New genetic resources for mammalian developmental biologists

The utilization of homologous recombination in embryonic stem cells as a means to generate mice carrying pre-determined modifications of genomic sequences has revolutionized the study of developmental biology. Recognizing the potential efficiencies that can be obtained by high-throughput production at centralized technology centers, a number of large-scale efforts for generating mice with targeted mutations have been funded. These programs are reaching fruition, and a variety of libraries of embryonic stem cells with defined mutations are now available

2001: A Mouse Genome Odyssey

A report on the 15th International Mouse Genome Conference, Edinburgh, UK, 21-24 October 2001

Activity patterns of nesting Mexican spotted owls

We collected 2,665 hr of behavioral information using video surveillance on 19 Mexican Spotted Owl (Strix occidentalis lucida) pairs between 25 April and 26 July 1996, Prey deliveries per day increased as the nesting season progressed, with an average of 2.68 prey deliveries during incubation, 4.10 items during brooding, and 4.51 items during the nestling phase. The highest delivery rates were concentrated between 1-3 hours before sunrise (02:00-05:00) and 1-3 hours after sunset(18:00-21:00). Trip duration during diurnal hours increased 14 fold from incubation through the nestling phase, compared with a 7.2 fold increase during nocturnal hours. Nest bout duration decreased during both diurnal (36%) and nocturnal hours (76%) across the nesting season. Nest attentiveness decreased as the nesting season progressed, from 97% during the incubation phase to 47% during the nestling phase. Owls attended nests at higher rates during diurnal hours than nocturnal hours across all nesting phases. Activity patterns of Mexican Spotted Owls showed marked cyclical changes in response to ecological factors. Fluctuations in nesting behavior were related to changes in nesting phase and time of day

The Notch Ligand JAG1 Is Required for Sensory Progenitor Development in the Mammalian Inner Ear

In mammals, six separate sensory regions in the inner ear are essential for hearing and balance function. Each sensory region is made up of hair cells, which are the sensory cells, and their associated supporting cells, both arising from a common progenitor. Little is known about the molecular mechanisms that govern the development of these sensory organs. Notch signaling plays a pivotal role in the differentiation of hair cells and supporting cells by mediating lateral inhibition via the ligands Delta-like 1 and Jagged (JAG) 2. However, another Notch ligand, JAG1, is expressed early in the sensory patches prior to cell differentiation, indicating that there may be an earlier role for Notch signaling in sensory development in the ear. Here, using conditional gene targeting, we show that the Jag1 gene is required for the normal development of all six sensory organs within the inner ear. Cristae are completely lacking in Jag1-conditional knockout (cko) mutant inner ears, whereas the cochlea and utricle show partial sensory development. The saccular macula is present but malformed. Using SOX2 and p27(kip1) as molecular markers of the prosensory domain, we show that JAG1 is initially expressed in all the prosensory regions of the ear, but becomes down-regulated in the nascent organ of Corti by embryonic day 14.5, when the cells exit the cell cycle and differentiate. We also show that both SOX2 and p27(kip1) are down-regulated in Jag1-cko inner ears. Taken together, these data demonstrate that JAG1 is expressed early in the prosensory domains of both the cochlear and vestibular regions, and is required to maintain the normal expression levels of both SOX2 and p27(kip1). These data demonstrate that JAG1-mediated Notch signaling is essential during early development for establishing the prosensory regions of the inner ear

Particle astrophysics

The following scientific areas are reviewed: (1) cosmology and particle physics (particle physics and the early universe, dark matter, and other relics); (2) stellar physics and particles (solar neutrinos, supernovae, and unconventional particle physics); (3) high energy gamma ray and neutrino astronomy; (4) cosmic rays (space and ground observations). Highest scientific priorities for the next decade include implementation of the current program, new initiatives, and longer-term programs. Essential technological developments, such as cryogenic detectors of particles, new solar neutrino techniques, and new extensive air shower detectors, are discussed. Also a certain number of institutional issues (the funding of particle astrophysics, recommended funding mechanisms, recommended facilities, international collaborations, and education and technology) which will become critical in the coming decade are presented

