Chk1 Haploinsufficiency Results in Anemia and Defective Erythropoiesis

Erythropoiesis is a highly regulated and well-characterized developmental process responsible for providing the oxygen transport system of the body. However, few of the mechanisms involved in this process have been elucidated. Checkpoint Kinase 1 (Chk1) is best known for its role in the cell cycle and DNA damage pathways, and it has been shown to play a part in several pathways which when disrupted can lead to anemia.Here, we show that haploinsufficiency of Chk1 results in 30% of mice developing anemia within the first year of life. The anemic Chk1+/- mice exhibit distorted spleen and bone marrow architecture, and abnormal erythroid progenitors. Furthermore, Chk1+/- erythroid progenitors exhibit an increase in spontaneous DNA damage foci and improper contractile actin ring formation resulting in aberrant enucleation during erythropoiesis. A decrease in Chk1 RNA has also been observed in patients with refractory anemia with excess blasts, further supporting a role for Chk1 in clinical anemia.Clinical trials of Chk1 inhibitors are currently underway to treat cancer, and thus it will be important to track the effects of these drugs on red blood cell development over an extended period. Our results support a role for Chk1 in maintaining the balance between erythroid progenitors and enucleated erythroid cells during differentiation. We show disruptions in Chk1 levels can lead to anemia

NPTX1 Regulates Neural Lineage Specification from Human Pluripotent Stem Cells

SummaryNeural induction is the first fundamental step in nervous system formation. During development, a tightly regulated niche modulates transient extracellular signals to influence neural lineage commitment. To date, however, the cascade of molecular events that sustain these signals in humans is not well understood. Here we show that NPTX1, a secreted protein, is rapidly upregulated during neural induction from human pluripotent stem cells (hPSCs). By manipulating its expression, we were able to reduce or initiate neural lineage commitment. A time-course transcriptome analysis and functional assays show that NPTX1 acts in part by binding the Nodal receptor cofactor TDGF1, reducing both Nodal and BMP signaling. Our findings identify one of the earliest genes expressed upon neural induction and provide insight into human neural lineage specification

Evidence for Diversity in Transcriptional Profiles of Single Hematopoietic Stem Cells

Hematopoietic stem cells replenish all the cells of the blood throughout the lifetime of an animal. Although thousands of stem cells reside in the bone marrow, only a few contribute to blood production at any given time. Nothing is known about the differences between individual stem cells that dictate their particular state of activation readiness. To examine such differences between individual stem cells, we determined the global gene expression profile of 12 single stem cells using microarrays. We showed that at least half of the genetic expression variability between 12 single cells profiled was due to biological variation in 44% of the genes analyzed. We also identified specific genes with high biological variance that are candidates for influencing the state of readiness of individual hematopoietic stem cells, and confirmed the variability of a subset of these genes using single-cell real-time PCR. Because apparent variation of some genes is likely due to technical factors, we estimated the degree of biological versus technical variation for each gene using identical RNA samples containing an RNA amount equivalent to that of single cells. This enabled us to identify a large cohort of genes with low technical variability whose expression can be reliably measured on the arrays at the single-cell level. These data have established that gene expression of individual stem cells varies widely, despite extremely high phenotypic homogeneity. Some of this variation is in key regulators of stem cell activity, which could account for the differential responses of particular stem cells to exogenous stimuli. The capacity to accurately interrogate individual cells for global gene expression will facilitate a systems approach to biological processes at a single-cell level

Discovery of Precursor LBV Outbursts in Two Recent Optical Transients: The Fitfully Variable Missing Links UGC 2773-OT and SN 2009ip

We present progenitor-star detections, light curves, and optical spectra of SN2009ip and the 2009 optical transient in UGC2773 (U2773-OT), which were not genuine SNe. Precursor variability in the decade before outburst indicates that both of the progenitor stars were LBVs. Their pre-outburst light curves resemble the S Doradus phases that preceded giant eruptions of eta Carinae and SN1954J (V12 in NGC2403), with intermediate progenitor luminosities. HST detections a decade before discovery indicate that the SN2009ip and U2773-OT progenitors were supergiants with likely initial masses of 50-80 Msun and \ga20 Msun, respectively. Both outbursts had spectra befitting known LBVs, although in different physical states. SN 2009ip exhibited a hot LBV spectrum with characteristic speeds of 550 km/s, plus faster material up to 5000 km/s, resembling the slow Homunculus and fast blast wave of eta Carinae. U2773-OT shows a forest of narrow absorption and emission lines comparable to that of S Dor in its cool state, plus [CaII] emission and an IR excess indicative of dust, similar to SN2008S and N300-OT. [CaII] emission is probably tied to a dusty pre-outburst environment, and not the outburst mechanism. SN2009ip and U2773-OT may provide a critical link between historical LBV eruptions, while U2773-OT may provide a link between LBVs and SN2008S and N300-OT. Future searches will uncover more examples of precursor LBV variability of this kind, providing key clues that may help unravel the instability driving LBVs.Comment: 18 pages, 13 Figures, accepted AJ. added significant material while revising after referee repor

