1,443 research outputs found
Branch Mode Selection during Early Lung Development
Many organs of higher organisms, such as the vascular system, lung, kidney,
pancreas, liver and glands, are heavily branched structures. The branching
process during lung development has been studied in great detail and is
remarkably stereotyped. The branched tree is generated by the sequential,
non-random use of three geometrically simple modes of branching (domain
branching, planar and orthogonal bifurcation). While many regulatory components
and local interactions have been defined an integrated understanding of the
regulatory network that controls the branching process is lacking. We have
developed a deterministic, spatio-temporal differential-equation based model of
the core signaling network that governs lung branching morphogenesis. The model
focuses on the two key signaling factors that have been identified in
experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well
as the SHH receptor patched (Ptc). We show that the reported biochemical
interactions give rise to a Schnakenberg-type Turing patterning mechanisms that
allows us to reproduce experimental observations in wildtype and mutant mice.
The kinetic parameters as well as the domain shape are based on experimental
data where available. The developed model is robust to small absolute and large
relative changes in the parameter values. At the same time there is a strong
regulatory potential in that the switching between branching modes can be
achieved by targeted changes in the parameter values. We note that the sequence
of different branching events may also be the result of different growth
speeds: fast growth triggers lateral branching while slow growth favours
bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is
sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio
Status of Muon Collider Research and Development and Future Plans
The status of the research on muon colliders is discussed and plans are
outlined for future theoretical and experimental studies. Besides continued
work on the parameters of a 3-4 and 0.5 TeV center-of-mass (CoM) energy
collider, many studies are now concentrating on a machine near 0.1 TeV (CoM)
that could be a factory for the s-channel production of Higgs particles. We
discuss the research on the various components in such muon colliders, starting
from the proton accelerator needed to generate pions from a heavy-Z target and
proceeding through the phase rotation and decay ()
channel, muon cooling, acceleration, storage in a collider ring and the
collider detector. We also present theoretical and experimental R & D plans for
the next several years that should lead to a better understanding of the design
and feasibility issues for all of the components. This report is an update of
the progress on the R & D since the Feasibility Study of Muon Colliders
presented at the Snowmass'96 Workshop [R. B. Palmer, A. Sessler and A.
Tollestrup, Proceedings of the 1996 DPF/DPB Summer Study on High-Energy Physics
(Stanford Linear Accelerator Center, Menlo Park, CA, 1997)].Comment: 95 pages, 75 figures. Submitted to Physical Review Special Topics,
Accelerators and Beam
Neutrality and Robustness in Evo-Devo: Emergence of Lateral Inhibition
Embryonic development is defined by the hierarchical dynamical process that translates genetic information (genotype) into a spatial gene expression pattern (phenotype) providing the positional information for the correct unfolding of the organism. The nature and evolutionary implications of genotype–phenotype mapping still remain key topics in evolutionary developmental biology (evo-devo). We have explored here issues of neutrality, robustness, and diversity in evo-devo by means of a simple model of gene regulatory networks. The small size of the system allowed an exhaustive analysis of the entire fitness landscape and the extent of its neutrality. This analysis shows that evolution leads to a class of robust genetic networks with an expression pattern characteristic of lateral inhibition. This class is a repertoire of distinct implementations of this key developmental process, the diversity of which provides valuable clues about its underlying causal principles
APOBEC3G-Induced Hypermutation of Human Immunodeficiency Virus Type-1 Is Typically a Discrete “All or Nothing” Phenomenon
The rapid evolution of Human Immunodeficiency Virus (HIV-1) allows studies of ongoing host–pathogen interactions. One key selective host factor is APOBEC3G (hA3G) that can cause extensive and inactivating Guanosine-to-Adenosine (G-to-A) mutation on HIV plus-strand DNA (termed hypermutation). HIV can inhibit this innate anti-viral defense through binding of the viral protein Vif to hA3G, but binding efficiency varies and hypermutation frequencies fluctuate in patients. A pivotal question is whether hA3G-induced G-to-A mutation is always lethal to the virus or if it may occur at sub-lethal frequencies that could increase viral diversification. We show in vitro that limiting-levels of hA3G-activity (i.e. when only a single hA3G-unit is likely to act on HIV) produce hypermutation frequencies similar to those in patients and demonstrate in silico that potentially non-lethal G-to-A mutation rates are ∼10-fold lower than the lowest observed hypermutation levels in vitro and in vivo. Our results suggest that even a single incorporated hA3G-unit is likely to cause extensive and inactivating levels of HIV hypermutation and that hypermutation therefore is typically a discrete “all or nothing” phenomenon. Thus, therapeutic measures that inhibit the interaction between Vif and hA3G will likely not increase virus diversification but expand the fraction of hypermutated proviruses within the infected host
