Increasing energetic demands on photoreceptors in diabetes corrects retinal lipid dysmetabolism and reduces subsequent microvascular damage

Mechanisms responsible for the pathogenesis of diabetic retinal disease remain incompletely understood, but they likely involve multiple cellular targets, including photoreceptors. Evidence suggests that dysregulated de novo lipogenesis in photoreceptors is a critical early target of diabetes. Following on this observation, the present study aimed to determine whether two interventions shown to improve diabetic retinopathy in mice-pharmacologic visual cycle inhibition and prolonged dark adaptation-reduce photoreceptor anabolic lipid metabolism. Elevated retinal lipid biosynthetic signaling was observed in two mouse models of diabetes, with both models showing reduced retinal AMP-activated kinase (AMPK) signaling, elevated acetyl CoA carboxylase (ACC) signaling, and increased activity of fatty acid synthase, which promotes lipotoxicity in photoreceptors. Although retinal AMPK-ACC axis signaling was dependent on systemic glucose fluctuations in healthy animals, mice with diabetes lacked such regulation. Visual cycle inhibition and prolonged dark adaptation reversed abnormal retinal AMPK-ACC signaling in mice with diabetes. Although visual cycle inhibition reduced the severity of diabetic retinopathy in control mice, as assessed by retinal capillary atrophy, this intervention was ineffective in fatty acid synthase gain-of-function mice. These results suggest that early diabetic retinopathy is characterized by glucose-driven elevations in retinal lipid biosynthetic activity, and that two interventions known to increase photoreceptor glucose demands alleviate disease by reversing these signals

Improving Completion Rates for Underrepresented Populations

Most experienced educators recognize that many students will not complete optional assignments, and often those students who need additional help do not seek assistance. Current research demonstrates that students in underrepresented populations (see definition below) are less likely to seek support than others because they see needing help as a confirmation that they don’t really “belong” in college in the first place. Research shows that those who do access currently optional supports such as tutoring are more likely to succeed, so this research group looked for ways to build structured connections between underrepresented students and resources. We found that our peers at various VCCS colleges had programs that were working to build these connections for our students, so in our resource-constrained environment, we chose to focus on what exists that works, is scalable, and could be implemented in stages as resources permit. Our proposal reflects increased resource allocation on both the academic support (tutoring) side and the student support (TRIO, Pathway to the Baccalaureate, Success Coaches) side to increase structured contact between the student and the support to decrease the “stigma” of seeking help. We propose this because in our roles as administrators and faculty we know that often our students need both academic support and holistic support

FASN-dependent de novo lipogenesis is required for brain development

Fate and behavior of neural progenitor cells are tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multienzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of Fasn in the mouse embryonic telencephalon, we show that loss of FASN causes severe microcephaly, largely due to altered polarity of apical, radial glia progenitors and reduced progenitor proliferation. Furthermore, genetic deletion and pharmacological inhibition of FASN in human embryonic stem cell-derived forebrain organoids identifies a conserved role of FASN-dependent lipogenesis for radial glia cell polarity in human brain organoids. Thus, our data establish a role of de novo lipogenesis for mouse and human brain development and identify a link between progenitor-cell polarity and lipid metabolism

Glucose-mediated de novo lipogenesis in photoreceptors drives early diabetic retinopathy

Diabetic retinopathy (DR) is an increasingly frequent cause of blindness across populations; however, the events that initiate pathophysiology of DR remain elusive. Strong preclinical and clinical evidence suggests that abnormalities in retinal lipid metabolism caused by diabetes may account for the origin of this disease. A major arm of lipid metabolism, de novo biosynthesis, is driven by elevation in available glucose, a common thread binding all forms of vision loss in diabetes. Therefore, we hypothesized that aberrant retinal lipid biogenesis is an important promoter of early DR. In murine models, we observed elevations of diabetes-associated retinal de novo lipogenesis ∼70% over control levels. This shift was primarily because of activation of fatty acid synthase (FAS), a rate-limiting enzyme in the biogenic pathway. Activation of FAS was driven by canonical glucose-mediated disinhibition of acetyl-CoA carboxylase, a major upstream regulatory enzyme. Mutant mice expressing gain-of-function FAS demonstrated increased vulnerability to DR, whereas those with FAS deletion in rod photoreceptors maintained preserved visual responses upon induction of diabetes. Excess retinal de novo lipogenesis—either because of diabetes or because of FAS gain of function—was associated with modestly increased levels of palmitate-containing phosphatidylcholine species in synaptic membranes, a finding with as yet uncertain significance. These findings implicate glucose-dependent increases in photoreceptor de novo lipogenesis in the early pathogenesis of DR, although the mechanism of deleterious action of this pathway remains unclear

