Distinguishing aggressive from indolent disease and developing effective therapy for advanced disease are the major challenges in prostate cancer research. Chromosomal rearrangements involving ETS ...transcription factors, such as ERG and ETV1, occur frequently in prostate cancer. How they contribute to tumorigenesis and whether they play similar or distinct in vivo roles remain elusive. Here we show that in mice with ERG or ETV1 targeted to the endogenous Tmprss2 locus, either factor cooperated with loss of a single copy of Pten, leading to localized cancer, but only ETV1 appeared to support development of invasive adenocarcinoma under the background of full Pten loss. Mechanistic studies demonstrated that ERG and ETV1 control a common transcriptional network but largely in an opposing fashion. In particular, while ERG negatively regulates the androgen receptor (AR) transcriptional program, ETV1 cooperates with AR signaling by favoring activation of the AR transcriptional program. Furthermore, we found that ETV1 expression, but not that of ERG, promotes autonomous testosterone production. Last, we confirmed the association of an ETV1 expression signature with aggressive disease and poorer outcome in patient data. The distinct biology of ETV1-associated prostate cancer suggests that this disease class may require new therapies directed to underlying programs controlled by ETV1.
Haematopoietic stem cells (HSCs) sustain blood production throughout life. HSCs are capable of extensive proliferative expansion, as a single HSC may reconstitute lethally irradiated hosts. In ...steady-state, HSCs remain largely quiescent and self-renew at a constant low rate, forestalling their exhaustion during adult life. Whereas nuclear regulatory factors promoting proliferative programmes of HSCs in vivo and ex vivo have been identified, transcription factors restricting their cycling have remained elusive. Here we report that the zinc-finger repressor Gfi-1 (growth factor independent 1), a cooperating oncogene in lymphoid cells, unexpectedly restricts proliferation of HSCs. After loss of Gfi-1, HSCs display elevated proliferation rates as assessed by 5-bromodeoxyuridine incorporation and cell-cycle analysis. Gfi-1-/- HSCs are functionally compromised in competitive repopulation and serial transplantation assays, and are rapidly out-competed in the bone marrow of mouse chimaeras generated with Gfi-1-/- embryonic stem cells. Thus, Gfi-1 is essential to restrict HSC proliferation and to preserve HSC functional integrity.
We report essential roles of zinc finger transcription factor Gfi-1 in myeloid development. Gene-targeted Gfi-1
−/− mice lack normal neutrophils and are highly susceptible to abscess formation by ...gram-positive bacteria. Arrested, morphologically atypical, Gr1
+Mac1
+ myeloid cells expand with age in the bone marrow. RNAs encoding primary but not secondary or tertiary neutrophil (granulocyte) granule proteins are expressed. The atypical Gr1
+Mac1
+ cell population shares characteristics of both the neutrophil and macrophage lineages and exhibits phagocytosis and respiratory burst activity
. Reexpression of Gfi-1 in sorted Gfi-1
−/− progenitors ex vivo rescues neutrophil differentiation in response to G-CSF. Thus, Gfi-1 not only promotes differentiation of neutrophils but also antagonizes traits of the alternate monocyte/macrophage program.
ERG, an ETS family transcription factor frequently overexpressed in human leukemia, has been implicated as a key regulator of hematopoietic stem cells. However, how ERG controls normal hematopoiesis, ...particularly at the stem and progenitor cell level, and how it contributes to leukemogenesis remain incompletely understood. Using homologous recombination, we generated an Erg knockdown allele (Erg
) in which Erg expression can be conditionally restored by Cre recombinase. Erg
animals die at E10.5-E11.5 due to defects in endothelial and hematopoietic cells, but can be completely rescued by Tie2-Cre-mediated restoration of Erg in these cells. In Erg
mice, ∼40% reduction in Erg dosage perturbs both fetal liver and bone marrow hematopoiesis by reducing the numbers of Lin
Sca-1
c-Kit
(LSK) hematopoietic stem and progenitor cells (HSPCs) and megakaryocytic progenitors. By genetic mosaic analysis, we find that Erg-restored HSPCs outcompete Erg
HSPCs for contribution to adult hematopoiesis in vivo. This defect is in part due to increased apoptosis of HSPCs with reduced Erg dosage, a phenotype that becomes more drastic during 5-FU-induced stress hematopoiesis. Expression analysis reveals that reduced Erg expression leads to changes in expression of a subset of ERG target genes involved in regulating survival of HSPCs, including increased expression of a pro-apoptotic regulator Bcl2l11 (Bim) and reduced expression of Jun. Collectively, our data demonstrate that ERG controls survival of HSPCs, a property that may be used by leukemic cells. Stem Cells 2017;35:1773-1785.
This paper describes a new approach for a course and laboratory designed to allow students to develop low-cost prototypes of robotic and other embedded devices that feature Internet connectivity, ...I/O, networking, a real-time operating system (RTOS), and object-oriented C/C++. The application programming interface (API) libraries provided permit students to work at a higher level of abstraction. A low-cost 32-bit SOC RISC microcontroller module with flash memory, numerous I/O interfaces, and on-chip networking hardware is used to build prototypes. A cloud-based C/C++ compiler is used for software development. All student files are stored on a server, and any Web browser can be used for software development. Breadboards are used in laboratory projects to rapidly build prototypes of robots and embedded devices using the microcontroller, networking, and other I/O subsystems on small breakout boards. The commercial breakout boards used provide a large assortment of modern sensors, drivers, display ICs, and external I/O connectors. Resources provided include eBooks, laboratory assignments, and extensive Wiki pages with schematics and sample microcontroller application code for each breakout board.
