MLL: How complex does it get?

The mixed lineage leukemia (MLL) gene encodes a very large nuclear protein homologous to Drosophila trithorax (trx). MLL is required for the proper maintenance of HOX gene expression during development and hematopoiesis. The exact regulatory mechanism of HOX gene expression by MLL is poorly understood, but it is believed that MLL functions at the level of chromatin organization. MLL was identified as a common target of chromosomal translocations associated with human acute leukemias. About 50 different MLL fusion partners have been isolated to date, and while similarities exist between groups of partners, there exists no unifying property shared by all the partners. MLL gene rearrangements are found in leukemias with both lymphoid and myeloid phenotypes and are often associated with infant and secondary leukemias. The immature phenotype of the leukemic blasts suggests an important role for MLL in the early stages of hematopoietic development. Mll homozygous mutant mice are embryonic lethal and exhibit deficiencies in yolk sac hematopoiesis. Recently, two different MLL-containing protein complexes have been isolated. These and other gain- and loss-of-function experiments have provided insight into normal MLL function and altered functions of MLL fusion proteins. This article reviews the progress made toward understanding the function of the wild-type MLL protein. While many advances in understanding this multifaceted protein have been made since its discovery, many challenging questions remain to be answered.     

Subfunctionalization: How often does it occur? How long does it take?

The mechanisms responsible for the preservation of duplicate genes have been debated for more than 70 years. Recently, Lynch and Force have proposed a new explanation: subfunctionalization--after duplication the two gene copies specialize to perform complementary functions. We investigate the probability that subfunctionalization occurs, the amount of time after duplication that it takes for the outcome to be resolved, and the relationship of these quantities to the population size and mutation rates.     

How does Cryptococcus get its coat?

During the past few decades, increasing attention has focused on pathogenic fungi both as fascinating research subjects and as the agents of serious illness in diverse patient populations. In particular, opportunistic fungi such as Cryptococcus neoformans command notice as the ranks of their immunocompromised victims grow. C. neoformans is unique among fungal pathogens for its major virulence factor, a complex polysaccharide capsule. In this article, our current understanding of the structure and biosynthesis of the capsule is reviewed, as are the many questions that remain to be answered about how Cryptococcus gets its coat.     

Synaptonemal complex formation: where does it start?

The synaptonemal complex is a prominent, evolutionarily conserved feature of meiotic prophase. The assembly of this structure is closely linked to meiotic recombination. A recent study in budding yeast reveals an unexpected role in centromere pairing for a protein component of the synaptonemal complex, Zip1. These findings have implications for synaptonemal complex formation.     

The synaptonemal complex: does it have contractile proteins?

Actin and myosin are commonly involved in cell motility systems. This study attempts to identify these two proteins in the synaptonemal complex (SC), a nuclear organelle associated with chromosome pairing during meiotic prophase. The several experimental approaches reported here give no evidence of SC staining with either anti-myosin or anti-actin antibodies. These findings differ from those of other reportings.     

Modulating social behavior with oxytocin: How does it work? What does it mean?

Among its many roles in body and brain, oxytocin influences social behavior. Understanding the precise nature of this influence is crucial, both within the broader theoretical context of neurobiology, social neuroscience and brain evolution, but also within a clinical context of disorders such as anxiety, schizophrenia, and autism. Research exploring oxytocin's role in human social behavior is difficult owing to its release in both body and brain and its interactive effects with other hormones and neuromodulators. Additional difficulties are due to the intricacies of the blood-brain barrier and oxytocin's instability, which creates measurement issues. Questions concerning how to interpret behavioral results of human experiments manipulating oxytocin are thus made all the more pressing. The current paper discusses several such questions. We highlight unresolved fundamental issues about what exactly happens when oxytocin is administered intranasally, whether such oxytocin does in fact reach appropriate receptors in brain, and whether central or peripheral influences account for the observed behavioral effects. We also highlight the deeper conceptual issue of whether the human data should be narrowly interpreted as implicating a specific role for oxytocin in complex social cognition, such a generosity, trust, or mentalizing, or more broadly interpreted as implicating a lower-level general effect on general states and dispositions, such as anxiety and social motivation. Using several influential studies, we show how seemingly specific, higher-level social-cognitive effects can emerge via a process by which oxytocin's broad influence is channeled into a specific social behavior in a context of an appropriate social and research setting. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.     

Single‐ or multistage regulation in complex life cycles: does it make a difference?

Data on the different stages of complex life cycles are often rather unbalanced, especially those concerning the effects of density. How does this affect our understanding of a species’ population dynamics? Two discrete three‐stage models with overlapping generations and delayed maturation are constructed to address this question. They assume that survival or emigration in any life stage and/or reproduction can be density dependent. A typical pond‐breeding amphibian species with a well‐studied larval stage serves as an example. Numerical results show that the population dynamics resulting from density dependence at a single (e.g. the larval) stage can be decisively and unpredictably modified by density dependence in additional stages. Superposition of density‐dependent processes could thus be one reason for the difficulties in identifying density dependence in the field. Moreover, in a simulated source‐refuge system with habitat‐specific density‐dependent dispersal of juveniles density dependence in multiple stages can stabilize or destabilize the dynamics and produce misleading age structures. From an applied perspective this model shows that excluding multistage regulation prematurely clearly affects our ability to predict consequences of human impacts.     

How to break recombinant bacteria: does it matter?

Recombinant proteins and other materials of industrial interest produced in?Escherichia coli are usually retained within the bacterial cell, in the cytoplasmic?space, where they have been produced. Different protocols for cell disruption?have been implemented as an initial downstream step, which keeps the?biological and mechanical properties of the process products. Being necessarily?mild, these approaches often result in 95-99% cell disruption, what is more than?acceptable from the yield point of view. However, when the bacterial product?are nano or microparticulate entities that tend to co-sediment with entire?bacterial cells, the remaining undisrupted bacteria appear as abounding?contaminants, making the product not suitable for a spectrum of biomedical?applications. Since bacterial inclusion bodies are now seen as bacterial?materials valuable in different fields, we have developed an alternative cell?disruption protocol that permits obtaining fully bacterial free protein particles,?keeping the conformational status of the embedded proteins and the?mechanical properties of the full aggregates.     

What does it take to get the job done?

I am extremely honored to be the recipient of the 2015 Women in Cell Biology Junior Award. When I reflect on my journey in science, many great people and memorable experiences come to mind. Some of these encounters were truly career-defining moments. Others provided priceless lessons. In this essay, I recount some of the moments and experiences that influenced my scientific trajectory with the hope that they may inspire others.     

Review article. How does water get through roots?

On the basis of recent results with young primary maize roots, a model is proposed for the movement of water across roots. It is shown how the complex, 'composite anatomical structure' of roots results in a 'composite transport' of both water and solutes. Parallel apoplastic, symplastic and transcellular pathways play an important role during the passage of water across the different tissues. These are arranged in series within the root cylinder (epidermis, exodermis, central cortex, endodermis, pericycle stelar parenchyma, and tracheary elements). The contribution of these structures to the root's overall radial hydraulic resistance is examined. It is shown that as soon as early metaxylem vessels mature, the axial (longitudinal) hydraulic resistance within the xylem is usually not rate-limiting. According to the model, there is a rapid exchange of water between parallel radial pathways because, in contrast to solutes such as nutrient ions, water permeates cell membranes readily. The roles of apoplastic barriers (Casparian bands and suberin lamellae) in the root's endo- and exodermis are discussed. The model allows for special characteristics of roots such as a high hydraulic conductivity (water permeability) in the presence of a low permeability of nutrient ions once taken up into the stele by active processes. Low root reflection coefficients indicate some apoplastic by-passes for water within the root cylinder. For a given root, the model explains the large variability in the hydraulic resistance in terms of a dependence of hydraulic conductivity on the nature and intensity of the driving forces involved to move water. By switching the apoplastic path on or off, the model allows for a regulation of water uptake according to the demands from the shoot. At high rates of transpiration, the apoplastic path will be partially used and the hydraulic resistance of the root will be low, allowing for a rapid uptake of water. On the contrary, at low rates of transpiration such as during the night or during stress conditions (drought, high salinity, nutrient deprivation), the apoplastic path will be less used and the hydraulic resistance will be high. The role of water channels (aquaporins) in the transcellular path is in the fine adjustment of water flow or in the regulation of uptake in older, suberized parts of plant roots lacking a substantial apoplastic component. The composite transport model explains how plants are designed to optimize water uptake according to demands from the shoot and how external factors may influence water passage across roots.     