Reconstructing the Inflaton Potential --- an Overview
We review the relation between the inflationary potential and the spectra of
density (scalar) perturbations and gravitational waves (tensor perturbations)
produced, with particular emphasis on the possibility of reconstructing the
inflaton potential from observations. The spectra provide a potentially
powerful test of the inflationary hypothesis; they are not independent but
instead are linked by consistency relations reflecting their origin from a
single inflationary potential. To lowest-order in a perturbation expansion
there is a single, now familiar, relation between the tensor spectral index and
the relative amplitude of the spectra. We demonstrate that there is an infinite
hierarchy of such consistency equations, though observational difficulties
suggest only the first is ever likely to be useful. We also note that since
observations are expected to yield much better information on the scalars than
on the tensors, it is likely to be the next-order version of this consistency
equation which will be appropriate, not the lowest-order one. If inflation
passes the consistency test, one can then confidently use the remaining
observational information to constrain the inflationary potential, and we
survey the general perturbative scheme for carrying out this procedure.
Explicit expressions valid to next-lowest order in the expansion are presented.
We then briefly assess the prospects for future observations reaching the
quality required, and consider a simulated data set that is motivated by this
outlook.Comment: 69 pages standard LaTeX plus 4 postscript figures. Postscript version
of text in landscape format (35 pages) available at
http://star-www.maps.susx.ac.uk/papers/infcos_papers.html Modifications are a
variety of updates to discussion and reference
Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes
Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants
The genetic architecture of type 2 diabetes
The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes
Host-Adaptation of Francisella tularensis Alters the Bacterium's Surface-Carbohydrates to Hinder Effectors of Innate and Adaptive Immunity
The gram-negative bacterium Francisella tularensis survives in arthropods, fresh water amoeba, and mammals with both intracellular and extracellular phases and could reasonably be expected to express distinct phenotypes in these environments. The presence of a capsule on this bacterium has been controversial with some groups finding such a structure while other groups report that no capsule could be identified. Previously we reported in vitro culture conditions for this bacterium which, in contrast to typical methods, yielded a bacterial phenotype that mimics that of the bacterium's mammalian, extracellular phase.SDS-PAGE and carbohydrate analysis of differentially-cultivated F. tularensis LVS revealed that bacteria displaying the host-adapted phenotype produce both longer polymers of LPS O-antigen (OAg) and additional HMW carbohydrates/glycoproteins that are reduced/absent in non-host-adapted bacteria. Analysis of wildtype and OAg-mutant bacteria indicated that the induced changes in surface carbohydrates involved both OAg and non-OAg species. To assess the impact of these HMW carbohydrates on the access of outer membrane constituents to antibody we used differentially-cultivated bacteria in vitro to immunoprecipitate antibodies directed against outer membrane moieties. We observed that the surface-carbohydrates induced during host-adaptation shield many outer membrane antigens from binding by antibody. Similar assays with normal mouse serum indicate that the induced HMW carbohydrates also impede complement deposition. Using an in vitro macrophage infection assay, we find that the bacterial HMW carbohydrate impedes TLR2-dependent, pro-inflammatory cytokine production by macrophages. Lastly we show that upon host-adaptation, the human-virulent strain, F. tularensis SchuS4 also induces capsule production with the effect of reducing macrophage-activation and accelerating tularemia pathogenesis in mice.F. tularensis undergoes host-adaptation which includes production of multiple capsular materials. These capsules impede recognition of bacterial outer membrane constituents by antibody, complement, and Toll-Like Receptor 2. These changes in the host-pathogen interface have profound implications for pathogenesis and vaccine development
- …