Hematopoietic Fingerprints: An Expression Database of Stem Cells and Their Progeny

SummaryHematopoietic stem cells (HSCs) continuously regenerate the hematologic system, yet few genes regulating this process have been defined. To identify candidate factors involved in differentiation and self-renewal, we have generated an expression database of hematopoietic stem cells and their differentiated progeny, including erythrocytes, granulocytes, monocytes, NK cells, activated and naive T cells, and B cells. Bioinformatic analysis revealed HSCs were more transcriptionally active than their progeny and shared a common activation mechanism with T cells. Each cell type also displayed unique biases in the regulation of particular genetic pathways, with Wnt signaling particularly enhanced in HSCs. We identified ∼100–400 genes uniquely expressed in each cell type, termed lineage “fingerprints.” In overexpression studies, two of these genes, Zfp105 from the NK cell lineage, and Ets2 from the monocyte lineage, were able to significantly influence differentiation toward their respective lineages, demonstrating the utility of the fingerprints for identifying genes that regulate differentiation

A Spitzer Survey for Dust in Type IIn Supernovae

Recent observations suggest that Type IIn supernovae (SNe IIn) may exhibit late-time (>100 days) infrared (IR) emission from warm dust more than other types of core-collapse SNe. Mid-IR observations, which span the peak of the thermal spectral energy distribution, provide useful constraints on the properties of the dust and, ultimately, the circumstellar environment, explosion mechanism, and progenitor system. Due to the low SN IIn rate (<10% of all core-collapse SNe), few IR observations exist for this subclass. The handful of isolated studies, however, show late-time IR emission from warm dust that, in some cases, extends for five or six years post-discovery. While previous Spitzer/IRAC surveys have searched for dust in SNe, none have targeted the Type IIn subclass. This article presents results from a warm Spitzer/IRAC survey of the positions of all 68 known SNe IIn within a distance of 250 Mpc between 1999 and 2008 that have remained unobserved by Spitzer more than 100 days post-discovery. The detection of late-time emission from ten targets (~15%) nearly doubles the database of existing mid-IR observations of SNe IIn. Although optical spectra show evidence for new dust formation in some cases, the data show that in most cases the likely origin of the mid-IR emission is pre-existing dust, which is continuously heated by optical emission generated by ongoing circumstellar interaction between the forward shock and circumstellar medium. Furthermore, an emerging trend suggests that these SNe decline at ~1000--2000 days post-discovery once the forward shock overruns the dust shell. The mass-loss rates associated with these dust shells are consistent with luminous blue variable (LBV) progenitors.Comment: Accepted for publication to ApJ, 17 pages, 10 figures, 10 table

Staphylococcus epidermidis biofilm-released cells induce a prompt and more marked in vivo inflammatory-type response than planktonic or biofilm cells

Staphylococcus epidermidis biofilm formation on indwelling medical devices is frequently associated with the development of chronic infections. Nevertheless, it has been suggested that cells released from these biofilms may induce severe acute infections with bacteraemia as one of its major associated clinical manifestations. However, how biofilm-released cells interact with the host remains unclear. Here, using a murine model of hematogenously disseminated infection, we characterized the interaction of cells released from S. epidermidis biofilms with the immune system. Gene expression analysis of mouse splenocytes suggested that biofilm-released cells might be particularly effective at activating inflammatory and antigen presenting cells and inducing cellular apoptosis. Furthermore, biofilm-released cells induced a higher production of pro-inflammatory cytokines, in contrast to mice infected with planktonic cells, even though these had a similar bacterial load in livers and spleens. Overall, these results not only provide insights into the understanding of the role of biofilm-released cells in S. epidermidis biofilm-related infections and pathogenesis, but may also help explain the relapsing character of these infections.This work was supported by European Union funds (FEDER/COMPETE) and by national funds (FCT) under the project with reference FCOMP-01-0124-FEDER-014309 (PTDC/BIA-MIC/113450/2009). The authors thank the FCT Strategic Project of UID/BIO/04469/2013 unit, and the project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462). NC is an Investigator FCT. AF is supported by the FCT fellowship SFRH/BPD/99961/2014 and AC by the fellowship SFRH/BPD/91623/2012.The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication

Student Compostiton Recital

Kennesaw State University School of Music presents Student Composition Recital.https://digitalcommons.kennesaw.edu/musicprograms/1390/thumbnail.jp

CD81 Is Essential for the Re-entry of Hematopoietic Stem Cells to Quiescence following Stress-Induced Proliferation Via Deactivation of the Akt Pathway

A protein that is thought to orchestrate the distribution of other signaling molecules on the cell membrane, CD81, is critical to maintaining the functional integrity of hematopoietic stem cells during their regeneration