Information Transfer in Gonadotropin-Releasing Hormone (GnRH) Signaling:Extracellular Signal-Regulated Kinase (ERK)-Mediated Feedback Loops Control Hormone Sensing

Cell signaling pathways are noisy communication channels, and statistical measures derived from information theory can be used to quantify the information they transfer. Here we use single cell signaling measures to calculate mutual information as a measure of information transfer via gonadotropin-releasing hormone (GnRH) receptors (GnRHR) to extracellular signal-regulated kinase (ERK) or nuclear factor of activated T-cells (NFAT). This revealed mutual information values <1 bit, implying that individual GnRH-responsive cells cannot unambiguously differentiate even two equally probable input concentrations. Addressing possible mechanisms for mitigation of information loss, we focused on the ERK pathway and developed a stochastic activation model incorporating negative feedback and constitutive activity. Model simulations revealed interplay between fast (min) and slow (min-h) negative feedback loops with maximal information transfer at intermediate feedback levels. Consistent with this, experiments revealed that reducing negative feedback (by expressing catalytically inactive ERK2) and increasing negative feedback (by Egr1-driven expression of dual-specificity phosphatase 5 (DUSP5)) both reduced information transfer from GnRHR to ERK. It was also reduced by blocking protein synthesis (to prevent GnRH from increasing DUSP expression) but did not differ for different GnRHRs that do or do not undergo rapid homologous desensitization. Thus, the first statistical measures of information transfer via these receptors reveals that individual cells are unreliable sensors of GnRH concentration and that this reliability is maximal at intermediate levels of ERK-mediated negative feedback but is not influenced by receptor desensitization

The type Ia supernova SNLS-03D3bb from a super-Chandrasekhar-mass white dwarf star

The acceleration of the expansion of the universe, and the need for Dark Energy, were inferred from the observations of Type Ia supernovae (SNe Ia). There is consensus that SNe Ia are thermonuclear explosions that destroy carbon-oxygen white dwarf stars that accrete matter from a companion star, although the nature of this companion remains uncertain. SNe Ia are thought to be reliable distance indicators because they have a standard amount of fuel and a uniform trigger -- they are predicted to explode when the mass of the white dwarf nears the Chandrasekhar mass -- 1.4 solar masses. Here we show that the high redshift supernova SNLS-03D3bb has an exceptionally high luminosity and low kinetic energy that both imply a super-Chandrasekhar mass progenitor. Super-Chandrasekhar mass SNe Ia should preferentially occur in a young stellar population, so this may provide an explanation for the observed trend that overluminous SNe Ia only occur in young environments. Since this supernova does not obey the relations that allow them to be calibrated as standard candles, and since no counterparts have been found at low redshift, future cosmology studies will have to consider contamination from such events.Comment: 9 pages, 4 figures. To appear in Nature Sept. 21. Accompanying News & Views in same issue. Supplementary information available at www.nature.com/natur

A Lassa virus mRNA vaccine confers protection but does not require neutralizing antibody in a guinea pig model of infection

Abstract Lassa virus is a member of the Arenaviridae family, which causes human infections ranging from asymptomatic to severe hemorrhagic disease with a high case fatality rate. We have designed and generated lipid nanoparticle encapsulated, modified mRNA vaccines that encode for the wild-type Lassa virus strain Josiah glycoprotein complex or the prefusion stabilized conformation of the Lassa virus glycoprotein complex. Hartley guinea pigs were vaccinated with two 10 µg doses, 28 days apart, of either construct. Vaccination induced strong binding antibody responses, specific to the prefusion conformation of glycoprotein complex, which were significantly higher in the prefusion stabilized glycoprotein complex construct group and displayed strong Fc-mediated effects. However, Lassa virus-neutralizing antibody activity was detected in some but not all animals. Following the challenge with a lethal dose of the Lassa virus, all vaccinated animals were protected from death and severe disease. Although the definitive mechanism of protection is still unknown, and assessment of the cell-mediated immune response was not investigated in this study, these data demonstrate the promise of mRNA as a vaccine platform against the Lassa virus and that protection against Lassa virus can be achieved in the absence of virus-neutralizing antibodies

