidative stress and cell injury and TNF-alpha mimicked these effects. This study suggests that a proper balance between IL-10 and TNF-alpha, rather than any of the individual cytokines is of more physiological importance in mediating oxidative-stress-induced cardiac injury.

Animals↗

The interplay of attention and bimanual coordination dynamics.

Despite their common origin, studies on motor coordination and on attentional load have developed into separate fields of investigation, bringing out findings, methods, and theories which are diverse if not mutually exclusive. Sitting at the intersection of these two fields, this article addresses the issue of behavioral flexibility by investigating how intention modifies the stability of existing patterns of coordination between moving limbs. It addresses the issue, largely ignored until now, of the attentional cost incurred by the central nervous system (CNS) in maintaining a coordination pattern at a given level of stability, in particular under different attentional priority requirements. The experimental paradigm adopted in these studies provides an original mix of a classical measure of attentional load, namely, reaction time, and of a dynamic approach to coordination, most suitable for characterizing the dynamic properties of coordinated behavior and behavioral change. Findings showed that central cost and pattern stability covary, suggesting that bimanual coordination and the attentional activity of the CNS involved in maintaining such a coordination bear on the same underlying dynamics. Such a conclusion provides a strong support to a unified approach to coordination encompassing a conceptualization in terms of information processing and another, more recent framework rooted in self-organization theories and dynamical systems models.

Attention↗