Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFβ cell cycle arrest

<p>Abstract</p> <p>Background</p> <p>TGFβ is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFβ in disease. We asked how <it>Rb</it>-deficiency would affect responses to TGFβ-induced cell cycle arrest.</p> <p>Results</p> <p>Primary hepatocytes isolated from <it>Rb-floxed </it>mice were infected with an adenovirus expressing CRE-recombinase to delete the <it>Rb </it>gene. In control cells treatment with TGFβ prevented cells to enter S phase via decreased cMYC activity, activation of P16^INK4Aand P21^Cipand reduction of E2F activity. In <it>Rb</it>-null hepatocytes, cMYC activity decreased slightly but P16^INK4Awas not activated and the great majority of cells continued cycling. <it>Rb </it>is therefore central to TGFβ-induced cell cycle arrest in hepatocytes. However some <it>Rb</it>-null hepatocytes remained sensitive to TGFβ-induced cell cycle arrest. As these hepatocytes expressed very high levels of P21^Cip1and P53 we investigated whether these proteins regulate pRb-independent signaling to cell cycle arrest by evaluating the consequences of disruption of <it>p53 </it>and <it>p21</it>^{<it>Cip1</it>}. Hepatocytes deficient in <it>p53 or p21</it>^{<it>Cip1 </it>}showed diminished growth inhibition by TGFβ. Double deficiency had a similar impact showing that in cells containing functional pRb; P21^Cipand P53 work through the same pathway to regulate G1/S in response to TGFβ. In <it>Rb</it>-deficient cells however, <it>p53 </it>but not <it>p21</it>^{<it>Cip </it>}deficiency had an additive effect highlighting a pRb-independent-P53-dependent effector pathway of inhibition of E2F activity.</p> <p>Conclusion</p> <p>The present results show that otherwise genetically normal hepatocytes with disabled <it>p53</it>, <it>p21</it>^{<it>Cip1 </it>}or <it>Rb </it>genes respond less well to the antiproliferative effects of TGFβ. As the function of these critical cellular proteins can be impaired by common causes of chronic liver disease and HCC, including viral hepatitis B and C proteins, we suggest that disruption of pRb function, and to a lesser extend P21^Cip1and P53 in hepatocytes may represent an additional new mechanism of escape from TGFβ-growth-inhibition in the inflammatory milieu of chronic liver disease and contribute to cancer development.</p

Classroom Learning Conditions Predict Academic Performance

A great deal is known about how _students'_ psychological characteristics; growth mindset, belonging, grit, and many more relate to students' academic achievement. Much less is known about how the classroom conditions under which students must learn affects their achievement. This study examines how classroom _learning conditions_ relate to students' academic achievement. Specifically we ask how students' experience of their teachers' caring, the feedback they receive to grow as learners, and the meaningfulness of their work relate to their academic achievement, controlling for factors such as prior academic achievement and prior psychological variables (grit, growth mindset, etc.)

Leading Indicators of Educational Outcomes

Students are more engaged, motivated, and resilient when they experience learning in specific ways—when they experience psychological safety, caring relationships, meaningful content, and personal agency. PERTS worked with leading researchers to develop Copilot, an advanced professional learning platform that helps educators create supportive conditions for social and emotional learning and development. Copilot enables teachers to get rapid feedback from their students about how they are experiencing key classroom learning conditions. It couples that feedback with best-practices for improving those conditions and promoting higher and more equitable academic achievement and social-emotional growth (see perts.net/creating-learning-conditions). Our research examines which Copilot student survey metrics serve as top leading indicators for equity gaps in students' outcomes. These leading indicators will then be used by educators across the country to improve learning conditions and promote more equitable social and emotional learning and academic outcomes for their students

Brief intervention to encourage empathic discipline cuts suspension rates in half among adolescents

Growing suspension rates predict major negative life outcomes, including adult incarceration and unemployment. Experiment 1 tested whether teachers (n = 39) could be encouraged to adopt an empathic rather than punitive mindset about discipline-to value students' perspectives and sustain positive relationships while encouraging better behavior. Experiment 2 tested whether an empathic response to misbehavior would sustain students' (n = 302) respect for teachers and motivation to behave well in class. These hypotheses were confirmed. Finally, a randomized field experiment tested a brief, online intervention to encourage teachers to adopt an empathic mindset about discipline. Evaluated at five middle schools in three districts (Nteachers = 31; Nstudents = 1,682), this intervention halved year-long student suspension rates from 9.6% to 4.8%. It also bolstered respect the most at-risk students, previously suspended students, perceived from teachers. Teachers' mindsets about discipline directly affect the quality of teacher-student relationships and student suspensions and, moreover, can be changed through scalable intervention

The Increase in Animal Mortality Risk following Exposure to Sparsely Ionizing Radiation Is Not Linear Quadratic with Dose

