Elevating the levels of Sox2 in embryonal carcinoma cells and embryonic stem cells inhibits the expression of Sox2:Oct-3/4 target genes†

Recent studies have identified large sets of genes in embryonic stem and embryonal carcinoma cells that are associated with the transcription factors Sox2 and Oct-3/4. Other studies have shown that Sox2 and Oct-3/4 work together cooperatively to stimulate the transcription of their own genes as well as a network of genes required for embryogenesis. Moreover, small changes in the levels of Sox2:Oct-3/4 target genes alter the fate of stem cells. Although positive feedforward and feedback loops have been proposed to explain the activation of these genes, little is known about the mechanisms that prevent their overexpression. Here, we demonstrate that elevating Sox2 levels inhibits the endogenous expression of five Sox2:Oct-3/4 target genes. In addition, we show that Sox2 repression is dependent on the binding sites for Sox2 and Oct-3/4. We also demonstrate that inhibition is dependent on the C-terminus of Sox2, which contains its transactivation domain. Finally, our studies argue that overexpression of neither Oct-3/4 nor Nanog broadly inhibits Sox2:Oct-3/4 target genes. Collectively, these studies provide new insights into the diversity of mechanisms that control Sox2:Oct-3/4 target genes and argue that Sox2 functions as a molecular rheostat for the control of a key transcriptional regulatory network

Reduction of \u3ci\u3eStabilin-2\u3c/i\u3e Contributes to a Protection Against Atherosclerosis

We have previously identified a novel atherosclerosis quantitative trait locus (QTL), Arch atherosclerosis 5 (Aath5), on mouse chromosome 10 by three-way QTL analyses between Apoe−/− mice on a DBA/2J, 129S6 and C57BL/6J background. The DBA/2J haplotype at the Aath5 locus was associated with smaller plaque size. One of the candidate genes underlying Aath5 was Stabilin-2 (Stab2), which encodes a clearance receptor for hyaluronan (HA) predominantly expressed in liver sinusoidal endothelial cells (LSECs). However, the role of Stab2 in atherosclerosis is unknown. A congenic line of Apoe−/− mice carrying Aath5 covering the Stab2DBA allele on a background of 129S6 confirmed the small reductions of atherosclerotic plaque development. To further determine whether Stab2 is an underlying gene for Aath5, we generated Stab2−/−Apoe−/− mice on a C57BL/6J background. When fed with a Western diet for 8 weeks, Stab2−/−Apoe−/− males developed approximately 30% smaller plaques than Stab2+/+Apoe−/− mice. HA was accumulated in circulation but not in major organs in the Stab2 deficient mice. STAB2-binding molecules that are involved in atherosclerosis, including acLDL, apoptotic cells, heparin and vWF were not likely the direct cause of the protection in the Stab2−/−Apoe−/− males. These data indicate that reduction of Stab2 is protective against atherosclerotic plaque development, and that Stab2 is a contributing gene underlying Aath5, although its effect is small. To test whether non-synonymous amino acid changes unique to DBA/2J affect the function of STAB2 protein, we made HEK293 cell lines expressing STAB2129 or STAB2DBA proteins, as well as STAB2129 proteins carrying each of five DBA-unique replacements that have been predicted to be deleterious. These mutant cells were capable of internalizing 125I -HA and DiI-acLDL similarly to the control cells. These results indicate that the amino acid changes unique to DBA/2J are not affecting the function of STAB2 protein, and support our previous observation that the reduced transcription of Stab2 in the liver sinusoid as a consequence of the insertion of a viral-derived sequence, intracisternal A particle, is the primary contributor to the athero-protection conferred by the DBA/2J allele

Reduction of Stabilin-2 Contributes to a Protection Against AtherosclerosisStabilin

We have previously identified a novel atherosclerosis quantitative trait locus (QTL), Arch atherosclerosis 5 (Aath5), on mouse chromosome 10 by three-way QTL analyses between Apoe−/− mice on a DBA/2J, 129S6 and C57BL/6J background. The DBA/2J haplotype at the Aath5 locus was associated with smaller plaque size. One of the candidate genes underlying Aath5 was Stabilin-2 (Stab2), which encodes a clearance receptor for hyaluronan (HA) predominantly expressed in liver sinusoidal endothelial cells (LSECs). However, the role of Stab2 in atherosclerosis is unknown. A congenic line of Apoe−/− mice carrying Aath5 covering the Stab2DBA allele on a background of 129S6 confirmed the small reductions of atherosclerotic plaque development. To further determine whether Stab2 is an underlying gene for Aath5, we generated Stab2−/−Apoe−/− mice on a C57BL/6J background. When fed with a Western diet for 8 weeks, Stab2−/−Apoe−/− males developed approximately 30% smaller plaques than Stab2+/+Apoe−/− mice. HA was accumulated in circulation but not in major organs in the Stab2 deficient mice. STAB2-binding molecules that are involved in atherosclerosis, including acLDL, apoptotic cells, heparin and vWF were not likely the direct cause of the protection in the Stab2−/−Apoe−/− males. These data indicate that reduction of Stab2 is protective against atherosclerotic plaque development, and that Stab2 is a contributing gene underlying Aath5, although its effect is small. To test whether non-synonymous amino acid changes unique to DBA/2J affect the function of STAB2 protein, we made HEK293 cell lines expressing STAB2129 or STAB2DBA proteins, as well as STAB2129 proteins carrying each of five DBA-unique replacements that have been predicted to be deleterious. These mutant cells were capable of internalizing 125I -HA and DiI-acLDL similarly to the control cells. These results indicate that the amino acid changes unique to DBA/2J are not affecting the function of STAB2 protein, and support our previous observation that the reduced transcription of Stab2 in the liver sinusoid as a consequence of the insertion of a viral-derived sequence, intracisternal A particle, is the primary contributor to the athero-protection conferred by the DBA/2J allele

