Glioblastoma Stem Cells Respond to Differentiation Cues but Fail to Undergo Commitment and Terminal Cell-Cycle Arrest.

Glioblastoma (GBM) is an aggressive brain tumor whose growth is driven by stemcell-like cells. BMP signaling triggers cell-cycle exit and differentiation of GBM stemcells (GSCs) and, therefore, might have therapeutic value. However, the epigenetic mechanisms that accompany differentiation remain poorly defined. It is also unclear whether cell-cycle arrest is terminal. Herewe find only a subset ofGSCcultures exhibit astrocyte differentiation in response to BMP. Although overtly differentiated non-cycling astrocytes are generated, they remain vulnerable to cell-cycle re-entry and fail to appropriately reconfigure DNA methylation patterns. Chromatin accessibility mapping identified loci that failed to alter in response to BMP and these were enriched in SOX transcription factor-binding motifs. SOX transcription factors, therefore, may limit differentiation commitment. A similar propensity for cell-cycle re-entry and de-differentiation was observed in GSC-derived oligodendrocyte-like cells. These findings highlight significant obstacles to BMP-induced differentiation as therapy forGBM

A Giant Metrewave Radio Telescope/Chandra view of IRAS 09104+4109: A type 2 QSO in a cooling flow

IRAS 09104+4109 is a rare example of a dust enshrouded type 2 QSO in the centre of a cool-core galaxy cluster. Previous observations of this z=0.44 system showed that as well as powering the hyper-luminous infrared emission of the cluster-central galaxy, the QSO is associated with a double-lobed radio source. However, the steep radio spectral index and misalignment between the jets and ionised optical emission suggested that the orientation of the QSO had recently changed. We use a combination of new, multi-band Giant Metrewave Radio Telescope observations and archival radio data to confirm that the jets are no longer powered by the QSO, and estimate their age to be 120-160 Myr. This is in agreement with the ~70-200 Myr age previously estimated for star-formation in the galaxy. Previously unpublished Very Long Baseline Array data reveal a 200 pc scale double radio source in the galaxy core which is more closely aligned with the current QSO axis and may represent a more recent period of jet activity. These results suggest that the realignment of the QSO, the cessation of jet activity, and the onset of rapid star-formation may have been caused by a gas-rich galaxy merger. A Chandra X-ray observation confirms the presence of cavities associated with the radio jets, and we estimate the energy required to inflate them to be ~7.7x10^60 erg. The mechanical power of the jets is sufficient to balance radiative cooling in the cluster, provided they are efficiently coupled to the intra-cluster medium (ICM). We find no evidence of direct radiative heating and conclude that the QSO either lacks the radiative luminosity to heat the ICM, or that it requires longer than 100-200 Myr to significantly impact its environment. [Abridged]Comment: 23 pages, 18 figures and 7 tables. Accepted for publication in MNRA

Characteristics of Staphylococcus aureus Isolated from Patients in Busia County Referral Hospital, Kenya

Staphylococcus aureus is an important pathogen associated with hospital, community, and livestock-acquired infections, with the ability to develop resistance to antibiotics. Nasal carriage by hospital inpatients is a risk for opportunistic infections. Antibiotic susceptibility patterns, virulence genes and genetic population structure of S. aureus nasal isolates, from inpatients at Busia County Referral Hospital (BCRH) were analyzed. A total of 263 inpatients were randomly sampled, from May to July 2015. The majority of inpatients (85.9%) were treated empirically with antimicrobials, including ceftriaxone (65.8%) and metronidazole (49.8%). Thirty S. aureus isolates were cultured from 29 inpatients with a prevalence of 11% (10.3% methicillin-susceptible S. aureus (MSSA), 0.8% methicillin resistant S. aureus (MRSA)). Phenotypic and genotypic resistance was highest to penicillin-G (96.8%), trimethoprim (73.3%), and tetracycline (13.3%) with 20% of isolates classified as multidrug resistant. Virulence genes, Panton-Valentine leukocidin (pvl), toxic shock syndrome toxin-1 (tsst-1), and sasX gene were detected in 16.7%, 23.3% and 3.3% of isolates. Phylogenetic analysis showed 4 predominant clonal complexes CC152, CC8, CC80, and CC508. This study has identified that inpatients of BCRH were carriers of S. aureus harbouring virulence genes and resistance to a range of antibiotics. This may indicate a public health risk to other patients and the community

