Skin-Derived TSLP Triggers Progression from Epidermal-Barrier Defects to Asthma

A skin-derived cytokine with high systemic availability provides a mechanistic explanation for atopic march and highlights a potential therapeutic target for preventing the development of asthma among people with atopic dermatitis

Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [

Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution

Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake Tt

In search of flavour-nutrient learning:A study of the Samburu pastoralists of North-Central Kenya

Much of our dietary behaviour is learned. In particular, one suggestion is that ‘flavour-nutrient learning’ (F-NL) influences both choice and intake of food. F-NL occurs when an association forms between the orosensory properties of a food and its postingestive effects. Unfortunately, this process has been difficult to evaluate because F-NL is rarely observed in controlled studies of adult humans. One possibility is that we are disposed to F-NL. However, learning is compromised by exposure to a complex Western diet that includes a wide range of energy-dense foods. To test this idea we explored evidence for F-NL in a sample of semi-nomadic pastoralists who eat a very limited diet, and who are lean and food stressed. Our Samburu participants (N = 68) consumed a sensory-matched portion (400 g) of either a novel low (0.72 kcal/g) or higher (1.57 kcal/g) energy-dense semi-solid food on two training days, and an intermediate version on day 3. Before and after each meal we measured appetite and assessed expected satiation and liking for the test food. We found no evidence of F-NL. Nevertheless, self-reported measures were very consistent and, as anticipated, expected satiation increased as the test food became familiar (expectedsatiation drift). Surprisingly,we observed insensitivity to the effects of test-meal energy density on measures of post-meal appetite. To explore this further we repeated a single training day using participants (N = 52) from the UK. Unlike in the Samburu, the higher energy-dense meal caused greater suppression of appetite. These observations expose interesting cross-cultural differences in sensitivity to the energy content of food. More generally, our work illustrates how measures can be translated to assess different populations, highlighting the potential for further comparisons of this kind

Imprints of radial migration on the Milky Way’s metallicity distribution functions

Recent analysis of the SDSS-III/Apache Point Observatory Galactic Evolution Experiment (APOGEE) Data Release 12 stellar catalog has revealed that the Milky Way’s (MW) metallicity distribution function (MDF) changes shape as a function of radius, transitioning from being negatively skewed at small Galactocentric radii to positively skewed at large Galactocentric radii. Using a high-resolution, N-body+SPH simulation, we show that the changing skewness arises from radial migration—metal-rich stars form in the inner disk and subsequently migrate to the metal-poorer outer disk. These migrated stars represent a large fraction (>50%) of the stars in the outer disk; they populate the high-metallicity tail of the MDFs and are, in general, more metal-rich than the surrounding outer disk gas. The simulation also reproduces another surprising APOGEE result: the spatially invariant high-[α/Fe] MDFs. This arises in the simulation from the migration of a population formed within a narrow range of radii (3.2 ±1.2 kpc) and time (8.8 ± 0.6 Gyr ago), rather than from spatially extended star formation in a homogeneous medium at early times. These results point toward the crucial role radial migration has played in shaping our MW

Discovery of Extended Blue Horizontal Branches in Two Metal-Rich Globular Clusters

We have used WFPC2 to construct B, V color-magnitude diagrams of four metal-rich globular clusters, NGC 104 (47 Tuc), NGC 5927, NGC 6388, and NGC 6441. All four clusters have well populated red horizontal branches (RHB), as expected for their metallicity. However, NGC 6388 and 6441 also exhibit a prominent blue HB (BHB) extension, including stars reaching as faint in V as the turnoff luminosity. This discovery demonstrates directly for the first time that a major population of hot HB stars can exist in old, metal-rich systems. This may have important implications for the interpretation of the integrated spectra of elliptical galaxies. The cause of the phenomenon remains uncertain. We examine the possibility that NGC 6388 and 6441 are older than the other clusters, but a simple difference in age may not be sufficient to produce the observed distributions along the HB. The high central densities in NGC 6388 and 6441 suggest that the existence of the blue HB (BHB) tails might be caused by stellar interactions in the dense cores of these clusters, which we calculate to have two of the highest collision rates among globular clusters in the Galaxy. Tidal collisions might act in various ways to enhance loss of envelope mass, and therefore populate the blue side of the HB. However, the relative frequency of tidal collisions does not seem large enough (compared to that of the clusters with pure RHBs) to account for such a drastic difference in HB morphology. While a combination of an age difference and dynamical interactions may help, prima facie the lack of a radial gradient in the BHB/RHB star ratio seems to argue against dynamical effects playing a role.Comment: LaTeX, includes one Postscript figure. To appear in ApJ

Specification of a foxj1-dependent lineage in the forebrain is required for embryonic-to-postnatal transition of neurogenesis in the olfactory bulb

Establishment of a neural stem cell niche in the postnatal subependymal zone (SEZ) and the rostral migratory stream (RMS) is required for postnatal and adult neurogenesis in the olfactory bulbs (OB). We report the discovery of a cellular lineage in the SEZ-RMS-OB continuum, the specification of which is dependent on the expression of the forkhead transcription factor Foxj1 in mice. Spatially- and temporally- restricted Foxj1+ neuronal progenitors emerge during embryonic periods, surge during perinatal development, and are active only for the first few postnatal weeks. We show that the development of the unique Foxj1-derived lineage is dependent on Foxj1 expression, and is required for overall postnatal neurogenesis in the OB. Strikingly, the production of neurons from Foxj1+ progenitors significantly declines after the early postnatal weeks, but Foxj1-derived neurons in the OB persist during adult periods. Our study for the first time identifies the time-and region-specific activity of a perinatal progenitor domain that is required for transition and progression of OB neurogenesis from the embryonic-to-postnatal periods

Novel mode of ISG15-mediated protection against influenza A virus and Sendai virus in mice

ISG15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type I interferon stimulation. Hundreds of host proteins and a number of viral proteins have been shown to be ISGylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. ISG15(−/−) mice exhibit increased susceptibility to viral infection, and in the case of influenza B virus and vaccinia virus, ISG15 conjugation has been shown to restrict virus replication in vivo. A number of studies have also found that ISG15 is capable of antagonizing replication of some viruses in tissue culture. However, recent findings have demonstrated that ISG15 can protect mice from Chikungunya virus infection without affecting the virus burden. In order to better understand the function of ISG15 in vivo, we characterized the pathogenesis of influenza A virus and Sendai virus in ISG15(−/−) mice. We found that ISG15 protects mice from virus induced lethality by a conjugation-dependent mechanism in both of these models. However, surprisingly, we found that ISG15 had minimal effect on virus replication and did not have an obvious role in the modulation of the acute immune response to infection. Instead, we observed an increase in the number of diseased small airways in mice lacking ISG15. This ability of ISG15 to protect mice in a conjugation-dependent, but nonantiviral, manner from respiratory virus infection represents a previously undescribed role for ISG15 and demonstrates the importance of further characterization of ISG15 in vivo. IMPORTANCE It has previously been demonstrated that ISG15(−/−) mice are more susceptible to a number of viral infections. Since ISG15 is one of the most strongly induced genes after type I interferon stimulation, analysis of ISG15 function has largely focused on its role as an antiviral molecule during acute infection. Although a number of studies have shown that ISG15 does have a small effect on virus replication in tissue culture, few studies have confirmed this mechanism of protection in vivo. In these studies we have found that while ISG15(−/−) mice are more susceptible to influenza A virus and Sendai virus infections, ISGylation does not appear to mediate this protection through the direct inhibition of virus replication or the modulation of the acute immune response. Thus, in addition to showing a novel mode of ISG15 mediated protection from virus infection, this study demonstrates the importance of studying the role of ISG15 in vivo