Reduction of Stabilin-2 Contributes to a Protection Against Atherosclerosis

We have previously identified a novel atherosclerosis quantitative trait locus (QTL), Arch atherosclerosis 5 (Aath5), on mouse chromosome 10 by three-way QTL analyses between Apoe−/− mice on a DBA/2J, 129S6 and C57BL/6J background. The DBA/2J haplotype at the Aath5 locus was associated with smaller plaque size. One of the candidate genes underlying Aath5 was Stabilin-2 (Stab2), which encodes a clearance receptor for hyaluronan (HA) predominantly expressed in liver sinusoidal endothelial cells (LSECs). However, the role of Stab2 in atherosclerosis is unknown. A congenic line of Apoe−/− mice carrying Aath5 covering the Stab2DBA allele on a background of 129S6 confirmed the small reductions of atherosclerotic plaque development. To further determine whether Stab2 is an underlying gene for Aath5, we generated Stab2−/−Apoe−/− mice on a C57BL/6J background. When fed with a Western diet for 8 weeks, Stab2−/−Apoe−/− males developed approximately 30% smaller plaques than Stab2+/+Apoe−/− mice. HA was accumulated in circulation but not in major organs in the Stab2 deficient mice. STAB2-binding molecules that are involved in atherosclerosis, including acLDL, apoptotic cells, heparin and vWF were not likely the direct cause of the protection in the Stab2−/−Apoe−/− males. These data indicate that reduction of Stab2 is protective against atherosclerotic plaque development, and that Stab2 is a contributing gene underlying Aath5, although its effect is small. To test whether non-synonymous amino acid changes unique to DBA/2J affect the function of STAB2 protein, we made HEK293 cell lines expressing STAB2129 or STAB2DBA proteins, as well as STAB2129 proteins carrying each of five DBA-unique replacements that have been predicted to be deleterious. These mutant cells were capable of internalizing 125I -HA and DiI-acLDL similarly to the control cells. These results indicate that the amino acid changes unique to DBA/2J are not affecting the function of STAB2 protein, and support our previous observation that the reduced transcription of Stab2 in the liver sinusoid as a consequence of the insertion of a viral-derived sequence, intracisternal A particle, is the primary contributor to the athero-protection conferred by the DBA/2J allele

Small Platforms, High Return: The Need to Enhance Investment in Small Satellites for Focused Science, Career Development, and Improved Equity

In the next decade, there is an opportunity for very high return on investment of relatively small budgets by elevating the priority of smallsat funding in heliophysics. We've learned in the past decade that these missions perform exceptionally well by traditional metrics, e.g., papers/year/\$M (Spence et al. 2022 -- arXiv:2206.02968). It is also well established that there is a "leaky pipeline" resulting in too little diversity in leadership positions (see the National Academies Report at https://www.nationalacademies.org/our-work/increasing-diversity-in-the-leadership-of-competed-space-missions). Prioritizing smallsat funding would significantly increase the number of opportunities for new leaders to learn -- a crucial patch for the pipeline and an essential phase of career development. At present, however, there are far more proposers than the available funding can support, leading to selection ratios that can be as low as 6% -- in the bottom 0.5th percentile of selection ratios across the history of ROSES. Prioritizing SmallSat funding and substantially increasing that selection ratio are the fundamental recommendations being made by this white paper.Comment: White paper submitted to the Decadal Survey for Solar and Space Physics (Heliophysics) 2024-2033; 6 pages, 1 figur

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

"I can only cognitively coach so much": heavy coaching efforts amidst disciplinary complexities in secondary school classrooms

Coaching often rests upon a “causal cascade” (Atteberry, Bryk, Walker & Biancarosa,2008) that posits that collaboration with a coach leads to a change in the attitude, beliefs and practices of teachers and therefore improves student learning. If efficacy expectations related to adolescent literacy are not met, instructional coaching runs the risk of being attempted and abandoned by secondary schools (Knight, 2007; Walpole & McKenna, 2008). Insufficient research has explored how secondary coaches attempt to impact adolescent literacy and the ways that instructional coaches use discourse to negotiate disciplinary tensions.The author explored how three secondary school instructional coaches each attempted to “coach heavy” (Killion, 2009, 2010) and impact the disciplinary literacy and learning of adolescents during a single, long-term collaboration over the course of a semester. The following three research questions guided this interpretive study: How do secondary instructional coaches attempt to coach heavy? What tensions make heavy coaching challenging? And, what coaching practices do secondary instructional coaches use to negotiate these tensions? Using a multi-case study design (Merriam, 1998), qualitative data were collected during semi-structured initial and exit interviews with each participating teacher and instructional coach. Over the course of these long-term collaborations, additional data included field notes of classroom coaching events, audio-taped debriefs between coach and teacher, and audio-taped debriefs between the coach and researcher. Data were examined via an analytical frame of heavy coaching (Killion, 2009, 2010), knowledge of practice (Cochran-Smith & Lytle, 1999), and stance taking (Du’Bois, 2007; Poggi, D’Errico, & Leone, 2010) in order to understand the challenges of coaching for impact in these three disciplinary contexts. While all three coaches in this study attempted to coach heavy for student impact, tensions within each unique collaborative context made heavy coaching challenging. Using an inquiry as coaching stance, each coach created situated coaching practices that reflected their own disciplinary knowledge. While acknowledging the expertise of all three instructional coaches in this study, this dissertation raises questions about the suitability of using instructional coaches as generalists across secondary school disciplines given the complexity of heavy coaching as a disciplinary outsider