Temporal Transcriptional Profiling of Somatic and Germ Cells Reveals Biased Lineage Priming of Sexual Fate in the Fetal Mouse Gonad

The divergence of distinct cell populations from multipotent progenitors is poorly understood, particularly in vivo. The gonad is an ideal place to study this process, because it originates as a bipotential primordium where multiple distinct lineages acquire sex-specific fates as the organ differentiates as a testis or an ovary. To gain a more detailed understanding of the process of gonadal differentiation at the level of the individual cell populations, we conducted microarrays on sorted cells from XX and XY mouse gonads at three time points spanning the period when the gonadal cells transition from sexually undifferentiated progenitors to their respective sex-specific fates. We analyzed supporting cells, interstitial/stromal cells, germ cells, and endothelial cells. This work identified genes specifically depleted and enriched in each lineage as it underwent sex-specific differentiation. We determined that the sexually undifferentiated germ cell and supporting cell progenitors showed lineage priming. We found that germ cell progenitors were primed with a bias toward the male fate. In contrast, supporting cells were primed with a female bias, indicative of the robust repression program involved in the commitment to XY supporting cell fate. This study provides a molecular explanation reconciling the female default and balanced models of sex determination and represents a rich resource for the field. More importantly, it yields new insights into the mechanisms by which different cell types in a single organ adopt their respective fates

OMEGA - OSIRIS mapping of emission-line galaxies in A901/2: III. - Galaxy properties across projected phase space in A901/2

We conduct a comprehensive projected phase-space analysis of the A901/2 multicluster system at z ∼ 0.165. Aggregating redshifts from spectroscopy, tunable-filter imaging and prism techniques, we assemble a sample of 856 cluster galaxies reaching 108.5 M⊙ in stellar mass. We look for variations in cluster galaxy properties between virialized and non-virialized regions of projected phase space (PPS). Our main conclusions point to relatively gentle environmental effects, expressed mainly on galaxy gas reservoirs. (1) Stacking the four subclusters in A901/2, we find galaxies in the virialized region are more massive, redder and have marginally higher Sérsic indices, but their half-light radii and Hubble types are not significantly different. (2) After accounting for trends in stellar mass, there is a remaining change in rest-frame colour across PPS. Primarily, the colour difference is due to the absence in the virialized region of galaxies with rest frame B − V 109.85 M⊙) stellar mass. (3) There is an infalling population of lower mass (M⋆ ≤ 109.85 M⊙), relatively blue (B − V < 0.7) elliptical or spheroidal galaxies that are strikingly absent in the virialized region. (4) The number of bona fide star-forming and active galactic nucleus galaxies in the PPS regions is strongly dictated by stellar mass. However, there remains a reduced fraction of star-forming galaxies in the centres of the clusters at fixed stellar mass, consistent with the star formation–density relation in galaxy clusters. (5) There is no change in specific Hα-derived star formation rates of star-forming galaxies at fixed mass across the cluster environment. This suggests that pre-processing of galaxies during infall plays a prominent role in quenching star formation

Non-classical ProIL-1beta activation during mammary gland infection is pathogen-dependent but caspase-1 independent

Infection of the mammary gland with live bacteria elicits a pathogen-specific host inflammatory response. To study these host-pathogen interactions wild type mice, NF-kappaB reporter mice as well as caspase-1 and IL-1beta knockout mice were intramammarily challenged with Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The murine mastitis model allowed to compare the kinetics of the induced cytokine protein profiles and their underlying pathways. In vivo and ex vivo imaging showed that E. coli rapidly induced NF-kappaB inflammatory signaling concomitant with high mammary levels of TNF-alpha, IL-1 alpha and MCP-1 as determined by multiplex analysis. In contrast, an equal number of S. aureus bacteria induced a low NF-kappaB activity concomitant with high mammary levels of the classical IL-1beta fragment. These quantitative and qualitative differences in local inflammatory mediators resulted in an earlier neutrophil influx and in a more extensive alveolar damage post-infection with E. coli compared to S. aureus. Western blot analysis revealed that the inactive proIL-1beta precursor was processed into pathogen-specific IL-1beta fragmentation patterns as confirmed with IL-1beta knockout animals. Additionally, caspase-1 knockout animals allowed to investigate whether IL-1beta maturation depended on the conventional inflammasome pathway. The lack of caspase-1 did not prevent extensive proIL-1beta fragmentation by either of S. aureus or E. coli. These non-classical IL-1beta patterns were likely caused by different proteases and suggest a sentinel function of IL-1beta during mammary gland infection. Thus, a key signaling nodule can be defined in the differential host innate immune defense upon E. coli versus S. aureus mammary gland infection, which is independent of caspase-1

Circulating tumour DNA is a promising biomarker for risk stratification of central chondrosarcoma with IDH1/2 and GNAS mutations

