High Heritability Is Compatible with the Broad Distribution of Set Point Viral Load in HIV Carriers.

Set point viral load in HIV patients ranges over several orders of magnitude and is a key determinant of disease progression in HIV. A number of recent studies have reported high heritability of set point viral load implying that viral genetic factors contribute substantially to the overall variation in viral load. The high heritability is surprising given the diversity of host factors associated with controlling viral infection. Here we develop an analytical model that describes the temporal changes of the distribution of set point viral load as a function of heritability. This model shows that high heritability is the most parsimonious explanation for the observed variance of set point viral load. Our results thus not only reinforce the credibility of previous estimates of heritability but also shed new light onto mechanisms of viral pathogenesis

Visual Cortex: Two-Photon Excitement

Current in vivo methods for imaging the visual cortex lack the ability to map response properties at the level of single cells. A new technique using two-photon imaging of calcium signals has now overcome this limitation

Why There Are No Essential Genes on Plasmids

Mobile genetic elements such as plasmids are important for the evolution of prokaryotes. It has been suggested that there are differences between functions coded for by mobile genes and those in the "core” genome and that these differences can be seen between plasmids and chromosomes. In particular, it has been suggested that essential genes, such as those involved in the formation of structural proteins or in basic metabolic functions, are rarely located on plasmids. We model competition between genotypically varying bacteria within a single population to investigate whether selection favors a chromosomal location for essential genes. We find that in general, chromosomal locations for essential genes are indeed favored. This is because the inheritance of chromosomes is more stable than that for plasmids. We define the "degradation” rate as the rate at which chance genetic processes, for example, mutation, deletion, or translocation, render essential genes nonfunctioning. The only way in which plasmids can be a location for functioning essential genes is if chromosomal genes degrade faster than plasmid genes. If the two degradation rates are equal, or if plasmid genes degrade faster than chromosomal genes, functioning essential genes will be found only on chromosome

Clusters of synaptic inputs on dendrites of layer 5 pyramidal cells in mouse visual cortex

The spatial organization of synaptic inputs on the dendritic tree of cortical neurons plays a major role for dendritic integration and neural computations, yet, remarkably little is known about it. We mapped the spatial organization of glutamatergic synapses between layer 5 pyramidal cells by combining optogenetics and 2-photon calcium imaging in mouse neocortical slices. To mathematically characterize the organization of inputs we developed an approach based on combinatorial analysis of the likelihoods of specific synapse arrangements. We found that the synapses of intralaminar inputs form clusters on the basal dendrites of layer 5 pyramidal cells. These clusters contain 4 to 14 synapses within <= 30 mu m of dendrite. According to the spatiotemporal characteristics of synaptic summation, these numbers suggest that there will be non-linear dendritic integration of synaptic inputs during synchronous activation

Is antimicrobial resistance evolution accelerating?

Globally, antimicrobials are a main pillar of medical, veterinary, and agriculture interventions [1,2]. In all cases, resistance of microbes against antimicrobials is prevalent. The problem is exacerbated by the drying up of the antibiotic pipeline, as economic incentives to develop new drugs are very limited. In antifungals, the range of available compounds is also low with only 4 main classes of drugs available to treat fungal infections in humans and 6 main classes used in agriculture, with 1 class, the azoles, used in both [1]. The problem of drug resistance evolution has been observed early on in the antibiotic era [3,4]. Ultimately, however, the introduction of each antimicrobial resulted in resistance evolution in target and nontarget microbes. In realization of this problem, some antibiotics such as daptomycin were even developed with avoiding resistance evolution in mind, yet it took only 2 years from the introduction of daptomycin until resistance was recorded [4]. But how fast is resistance evolving? Here, we want to discuss how fast resistance emerges after the introduction of antimicrobials. We base this on widely cited data in the literature for antibiotics ([4–7]; see also Fig 1A, based on [8]) and compared this to data on antifungal resistance [9,10]. Replotting the antibiotic data (Fig 1B), by displaying the time from introduction to resistance emergence over the year of introduction, suggests that the evolution of antibiotic resistance is accelerating over time. The same trend can be observed for antifungals (Fig 1C and 1D). In the following, we focus on (1) the quality of the underlying data and (2) possible explanations for this pattern of accelerating resistance

Can high-risk fungicides be used in mixtures without selecting for fungicide resistance?

Fungicide mixtures produced by the agrochemical industry often contain low-risk fungicides, to which fungal pathogens are fully sensitive, together with high-risk fungicides known to be prone to fungicide resistance. Can these mixtures provide adequate disease control while minimizing the risk for the development of resistance? We present a population dynamics model to address this question. We found that the fitness cost of resistance is a crucial parameter to determine the outcome of competition between the sensitive and resistant pathogen strains and to assess the usefulness of a mixture. If fitness costs are absent, then the use of the high-risk fungicide in a mixture selects for resistance and the fungicide eventually becomes nonfunctional. If there is a cost of resistance, then an optimal ratio of fungicides in the mixture can be found, at which selection for resistance is expected to vanish and the level of disease control can be optimized