A Century of Grading Research: Meaning and Value in the Most Common Educational Measure

Grading refers to the symbols assigned to individual pieces of student work or to composite measures of student performance on report cards. This review of over 100 years of research on grading considers five types of studies: (a) early studies of the reliability of grades, (b) quantitative studies of the composition of K-12 report card grades, (c) survey and interview studies of teachers’ perceptions of grades, (d) studies of standards-based grading, and (e) grading in higher education. Early 20th century studies generally condemned teachers’ grades as unreliable. More recent studies of the relationships of grades to tested achievement and survey studies of teachers’ grading practices and beliefs suggest that grades assess a multidimensional construct containing both cognitive and non-cognitive factors reflecting what teachers value in student work. Implications for future research and for grading practices are discussed

Obesity Suppresses Estrogen Receptor Beta Expression in Breast Cancer Cells via a HER2-Mediated Pathway

Obesity is associated with a worse breast cancer prognosis, while greater breast tumor estrogen receptor beta (ERβ) expression is correlated with improved therapy response and survival. The objective of this study was to determine the impact of obesity on breast cancer cell ERβ expression, which is currently unknown. We utilized an in vitro model of obesity in which breast cancer cells were exposed to patient serum pooled by body mass index category (obese (OB): ≥30 kg/m2; normal weight (N): 18.5–24.9 kg/m2). Four human mammary tumor cell lines representing the major breast cancer subtypes (SKBR3, MCF-7, ZR75, MDA-MB-231) and mammary tumor cells from MMTV-neu mice were used. ERβ expression, assessed by qPCR and western blotting, was suppressed in the two HER2-overexpressing cell lines (SKBR3, MMTV-neu) following OB versus N sera exposure, but did not vary in the other cell lines. Expression of Bcl-2 and cyclin D1, two genes negatively regulated by ERβ, was elevated in SKBR3 cells following exposure to OB versus N sera, but this difference was eliminated when the ERβ gene was silenced with siRNA. Herceptin, a HER2 antagonist, and siRNA to HER2 were used to evaluate the role of HER2 in sera-induced ERβ modulation. SKBR3 cell treatment with OB sera plus Herceptin increased ERβ expression three-fold. Similar results were obtained when HER2 expression was silenced with siRNA. OB sera also promoted greater SKBR3 cell viability and growth, but this variance was not present when ERβ was silenced or the cells were modified to overexpress ERβ. Based on this data, we conclude that obesity-associated systemic factors suppress ERβ expression in breast cancer cells via a HER2-mediated pathway, leading to greater cell viability and growth. Elucidation of the mechanism(s) mediating this effect could provide important insights into how ERβ expression is regulated as well as how obesity promotes a more aggressive disease

Good and ‘bad’ deaths during the COVID-19 pandemic: insights from a rapid qualitative study

Dealing with excess death in the context of the COVID-19 pandemic has thrown the question of a good or bad death' into sharp relief as countries across the globe have grappled with multiple peaks of cases and mortality; and communities mourn those lost. In the UK, these challenges have included the fact that mortality has adversely affected minority communities. Corpse disposal and social distancing guidelines do not allow a process of mourning in which families and communities can be involved in the dying process. This study aimed to examine the main concerns of faith and non-faith communities across the UK in relation to death in the context of the COVID-19 pandemic. The research team used rapid ethnographic methods to examine the adaptations to the dying process prior to hospital admission, during admission, during the disposal and release of the body, during funerals and mourning. The study revealed that communities were experiencing collective loss, were making necessary adaptations to rituals that surrounded death, dying and mourning and would benefit from clear and compassionate communication and consultation with authorities