Nuclear architecture organized by Rif1 underpins the replication-timing program

DNA replication is temporally and spatially organized in all eukaryotes, yet the molecular control and biological function of the replication-timing program are unclear. Rif1 is required for normal genome-wide regulation of replication timing, but its molecular function is poorly understood. Here we show that in mouse embryonic stem cells, Rif1 coats late-replicating domains and, with Lamin B1, identifies most of the late-replicating genome. Rif1 is an essential determinant of replication timing of non-Lamin B1-bound late domains. We further demonstrate that Rif1 defines and restricts the interactions between replication-timing domains during the G1 phase, thereby revealing a function of Rif1 as organizer of nuclear architecture. Rif1 loss affects both number and replication-timing specificity of the interactions between replication-timing domains. In addition, during the S phase, Rif1 ensures that replication of interacting domains is temporally coordinated. In summary, our study identifies Rif1 as the molecular link between nuclear architecture and replication-timing establishment in mammals

Production of transgenic lamb foetuses by sub-zonal injection of feline leukaemia virus

No abstract available

Plasmids containing a murine autonomous replicating sequence in transgenic mice: function as an origin of replication, but inability to persist in an episomal state

No abstract available

The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression.

Chromatin remodeling complexes play essential roles in metazoan development through widespread control of gene expression, but the precise molecular mechanisms by which they do this in vivo remain ill defined. Using an inducible system with fine temporal resolution, we show that the nucleosome remodeling and deacetylation (NuRD) complex controls chromatin architecture and the protein binding repertoire at regulatory regions during cell state transitions. This is primarily exerted through its nucleosome remodeling activity while deacetylation at H3K27 follows changes in gene expression. Additionally, NuRD activity influences association of RNA polymerase II at transcription start sites and subsequent nascent transcript production, thereby guiding the establishment of lineage-appropriate transcriptional programs. These findings provide a detailed molecular picture of genome-wide modulation of lineage-specific transcription by an essential chromatin remodeling complex as well as insight into the orchestration of molecular events involved in transcriptional transitions in vivo. VIDEO ABSTRACT.MX was funded through an EMBL PhD studentship, EJ through a BBSRC PhD studentship and JS through an MRC PhD studentship. Funding in the BH lab was provided by a Wellcome Trust Senior Fellowship and the EU FP7 Integrated Project “4DCellFate.” Funding in the PB lab was provided by EMBL and BBSRC. BH and PB labs further benefit from core funding to the Cambridge Stem Cell Institute from the Wellcome Trust and Medical Research Council

Characteristics of <i>Staphylococcus aureus</i> Isolated from Patients in Busia County Referral Hospital, Kenya

Staphylococcus aureus is an important pathogen associated with hospital, community, and livestock-acquired infections, with the ability to develop resistance to antibiotics. Nasal carriage by hospital inpatients is a risk for opportunistic infections. Antibiotic susceptibility patterns, virulence genes and genetic population structure of S. aureus nasal isolates, from inpatients at Busia County Referral Hospital (BCRH) were analyzed. A total of 263 inpatients were randomly sampled, from May to July 2015. The majority of inpatients (85.9%) were treated empirically with antimicrobials, including ceftriaxone (65.8%) and metronidazole (49.8%). Thirty S. aureus isolates were cultured from 29 inpatients with a prevalence of 11% (10.3% methicillin-susceptible S. aureus (MSSA), 0.8% methicillin resistant S. aureus (MRSA)). Phenotypic and genotypic resistance was highest to penicillin-G (96.8%), trimethoprim (73.3%), and tetracycline (13.3%) with 20% of isolates classified as multidrug resistant. Virulence genes, Panton-Valentine leukocidin (pvl), toxic shock syndrome toxin-1 (tsst-1), and sasX gene were detected in 16.7%, 23.3% and 3.3% of isolates. Phylogenetic analysis showed 4 predominant clonal complexes CC152, CC8, CC80, and CC508. This study has identified that inpatients of BCRH were carriers of S. aureus harbouring virulence genes and resistance to a range of antibiotics. This may indicate a public health risk to other patients and the community