Chondrosarcoma (CS) is a rare tumour type and the most common primary malignant bone cancer in adults. The prognosis, currently based on tumour grade, imaging and anatomical location, is not reliable, and more objective biomarkers are required. We aimed to determine whether the level of circulating tumour DNA (ctDNA) in the blood of CS patients could be used to predict outcome. In this multi-institutional study, we recruited 145 patients with cartilaginous tumours, of which 41 were excluded. ctDNA levels were assessed in 83 of the remaining 104 patients, whose tumours harboured a hotspot mutation in IDH1/2 or GNAS. ctDNA was detected pre-operatively in 31/83 (37%) and in 12/31 (39%) patients postoperatively. We found that detection of ctDNA was more accurate than pathology for identification of high-grade tumours and was associated with a poor prognosis; ctDNA was never associated with CS grade 1/atypical cartilaginous tumours (ACT) in the long bones, in neoplasms sited in the small bones of the hands and feet or in tumours measuring less than 80 mm. Although the results are promising, they are based on a small number of patients, and therefore, introduction of this blood test into clinical practice as a complementary assay to current standard-of-care protocols would allow the assay to be assessed more stringently and developed for a more personalised approach for the treatment of patients with CS

A genetic model for central chondrosarcoma evolution correlates with patient outcome

Background Central conventional chondrosarcoma (CS) is the most common subtype of primary malignant bone tumour in adults. Treatment options are usually limited to surgery, and prognosis is challenging. These tumours are characterised by the presence and absence of IDH1 and IDH2 mutations, and recently, TERT promoter alterations have been reported in around 20% of cases. The effect of these mutations on clinical outcome remains unclear. The purpose of this study was to determine if prognostic accuracy can be improved by the addition of genomic data, and specifically by examination of IDH1, IDH2, and TERT mutations. Methods In this study, we combined both archival samples and data sourced from the Genomics England 100,000 Genomes Project (n = 356). Mutations in IDH1, IDH2, and TERT were profiled using digital droplet PCR (n = 346), whole genome sequencing (n=68), or both (n = 64). Complex events and other genetic features were also examined, along with methylation array data (n = 84). We correlated clinical features and patient outcomes with our genetic findings. Results IDH2-mutant tumours occur in older patients and commonly present with high-grade or dedifferentiated disease. Notably, TERT mutations occur most frequently in IDH2-mutant tumours, although have no effect on survival in this group. In contrast, TERT mutations are rarer in IDH1-mutant tumours, yet they are associated with a less favourable outcome in this group. We also found that methylation profiles distinguish IDH1- from IDH2-mutant tumours. IDH wild-type tumours rarely exhibit TERT mutations and tend to be diagnosed in a younger population than those with tumours harbouring IDH1 and IDH2 mutations. A major genetic feature of this group is haploidisation and subsequent genome doubling. These tumours evolve less frequently to dedifferentiated disease and therefore constitute a lower risk group. Conclusions Tumours with IDH1 or IDH2 mutations or those that are IDHwt have significantly different genetic pathways and outcomes in relation to TERT mutation. Diagnostic testing for IDH1, IDH2, and TERT mutations could therefore help to guide clinical monitoring and prognostication

GAMA/G10-COSMOS/3D-HST: The 0<z<5 cosmic star-formation history, stellar- and dust-mass densities

We use the energy-balance code MAGPHYS to determine stellar and dust masses, and dust corrected star-formation rates for over 200,000 GAMA galaxies, 170,000 G10-COSMOS galaxies and 200,000 3D-HST galaxies. Our values agree well with previously reported measurements and constitute a representative and homogeneous dataset spanning a broad range in stellar mass (10^8---10^12 Msol), dust mass (10^6---10^9 Msol), and star-formation rates (0.01---100 Msol per yr), and over a broad redshift range (0.0 < z < 5.0). We combine these data to measure the cosmic star-formation history (CSFH), the stellar-mass density (SMD), and the dust-mass density (DMD) over a 12 Gyr timeline. The data mostly agree with previous estimates, where they exist, and provide a quasi-homogeneous dataset using consistent mass and star-formation estimators with consistent underlying assumptions over the full time range. As a consequence our formal errors are significantly reduced when compared to the historic literature. Integrating our cosmic star-formation history we precisely reproduce the stellar-mass density with an ISM replenishment factor of 0.50 +/- 0.07, consistent with our choice of Chabrier IMF plus some modest amount of stripped stellar mass. Exploring the cosmic dust density evolution, we find a gradual increase in dust density with lookback time. We build a simple phenomenological model from the CSFH to account for the dust mass evolution, and infer two key conclusions: (1) For every unit of stellar mass which is formed 0.0065---0.004 units of dust mass is also formed; (2) Over the history of the Universe approximately 90 to 95 per cent of all dust formed has been destroyed and/or ejected

Some Effects of Early Visual Environments on Adult Discrimination Abilities in the Rat

76 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1966.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD