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Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson’s disease (PD). Iron-loaded microglia are frequently found in affected brain regions, but how iron accumulation influences microglia physiology and contributes to neurodegeneration is poorly understood. Here we show that human induced pluripotent stem cell-derived microglia grown in a tri-culture system are highly responsive to iron and susceptible to ferroptosis, an iron-dependent form of cell death. Furthermore, iron overload causes a marked shift in the microglial transcriptional state that overlaps with a transcriptomic signature found in PD postmortem brain microglia. Our data also show that this microglial response contributes to neurodegeneration, as removal of microglia from the tri-culture system substantially delayed iron-induced neurotoxicity. To elucidate the mechanisms regulating iron response in microglia, we performed a genome-wide CRISPR screen and identified novel regulators of ferroptosis, including the vesicle trafficking gene SEC24B . These data suggest a critical role for microglia iron overload and ferroptosis in neurodegeneration. Iron-laden microglia assume a disease-relevant, ferroptosis-associated signature and cause neurotoxicity. CRISPR screen uncovered regulators of ferroptosis in microglia. This ferroptosis–microglia–neurodegeneration axis could be targeted therapeutically.

Purpose of ReviewThe purpose of this review is to provide an update on the recent body of evidence emerging for type 2 diabetes as identified through the SEARCH for Diabetes in Youth study.Recent FindingsThis body of evidence illustrates that type 2 diabetes continues to increase in incidence, although this increase may be partially attributable to increased surveillance. Disease management is influenced by the transition from adolescent to adult care and psychosocial factors may also contribute. This evidence also describes a high prevalence of disease-associated complications and comorbidities. Risk factors for cardiovascular disease are also highly prevalent.SummaryThe SEARCH for Diabetes in Youth study continues to inform our understanding of the descriptive epidemiology and natural history of type 2 diabetes in youth. As the cohort matures, new opportunities emerge for building on our understanding of how youth-onset type 2 diabetes impacts future health.

Eosinophilic esophagitis (EoE) has rapidly become a major cause of upper GI morbidity, but health-care costs related to EoE have not been described. This study aimed to estimate EoE-related health-care costs and utilization in the United States. We performed a study on health-care utilization of EoE cases compared with age- and sex-matched controls using administrative claims data, representative of the commercially insured population in the United States. Cases of EoE were identified using a previously validated definition. We assessed inpatient, outpatient, emergency department, outpatient prescription, and endoscopy-related costs for patients with EoE, and estimated total costs related to EoE extrapolated to the US population. We identified 8,135 cases of EoE and 32,540 controls. The median total annual cost per EoE case was $3,304 compared with $1,001 for controls (P<0.001). For EoE, the median costs included $2,508/year for outpatient visits, $157 for endoscopies, and $325 for pharmacy claims, compared with $699, $0, and $76 for controls (P<0.001 for all). The overall median cost associated with EoE was $2,302/year/patient. Total costs in the United States ranged from $503 million to $1.36 billion/year, depending on the prevalence estimate, with costs attributable to EoE ranging from $350 to $947 million/year. Patients with EoE have an estimated annual health-care cost of as much as $1.4 billion in the United States. This represents a remarkable burden of disease for an entity that was essentially unknown two decades ago. These cost data can be used by policy makers to guide resource allocation.

O-GlcNAc glycosylation (or O-GlcNAcylation) is a dynamic, inducible posttranslational modification found on proteins associated with neurodegenerative diseases such as α-synuclein, amyloid precursor protein, and tau. Deletion of the O-GlcNAc transferase (ogt) gene responsible for the modification causes early postnatal lethality in mice, complicating efforts to study O-GlcNAcylation in mature neurons and to understand its roles in disease. Here, we report that forebrain-specific loss of OGT in adult mice leads to progressive neurodegeneration, including widespread neuronal cell death, neuroinflammation, increased production of hyperphosphorylated tau and amyloidogenic Aβ-peptides, and memory deficits. Furthermore, we show that human cortical brain tissue from Alzheimer’s disease patients has significantly reduced levels of OGT protein expression compared with cortical tissue from control individuals. Together, these studies indicate that O-GlcNAcylation regulates pathways critical for the maintenance of neuronal health and suggest that dysfunctional O-GlcNAc signaling may be an important contributor to neurodegenerative diseases.

Purpose of ReviewAs the rising prevalence and incidence of eosinophilic esophagitis (EoE) has quickly outpaced the rate of esophageal biopsies, particularly in Westernized countries, several studies have suggested a link between intrinsic genetic and extrinsic environmental risk factors and the development, presentation, and diagnosis of EoE. This review aims to critically assess existing studies describing the role of the environment on the development, symptomatic presentation, and diagnosis of this recently recognized chronic immune-mediated disease.Recent FindingsWe present and critically evaluate the working hypotheses and supportive studies thus far on environmental factors on EoE, describe sources of potential bias in diagnosis due to socioeconomic factors and thus undermining studies of EoE etiology, and highlight opportunities for future research.SummaryAs genetics alone do not explain the rapid rise of EoE, we must look to environmental, or extrinsic, factors both in the early-life period which shape the development of the gut microbiome, as well as later life contributing to diagnosis of this new disease. Future etiologic studies linking risk factors to EoE development in individual patients are needed.

BackgroundVitamin D deficiency is associated with atopic and immune-mediated diseases but has not been extensively assessed in eosinophilic esophagitis (EoE). We aimed to assess if vitamin D levels in newly diagnosed EoE patients were lower than in non-EoE controls and examine levels in relation to EoE clinical features.MethodsThis secondary analysis of a prospective cohort study used data and biosamples from adults who underwent outpatient esophagogastroduodenoscopy. Before each procedure, blood was obtained and stored at -80oC. Serum 25-hydroxy-vitamin D3 (25(OH)D3) was measured by ELISA. Levels for cases and controls were compared at baseline. Within cases, 25(OH)D3 levels were compared for clinical, endoscopic, and histologic measures.ResultsWe analyzed 40 EoE and 40 non-EoE controls. Mean serum 25(OH)D3 level was slightly lower in EoE patients than controls (30.9 ± 15.3 ng/mL vs. 35.9 ± 15.4; p = 0.15). After controlling for age, sex, and race, adjusted levels were 10.8 ng/mL lower in EoE patients (95% CI: -19.0, -2.5), but 25(OH)D3 deficiency (< 20ng/mL) was similar in cases and controls (20% vs. 15%; p = 0.56). Levels of 25(OH)D3 were not associated with differences in clinical or endoscopic features of EoE, and EREFS and eosinophil counts did not significantly correlate with 25(OH)D3 levels (R of -0.28 [p = 0.08] and − 0.01 [p = 0.93], respectively). 25(OH)D3 levels were lower in EoE cases with lamina propria fibrosis (23.2 ± 9.6 vs. 45.0 ± 17.7; p = 0.03).ConclusionsAfter adjusting for age, sex, and race, 25(OH)D3 levels were lower in EoE cases than controls, but deficiency was not common. 25(OH)D3 levels were generally similar across most EoE disease features.