Phylogenomic Analyses Reveal the Evolutionary Origin of the Inhibin α-Subunit, a Unique TGFβ Superfamily Antagonist

Transforming growth factor-beta (TGFβ) homologues form a diverse superfamily that arose early in animal evolution and control cellular function through membrane-spanning, conserved serine-threonine kinases (RII and RI receptors). Activin and inhibin are related dimers within the TGFβ superfamily that share a common β-subunit. The evolution of the inhibin α-subunit created the only antagonist within the TGFβ superfamily and the only member known to act as an endocrine hormone. This hormone introduced a new level of complexity and control to vertebrate reproductive function. The novel functions of the inhibin α-subunit appear to reflect specific insertion-deletion changes within the inhibin β-subunit that occurred during evolution. Using phylogenomic analysis, we correlated specific insertions with the acquisition of distinct functions that underlie the phenotypic complexity of vertebrate reproductive processes. This phylogenomic approach presents a new way of understanding the structure-function relationships between inhibin, activin, and the larger TGFβ superfamily

Halo orbits in cosmological disk galaxies : tracers of information history

We analyze the orbits of stars and dark matter particles in the halo of a disk galaxy formed in a cosmological hydrodynamical simulation. The halo is oblate within the inner ∼20 kpc and triaxial beyond this radius. About 43% of orbits are short axis tubes—the rest belong to orbit families that characterize triaxial potentials (boxes, long-axis tubes and chaotic orbits), but their shapes are close to axisymmetric. We find no evidence that the self-consistent distribution function of the nearly oblate inner halo is comprised primarily of axisymmetric short-axis tube orbits. Orbits of all families and both types of particles are highly eccentric, with mean eccentricity �0.6. We find that randomly selected samples of halo stars show no substructure in “integrals of motion” space. However, individual accretion events can clearly be identified in plots of metallicity versus formation time. Dynamically young tidal debris is found primarily on a single type of orbit. However, stars associated with older satellites become chaotically mixed during the formation process (possibly due to scattering by the central bulge and disk, and baryonic processes), and appear on all four types of orbits. We find that the tidal debris in cosmological hydrodynamical simulations experiences significantly more chaotic evolution than in collisionless simulations, making it much harder to identify individual progenitors using phase space coordinates alone. However, by combining information on stellar ages and chemical abundances with the orbital properties of halo stars in the underlying self-consistent potential, the identification of progenitors is likely to be possible

The price of your soul: neural evidence for the non-utilitarian representation of sacred values

Sacred values, such as those associated with religious or ethnic identity, underlie many important individual and group decisions in life, and individuals typically resist attempts to trade off their sacred values in exchange for material benefits. Deontological theory suggests that sacred values are processed based on rights and wrongs irrespective of outcomes, while utilitarian theory suggests that they are processed based on costs and benefits of potential outcomes, but which mode of processing an individual naturally uses is unknown. The study of decisions over sacred values is difficult because outcomes cannot typically be realized in a laboratory, and hence little is known about the neural representation and processing of sacred values. We used an experimental paradigm that used integrity as a proxy for sacredness and which paid real money to induce individuals to sell their personal values. Using functional magnetic resonance imaging (fMRI), we found that values that people refused to sell (sacred values) were associated with increased activity in the left temporoparietal junction and ventrolateral prefrontal cortex, regions previously associated with semantic rule retrieval. This suggests that sacred values affect behaviour through the retrieval and processing of deontic rules and not through a utilitarian evaluation of costs and benefits

Associations between transcranial Doppler vasospasm and clinical outcomes after aneurysmal subarachnoid hemorrhage: A retrospective observational study

OBJECTIVE: The objective is to examine the relationship between transcranial Doppler cerebral vasospasm (TCD-vasospasm), and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH). METHODS: In a retrospective cohort study, using univariate and multivariate analysis, we examined the association between TCD-vasospasm (defined as Lindegaard ratio \u3e3) and patient\u27s ability to ambulate without assistance, the need for tracheostomy and gastrostomy tube placement, and the likelihood of being discharged home from the hospital. RESULTS: We studied 346 patients with aSAH; median age 55 years (Interquartile range IQR 46,64), median Hunt and Hess 3 [IQR 1-5]. Overall, 68.6% (n=238) had TCD-vasospasm, and 28% (n=97) had delayed cerebral ischemia. At hospital discharge, 54.3% (n=188) were able to walk without assistance, 5.8% (n=20) had received a tracheostomy, and 12% (n=42) had received a gastrostomy tube. Fifty-three percent (n=183) were discharged directly from the hospital to their home. TCD-vasospasm was not associated with ambulation without assistance at discharge (adjusted odds ratio, aOR 0.54, 95% 0.19,1.45), tracheostomy placement (aOR 2.04, 95% 0.23,18.43), gastrostomy tube placement (aOR 0.95, 95% CI 0.28,3.26), discharge to home (aOR 0.36, 95% CI 0.11,1.23). CONCLUSION: This single-center retrospective study finds that TCD-vasospasm is not associated with clinical outcomes such as ambulation without assistance, discharge to home from the hospital, tracheostomy, and gastrostomy feeding tube placement. Routine screening for cerebral vasospasm and its impact on vasospasm diagnostic and therapeutic interventions and their associations with improved clinical outcomes warrant an evaluation in large, prospective, case-controlled, multi-center studies

Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema

Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Main Results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. © 2013 D'Armiento et al

An Age-Dependent Pharmacokinetic Study of Intravenous and Oral Mycophenolate Mofetil in Combination with Tacrolimus for GVHD Prophylaxis in Pediatric Allogeneic Stem Cell Transplantation Recipients

Acute graft-versus-host disease (aGVHD) still remains a major limiting factor following allogeneic stem cell transplantation (AlloSCT) in pediatric recipients. Mycophenolate mofetil (MMF), an uncompetitive selective inhibitor of inosine monophosphate dehydrogenase, is a new immunosuppressant agent without major mucosal, hepatic, or renal toxicity compared to other prophylactic aGVHD immunosuppressant drugs. Although there has been an extensive pharmacokinetic (PK) experience with MMF administration following solid organ transplantation in children, there is a paucity of PK data following its use in pediatric AlloSCT recipients. We investigated the safety and PK of MMF as GVHD prophylaxis following intravenous (i.v.) and oral (p.o.) administration (900 mg/m2 every 6 hours) in conjunction with tacrolimus, after myeloablative (MA) and nonmyeloablative (NMA) conditioning and AlloSCT in 3 distinct age groups of pediatric AlloSCT recipients (0-6 years, 6-12 years, and 12-16 years). Mycophenolic acid (MPA) in plasma samples was measured either by high-performance liquid chromatography (HPLC) or liquid chromatography/mass spectrometry (LC/MS/MS) as we have previously described. Plasma samples were obtained at baseline and at 0.5, 1, 2, 3, 4, and 6 hours after i.v. dosing on days +1, +7, +14, and at 2 time points between day +45 and +100 after p.o. administration post AlloSCT. MPA PK analysis included AUC (0-6 hours), Cmax, Tmax, Css, Vss, C trough (C0), CL, and T½. Thirty-eight patients, with a median age of 8 years (0.33-16 years), 20/18 M:F ratio, 21/17 malignant/nonmalignant disease, 17/21 MA: NMA conditioning, 16 of 22 related/unrelated allografts. Median time to myeloid and platelet engraftment was 18 and 31 days, respectively. Mean donor chimerism on day +60 and +100 was 83% and 90%, respectively. Probability of developing aGVHD grade II-IV and extensive chronic GVHD (cGVHD) was 54% and 34%, respectively. There was significant intra- and interpatient MMF PK variability. There was a significant increase in i.v. MPA area under the curve (AUC)0-6hour and Cmax (P < .0003) and a significant decrease in CLss (P < .002) and Vss (P < .001) on day +14 versus day +7. Children <12 years of age had a significant increase in i.v. MPA Tmax (P = .01), Vss (P = .028), and CLss (P < .001) compared to the older age group. There was a trend in increased i.v. MPA CLss following MA versus NMA conditioning (P < .054); i.v. and p.o. MMF administration (900 mg/m2 every 6 hours) in combination with tacrolimus was well tolerated in pediatric AlloSCT recipients. There was a significant increase in MPA exposure on day +14 versus day +7, suggesting improved enterohepatic recirculation at day +14 post-AlloSCT. Children <12 years of age appear to have a significantly different MPA PK profile compared to older children and adolescents and may require more frequent dosing

The Metamorphosis of Tidally Stirred Dwarf Galaxies

We present results from high-resolution N-Body/SPH simulations of rotationally supported dwarf irregular galaxies moving on bound orbits in the massive dark matter halo of the Milky Way.The dwarf models span a range in disk surface density and the masses and sizes of their dark halos are consistent with the predictions of cold dark matter cosmogonies. We show that the strong tidal field of the Milky Way determines severe mass loss in their halos and disks and induces bar and bending instabilities that transform low surface brightness dwarfs (LSBs) into dwarf spheroidals (dSphs) and high surface brightness dwarfs (HSBs) into dwarf ellipticals (dEs) in less than 10 Gyr. The final central velocity dispersions of the remnants are in the range 8-30 km/s and their final $v/\sigma$ falls to values $< 0.5$, matching well the kinematics of early-type dwarfs. The transformation requires the orbital time of the dwarf to be \simlt 3-4 Gyr, which implies a halo as massive and extended as predicted by hierarchical models of galaxy formation to explain the origin of even the farthest dSph satellites of the Milky Way, Leo I and Leo II. Only dwarfs with central dark matter densities as high as those of Draco and Ursa Minor can survive for 10 Gyr in the proximity of the Milky Way: this is naturally achieved within hierarchical models, where the densest objects should have small orbital times due to their early formation epochs. Part of the gas is stripped and part is funneled to the center due to the bar, generating one strong burst of star formation in HSBs and smaller, multiple bursts in LSBs. Extended low-surface brightness stellar and gaseous streams originate from LSBs and, when projected along the line of sight, can lead to overestimate the mass-to-light ratio of the bound remnant by a factor \simlt 2,Comment: 29 pages, 34 figures, submitted to ApJ. Figures 5,11 and 32 are given as separate GIF files. Other figures and the movies of the simulations can be found at http://pcblu.mib.infn.it/~lucio/LG/LG.htm

Predictors of Gestational Weight Gain among White and Latina Women and Associations with Birth Weight

This study examined racial/ethnic differences in gestational weight gain (GWG) predictors and association of first-trimester GWG to overall GWG among 271 White women and 300 Latina women. Rates of within-guideline GWG were higher among Latinas than among Whites (28.7% versus 24.4%, p < 0.016). Adjusted odds of above-guideline GWG were higher among prepregnancy overweight (OR = 3.4, CI = 1.8–6.5) and obese (OR = 4.5, CI = 2.3–9.0) women than among healthy weight women and among women with above-guideline first-trimester GWG than among those with within-guideline first-trimester GWG (OR = 4.9, CI = 2.8–8.8). GWG was positively associated with neonate birth size (p < 0.001). Interventions targeting prepregnancy overweight or obese women and those with excessive first-trimester GWG are needed