In relativistic heavy-ion collisions, anisotropic collective flow is driven, event by event, by the initial eccentricity of the matter created in the nuclear overlap zone. Interpretation of the ...anisotropic flow data thus requires a detailed understanding of the effective initial source eccentricity of the event sample. In this paper, we investigate various ways of defining this effective eccentricity using the Monte Carlo Glauber (MCG) approach. In particular, we examine the participant eccentricity, which quantifies the eccentricity of the initial source shape by the major axes of the ellipse formed by the interaction points of the participating nucleons. We show that reasonable variation of the density parameters in the Glauber calculation, as well as variations in how matter production is modeled, do not significantly modify the already established behavior of the participant eccentricity as a function of collision centrality. Focusing on event-by-event fluctuations and correlations of the distributions of participating nucleons, we demonstrate that, depending on the achieved event-plane resolution, fluctuations in the elliptic flow magnitude v{sub 2} lead to most measurements being sensitive to the root-mean-square rather than the mean of the v{sub 2} distribution. Neglecting correlations among participants, we derive analytical expressions for the participant eccentricity cumulants as a function of the number of participating nucleons, N{sub part}, keeping nonnegligible contributions up to O(1/N{sub part}{sup 3}). We find that the derived expressions yield the same results as obtained from mixed-event MCG calculations which remove the correlations stemming from the nuclear collision process. Most importantly, we conclude from the comparison with MCG calculations that the fourth-order participant eccentricity cumulant does not approach the spatial anisotropy obtained assuming a smooth nuclear matter distribution. In particular, for the Cu+Cu system, these quantities deviate from each other by almost a factor of 2 over a wide range in centrality. This deviation reflects the essential role of participant spatial correlations in the interaction of two nuclei.
Since 2006, the Veterans Health Administration (VHA) has instituted policy changes and training programs to support system-wide implementation of two evidence-based psychotherapies (EBPs) for ...posttraumatic stress disorder (PTSD). To assess lessons learned from this unprecedented effort, we used PubMed and the PILOTS databases and networking with researchers to identify 32 reports on contextual influences on implementation or sustainment of EBPs for PTSD in VHA settings. Findings were initially organized using the exploration, planning, implementation, and sustainment framework (EPIS; Aarons et al. in Adm Policy Ment Health Health Serv Res 38:4–23,
2011
). Results that could not be adequately captured within the EPIS framework, such as implementation outcomes and adopter beliefs about the innovation, were coded using constructs from the reach, effectiveness, adoption, implementation, maintenance (RE-AIM) framework (Glasgow et al. in Am J Public Health 89:1322–1327,
1999
) and Consolidated Framework for Implementation Research (CFIR; Damschroder et al. in Implement Sci 4(1):50,
2009
). We highlight key areas of progress in implementation, identify continuing challenges and research questions, and discuss implications for future efforts to promote EBPs in large health care systems.
This paper describes the authors' experiences using a system-on-a-programmable-chip (SOPC) approach to support the development of design projects for upper-level undergraduate students in their ...electrical and computer engineering curriculum. Commercial field-programmable gate-array (FPGA)-based SOPC development boards with reduced instruction set computer (RISC) processor cores are used to support a wide variety of student design projects. A top-down rapid prototyping approach with commercial FPGA computer-aided design tools, a C compiler targeted for the RISC soft-processor core, and a large FPGA with memory is used and reused to support a wide variety of student projects.
Of the mutationally defined rhythm genes in Drosophila melanogaster, period (per) has been studied the most. We have molecularly characterized three older per mutants-perT, perClk, and per04-along ...with a novel long-period one (perSLIH). Each mutant is the result of a single nucleotide change. perT, perClk, and perSLIH are accounted for by amino acid substitutions; per04 is altered at a splice site acceptor and causes aberrant splicing. perSLIH exhibits a long period of 27 hr in constant darkness and entrains to light/dark (L/D) cycles with a later-than-normal evening peak of locomotion. perSLIH males are more rhythmic than females. perSLIH's clock runs faster at higher temperatures and slower at lower ones, exhibiting a temperature-compensation defect opposite to that of perLong. The per-encoded protein (PER) in the perT mutant cycles in L/D with an earlier-than-normal peak; this peak in perSLIH is later than normal, and there was a slight difference in the PER timecourse of males vs. females. PER in per04 was undetectable. Two of these mutations, perSLIH and perClk, lie within regions of PER that have not been studied previously and may define important functional domains of this clock protein.
Introduction: The goal in the treatment of strabismus is to realign the visual axes to eliminate diplopia, produce or restore binocular vision, expand the binocular visual field, and/or provide a ...normal appearance. The treatment of strabismus in adults who do not experience diplopia or who do not have binocular potential has sometimes been regarded as “cosmetic.” Many adults with strabismus have stated that it has had a negative effect on their lives. This study was designed to ascertain whether there is a negative social bias against adult patients with strabismus that could affect interpersonal relationships and limit employment opportunities.
Methods: An orthotropic person was photographed in primary, right, and left gaze. These photographs were then digitally altered to produce an esotropia and exotropia of similar magnitude. Subjects were then asked to evaluate a single photograph with reference to personality characteristics that are important for social interaction and employment capability.
Results: Overall, the strabismic faces were judged significantly more negatively, across 11 descriptive characteristics, than the nonstrabismic face. The effect of esotropia was worse than exotropia.
Conclusion: Strabismus creates a significant negative social prejudice. These biases can have a detrimental impact on socialization and employability. Treatment of strabismus may positively alter perceived characteristics of individuals and improve their ability to socialize normally and obtain employment. Therefore, the treatment of strabismus should not be considered cosmetic even when there is no hope of improving binocular vision. (J AAPOS 1999;3:209-11)
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