The type Ia supernova SNLS-03D3bb from a super-Chandrasekhar-mass white dwarf star

The acceleration of the expansion of the universe, and the need for Dark Energy, were inferred from the observations of Type Ia supernovae (SNe Ia) 1;2. There is consensus that SNeIa are thermonuclear explosions that destroy carbon-oxygen white dwarf stars that accrete matter from a companion star3, although the nature of this companion remains uncertain. SNe Ia are thought to be reliable distance indicators because they have a standard amount of fuel and a uniform trigger they are predicted to explode when the mass of the white dwarf nears the Chandrasekhar mass 4 - 1.4 solar masses. Here we show that the high redshift supernova SNLS-03D3bb has an exceptionally high luminosity and low kinetic energy that both imply a super-Chandrasekhar mass progenitor. Super-Chandrasekhar mass SNeIa should preferentially occur in a young stellar population, so this may provide an explanation for the observed trend that overluminous SNe Ia only occur in young environments5;6. Since this supernova does not obey the relations that allow them to be calibrated as standard candles, and since no counterparts have been found at low redshift, future cosmology studies will have to consider contamination from such events

The type Ia supernova SNLS-03D3bb from a super-Chandrasekhar-mass white dwarf star

The acceleration of the expansion of the universe, and the need for Dark Energy, were inferred from the observations of Type Ia supernovae (SNe Ia) 1;2. There is consensus that SNeIa are thermonuclear explosions that destroy carbon-oxygen white dwarf stars that accrete matter from a companion star3, although the nature of this companion remains uncertain. SNe Ia are thought to be reliable distance indicators because they have a standard amount of fuel and a uniform trigger they are predicted to explode when the mass of the white dwarf nears the Chandrasekhar mass 4 - 1.4 solar masses. Here we show that the high redshift supernova SNLS-03D3bb has an exceptionally high luminosity and low kinetic energy that both imply a super-Chandrasekhar mass progenitor. Super-Chandrasekhar mass SNeIa should preferentially occur in a young stellar population, so this may provide an explanation for the observed trend that overluminous SNe Ia only occur in young environments5;6. Since this supernova does not obey the relations that allow them to be calibrated as standard candles, and since no counterparts have been found at low redshift, future cosmology studies will have to consider contamination from such events

Disk-Bulge-Halo Models for the Andromeda Galaxy

We present a suite of semi-analytic disk-bulge-halo models for the Andromeda galaxy (M31) which satisfy three fundamental conditions: (1) internal selfconsistency; (2) consistency with observational data; and (3) stability of the disk against the formation of a central bar. The models are chosen from a set first constructed by Kuijken and Dubinski. We develop an algorithm to search the parameter space for this set in order to best match observations of the M31 rotation curve, inner velocity dispersion profile, and surface brightness profile. Models are obtained for a large range of bulge and disk masses; we find that the disk mass must be � 8 × 10 10 M ⊙ and that the preferred value for the bulge mass is 2.5 × 10 10 M⊙. N-body simulations are carried out to test the stability of our models against the formation of a bar within the disk. We also calculate the baryon fraction and halo concentration parameter for a subset of our models and show that the results are consistent with the predictions from cosmological theories of structure formation. In addition, we describe how gravitational microlensing surveys and dynamical studies of globular clusters and satellites can further constrain the models

Guidelines of care for the management of atopic dermatitis

Atopic dermatitis (AD) is a chronic, pruritic inflammatory dermatosis that affects up to 25% of children and 2-3% of adults. This guideline addresses important clinical questions that arise in AD management and care, providing recommendations based on the available evidence. In this third of four sections, treatment of AD with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed, including indications for use and the risk-benefit profile of each treatment option