Nucleosome positioning: How is it established, and why does it matter?

Packaging of eukaryotic genomes into chromatin affects every process that occurs on DNA. The positioning of nucleosomes on underlying DNA plays a key role in the regulation of these processes, as the nucleosome occludes underlying DNA sequences. Here, we review the literature on mapping nucleosome positions in various organisms, and discuss how nucleosome positions are established, what effect nucleosome positioning has on control of gene expression, and touch on the correlations between chromatin packaging, sequence evolution, and the evolution of gene expression programs.     

What does it take to evolve behaviorally complex organisms?

What genotypic features explain the evolvability of organisms that have to accomplish many different tasks? The genotype of behaviorally complex organisms may be more likely to encode modular neural architectures because neural modules dedicated to distinct tasks avoid neural interference, i.e. the arrival of conflicting messages for changing the value of connection weights during learning. However, if the connection weights for the various modules are genetically inherited, this raises the problem of genetic linkage: favorable mutations may fall on one portion of the genotype encoding one neural module and unfavorable mutations on another portion encoding another module. We show that this can prevent the genotype from reaching an adaptive optimum. This effect is different from other linkage effects described in the literature and we argue that it represents a new class of genetic constraints. Using simulations we show that sexual reproduction can alleviate the problem of genetic linkage by recombining separate modules all of which incorporate either favorable or unfavorable mutations. We speculate that this effect may contribute to the taxonomic prevalence of sexual reproduction among higher organisms. In addition to sexual recombination, the problem of genetic linkage for behaviorally complex organisms may be mitigated by entrusting evolution with the task of finding appropriate modular architectures and learning with the task of finding the appropriate connection weights for these architectures.     

How does intraspecific density regulation influence metapopulation synchrony and persistence?

Intraspecific density regulation influences the synchronization of local population dynamics through dispersal. Spatial synchrony in turn may jeopardize metapopulation persistence. Joining results from previous studies suggests that spatial synchrony is highest at moderate over-compensation and is low at compensating and at very strong over-compensating density regulation. We scrutinize this supposition of a unimodal relationship using a process-based metapopulation model with explicit local population dynamics. We extend the usually studied range of density regulation to under-compensation and analyse resulting metapopulation persistence. We find peaks of spatial synchrony not only at over-compensatory but also under-compensatory density regulation and show that effects of local density compensation on synchrony follow a bimodal rather than unimodal relationship. Persistence of metapopulations however, shows a unimodal relationship with a broad plateau of high persistence from compensatory to over-compensatory density regulation. This range of high persistence comprises both levels of low and high spatial synchrony. Thus, not synchrony alone jeopardizes metapopulation persistence, but only in interplay with high local extinction risk. The functional forms of the relations of density compensation with spatial synchrony and persistence are robust to increases in dispersal mortality, landscape dynamics, or density dependence of dispersal. However, with each of these increases the maxima of spatial synchrony and persistence shift to higher over-compensation and levels of synchrony are reduced. Overall, for over-compensation high landscape connectivity has negative effects while for under-compensation connectivity affects persistence positively. This emphasizes the importance of species life-history traits for management decisions with regard to landscape connectivity: while dispersal corridors are essential for species with under-compensatory density regulation, they may have detrimental effects for endangered species with over-compensation.