Diabetes Insipidus in Mice with a Mutation in Aquaporin-2

Congenital nephrogenic diabetes insipidus (NDI) is a disease characterized by failure of the kidney to concentrate urine in response to vasopressin. Human kindreds with nephrogenic diabetes insipidus have been found to harbor mutations in the vasopressin receptor 2 (Avpr2) gene or the vasopressin-sensitive water channel aquaporin-2 (Aqp2) gene. Development of a treatment is rendered difficult due to the lack of a viable animal model. Through forward genetic screening of ethylnitrosourea-mutagenized mice, we report the identification and characterization of a mouse model of NDI, with an F204V mutation in the Aqp2 gene. Unlike previously attempted murine models of NDI, our mice survive to adulthood and more exactly recapitulate the human disorder. Previous in vitro experiments using renal cell lines suggest recessive Aqp2 mutations result in improper trafficking of the mutant water pore. Using these animals, we have directly proven this hypothesis of improper AQP2 translocation as the molecular defect in nephrogenic diabetes insipidus in the intact organism. Additionally, using a renal cell line we show that the mutated protein, AQP2-F204V, is retained in the endoplasmic reticulum and that this abnormal localization can be rescued by wild-type protein. This novel mouse model allows for further mechanistic studies as well as testing of pharmacological and gene therapies for NDI

Smoothed Complexity Theory

Smoothed analysis is a new way of analyzing algorithms introduced by Spielman and Teng (J. ACM, 2004). Classical methods like worst-case or average-case analysis have accompanying complexity classes, like P and AvgP, respectively. While worst-case or average-case analysis give us a means to talk about the running time of a particular algorithm, complexity classes allows us to talk about the inherent difficulty of problems. Smoothed analysis is a hybrid of worst-case and average-case analysis and compensates some of their drawbacks. Despite its success for the analysis of single algorithms and problems, there is no embedding of smoothed analysis into computational complexity theory, which is necessary to classify problems according to their intrinsic difficulty. We propose a framework for smoothed complexity theory, define the relevant classes, and prove some first hardness results (of bounded halting and tiling) and tractability results (binary optimization problems, graph coloring, satisfiability). Furthermore, we discuss extensions and shortcomings of our model and relate it to semi-random models.Comment: to be presented at MFCS 201

Where to restore ecological connectivity? Detecting barriers and quantifying restoration benefits

Landscape connectivity is crucial for many ecological processes, including dispersal, gene flow, demographic rescue, and movement in response to climate change. As a result, governmental and non-governmental organizations are focusing efforts to map and conserve areas that facilitate movement to maintain population connectivity and promote climate adaptation. In contrast, little focus has been placed on identifying barriers—landscape features which impede movement between ecologically important areas—where restoration could most improve connectivity. Yet knowing where barriers most strongly reduce connectivity can complement traditional analyses aimed at mapping best movement routes. We introduce a novel method to detect important barriers and provide example applications. Our method uses GIS neighborhood analyses in conjunction with effective distance analyses to detect barriers that, if removed, would significantly improve connectivity. Applicable in least-cost, circuit-theoretic, and simulation modeling frameworks, the method detects both complete (impermeable) barriers and those that impede but do not completely block movement. Barrier mapping complements corridor mapping by broadening the range of connectivity conservation alternatives available to practitioners. The method can help practitioners move beyond maintaining currently important areas to restoring and enhancing connectivity through active barrier removal. It can inform decisions on trade-offs between restoration and protection; for example, purchasing an intact corridor may be substantially more costly than restoring a barrier that blocks an alternative corridor. And it extends the concept of centrality to barriers, highlighting areas that most diminish connectivity across broad networks. Identifying which modeled barriers have the greatest impact can also help prioritize error checking of land cover data and collection of field data to improve connectivity maps. Barrier detection provides a different way to view the landscape, broadening thinking about connectivity and fragmentation while increasing conservation options