Introduction: The US government regulates allowable radiation exposures relying, in large part, on the seventh report from the committee to estimate the Biological Effect of Ionizing Radiation (BEIR VII), which estimated that most contemporary exposures- protracted or low-dose, carry 1.5 fold less risk of carcinogenesis and mortality per Gy than acute exposures of atomic bomb survivors. This correction is known as the dose and dose rate effectiveness factor for the life span study of atomic bomb survivors (DDREFLSS). It was calculated by applying a linear-quadratic dose response model to data from Japanese atomic bomb survivors and a limited number of animal studies. Methods and Results: We argue that the linear-quadratic model does not provide appropriate support to estimate the risk of contemporary exposures. In this work, we re-estimated DDREFLSS using 15 animal studies that were not included in BEIR VII’s original analysis. Acute exposure data led to a DDREFLSS estimate from 0.9 to 3.0. By contrast, data that included both acute and protracted exposures led to a DDREFLSS estimate from 4.8 to infinity. These two estimates are significantly different, violating the assumptions of the linear-quadratic model, which predicts that DDREFLSS values calculated in either way should be the same. Conclusions: Therefore, we propose that future estimates of the risk of protracted exposures should be based on direct comparisons of data from acute and protracted exposures, rather than from extrapolations from a linear-quadratic model. The risk of low dose exposures may be extrapolated from these protracted estimates, though we encourage ongoing debate as to whether this is the most valid approach. We also encourage efforts to enlarge the datasets used to estimate the risk of protracted exposures by including both human and animal data, carcinogenesis outcomes, a wider range of exposures, and by making more radiobiology data publicly accessible. We believe that these steps will contribute to better estimates of the risks of contemporary radiation exposures.</p

Brief intervention to encourage empathic discipline cuts suspension rates in half among adolescents

Growing suspension rates predict major negative life outcomes, including adult incarceration and unemployment. Experiment 1 tested whether teachers (n = 39) could be encouraged to adopt an empathic rather than punitive mindset about discipline—to value students’ perspectives and sustain positive relationships while encouraging better behavior. Experiment 2 tested whether an empathic response to misbehavior would sustain students’ (n = 302) respect for teachers and motivation to behave well in class. These hypotheses were confirmed. Finally, a randomized field experiment tested a brief, online intervention to encourage teachers to adopt an empathic mindset about discipline. Evaluated at five middle schools in three districts (N(teachers) = 31; N(students) = 1,682), this intervention halved year-long student suspension rates from 9.6% to 4.8%. It also bolstered respect the most at-risk students, previously suspended students, perceived from teachers. Teachers’ mindsets about discipline directly affect the quality of teacher–student relationships and student suspensions and, moreover, can be changed through scalable intervention

The Increase in Animal Mortality Risk following Exposure to Sparsely Ionizing Radiation Is Not Linear Quadratic with Dose

<div><p>Introduction</p><p>The US government regulates allowable radiation exposures relying, in large part, on the seventh report from the committee to estimate the Biological Effect of Ionizing Radiation (BEIR VII), which estimated that most contemporary exposures- protracted or low-dose, carry 1.5 fold less risk of carcinogenesis and mortality per Gy than acute exposures of atomic bomb survivors. This correction is known as the dose and dose rate effectiveness factor for the life span study of atomic bomb survivors (DDREF_LSS). It was calculated by applying a linear-quadratic dose response model to data from Japanese atomic bomb survivors and a limited number of animal studies.</p><p>Methods and Results</p><p>We argue that the linear-quadratic model does not provide appropriate support to estimate the risk of contemporary exposures. In this work, we re-estimated DDREF_LSS using 15 animal studies that were not included in BEIR VII’s original analysis. Acute exposure data led to a DDREF_LSS estimate from 0.9 to 3.0. By contrast, data that included both acute and protracted exposures led to a DDREF_LSS estimate from 4.8 to infinity. These two estimates are significantly different, violating the assumptions of the linear-quadratic model, which predicts that DDREF_LSS values calculated in either way should be the same.</p><p>Conclusions</p><p>Therefore, we propose that future estimates of the risk of protracted exposures should be based on direct comparisons of data from acute and protracted exposures, rather than from extrapolations from a linear-quadratic model. The risk of low dose exposures may be extrapolated from these protracted estimates, though we encourage ongoing debate as to whether this is the most valid approach. We also encourage efforts to enlarge the datasets used to estimate the risk of protracted exposures by including both human and animal data, carcinogenesis outcomes, a wider range of exposures, and by making more radiobiology data publicly accessible. We believe that these steps will contribute to better estimates of the risks of contemporary radiation exposures.</p></div

Predicting Future Risk of Depressive Episode in Adolescents: The Chicago Adolescent Depression Risk Assessment (CADRA)

PURPOSE A risk prediction index, similar to those used for other disorders, such as cardiovascular disease, would facilitate depression prevention by identifying those who would benefit most from preventative measures in primary care settings

Two possible dose response models based on linear-quadratic model (A) and linear/linear model (B).

<p>A schematic representation of a linear-quadratic dose response model, like the one used in the BEIR VII report (A), is shown above an idealized representation of the results of this analysis (B). Each panel shows dose (x-axis) vs. risk (y-axis) in which risk represents the excess risk of carcinogenesis or organism mortality. Black lines represent the response to acute exposures. Red lines represent the response to protracted exposures. Both are applicable to exposures less 1.5 Sv or 2.0 Sv, the maximum doses considered in the BEIR VII report and this one. While the linear-quadratic model predicts that protracted dose-response can be estimated based on the curvature of acute dose response our results show that this is not the case. Also, while the linear-quadratic model predicts that responses to low dose exposure are collinear with responses to protracted exposures, our observations are inconclusive.</p