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BackgroundEndotracheal intubation in the intensive care unit (ICU) is a high-risk procedure. Competence in endotracheal intubation is a requirement for Pulmonary and Critical Care Medicine (PCCM) training programs, but fellow experience as the primary operator in intubating ICU patients has not been described on a large scale.ObjectiveWe hypothesized that significant variation surrounding endotracheal intubation practices in medical ICUs exists in United States (US) PCCM training programs.MethodsWe administered a survey to a convenience sample of US PCCM fellows to elicit typical intubation practices in the medical ICU.Results89 discrete US PCCM and Internal Medicine CCM training programs (77% response rate) were represented. At 43% of programs, the PCCM fellow was "always or almost always" designated the primary operator for intubation of a medical ICU patient, whereas at 21% of programs, the PCCM fellow was "rarely or never" the primary operator responsible for intubating in the ICU. Factors influencing this variation included time of day, hospital policies, attending skill or preference, ICU census and acuity, and patient factors. There was an association between location of the training program, but not program size, and whether the PCCM fellow was the primary operator.ConclusionThere is significant variation in whether PCCM fellows are the primary operators to intubate medical ICU patients during training. Further work should explore how this variation affects fellow career development and competence in intubation.

Endotracheal intubation (EI) is a potentially lifesaving but high-risk procedure in critically ill patients. While the ACGME mandates that trainees in pulmonary and critical care medicine (PCCM) achieve competence in this procedure, there is wide variation in EI training across the USA. One study suggests that 40% of the US PCCM trainees feel they would not be proficient in EI upon graduation. This article presents a review of the EI training literature; the recommendations of a national group of PCCM, anesthesiology, emergency medicine, and pediatric experts; and a call for further research, collaboration, and consensus guidelines.

ObjectivesThe aim of this study was to assess common laboratory tests in identifying severe ulcerative colitis in children at diagnosis.MethodsA cohort of 427 children 4 to 17 years of age newly diagnosed with ulcerative colitis (UC) was prospectively enrolled. Boosted classification trees were used to characterize predictive ability of disease attributes based on clinical disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI), severe (65+) versus not severe (

This study was designed to determine and compare the effects of smoking processes on the proximal composition, fatty acid profile, minerals, vitamins, total polycyclic aromatic hydrocarbons, and sensory characteristics of cultured Clarias gariepinus. Nine fatty acids were identified from the muscle of fish samples, with all nine fatty acids recorded for both smoked samples (hot and cold), while the raw sample had only eight. Furthermore, the most abundant fatty acids in the smoked samples were palmitic acid, oleic acid, stearic acid, and palmitoleic acid. Vitamins A, D, E, and K were higher in smoked samples than in raw samples, while vitamins B1, B2, and B3 were higher in raw samples than in smoke samples. Raw, cold, and hot smoked samples had significantly different mineral profiles (p

Formal learning environments have struggled to introduce STEM content and STEM careers to students from underrepresented populations. This problem is exacerbated when dealing with students who live in rural areas where access to quality materials and instruction is limited. The eMentorship project is an innovative approach to mentoring that utilizes the latest in communication technology to help support a formal mentoring program. This study investigates the impact of a virtual mentorship program on underrepresented students living in rural North Carolina. The project was an eight-week mentoring program that matched underrepresented student teams with graduate student mentors from a local university. In addition to the mentoring experience student participants were also taught three-dimensional (3-D) modeling skills using a "flipped" classroom approach to instruction. The paper presents the curriculum developed to guide the program, student examples of 3-D models, self-efficacy scores and qualitative interviews conducted with the student participants. Results of the study provide evidence that students found great value in the mentoring experience and were able to learn 3-D modeling skills in a virtual learning environment.

Although social networking sites (SNS) have been widely investigated, very limited information is available about how teachers navigate them within a fully online learning space, the challenges they confront, and the strategies they use to overcome them. Thus, we examined these underexplored areas by interviewing 14 higher education teachers in the field of social sciences. Using a cross-case analysis, overall data indicates that teachers had varied reasons for and considered different factors when adopting SNS for online teaching. Our study also reveals that they used SNS affordances depending on their own teaching contexts and took different roles when teaching online via this platform. Although teachers generally viewed SNS as an instructional approach, they also reported several technical, pedagogical, and learner-related challenges, which they attempted to confront using a variety of strategies. These findings confirmed that teachers' pedagogical practices and decisions in an SNS-mediated learning environment are shaped by the interaction between and among the teacher-related factors, SNS as an instructional tool, and teaching goals mediated by the policies (existing or not) and their peers. Some key implications of our findings are on designing teacher development programs, recalibrating national, institutional, and classroom policies, and implementing a systemic approach to mitigating pedagogical challenges in an online learning space. Implications for future studies are also discussed.

The challenge of mothering while pursuing an academic career is the most significant obstacle to women's success. However, there is a lack of research examining how being a woman who intensively mothers co-exist with her autonomous subjectivity as an academic. In this qualitative study, academic mothers adhere both to an intensive mothering ideology and the ideal worker construct reified in neo-liberalised academic culture. We argue that these women negotiate the co-existence of these subjectivities from within a 'new' maternal subjectivity. These academic women are not victims of the patriarchal norms of the academy or the ideological constraints of intensive mothering. Instead, they actively negotiate institutional and ideological constraints in a way that incorporates their autonomous subjectivity and their maternal subjectivity.

College graduation rates for racially minoritized students are adversely affected by structural barriers and hostile campus racial climates, which lead to notable equity gaps within and across institutions. Theory and prior literature suggest that the representation of racially minoritized students and instructors may play a role in shaping these disparities, but the evidence to date is limited and has yielded divergent findings. Therefore, the present study directly explored the link between the representation of several minoritized racial groups and equity gaps in six-year graduation rates. The results indicate that same-race representation and the representation of students and instructors from other racially minoritized groups were associated with greater racial equity in graduation outcomes; in fact, no Black-White and Latinx-White gaps were present when Black or Latinx students, respectively, comprised at least half of undergraduates at that institution. Moreover, these patterns occurred predominantly at institutions with virtually no fully online students, which suggests the importance of face-to-face interactions that facilitate situational racial cues and interpersonal experiences that may foster success for racially minoritized students.

This study built upon research examining the effects of diversity in STEM (science, technology, engineering, and mathematics) fields and higher education by investigating the relationship between student perceptions of campus diversity and classroom engagement for first- and second-year Latinx and White students at two structurally diverse institutions. Findings suggested that perceptions of campus climate have a positive and significant relationship with classroom engagement--which is an important indicator of overall grade point average.

Colleges and universities play a critical role in shaping intergroup dynamics in an era of increasing racial tensions in the United States. Diversity courses may serve as one important approach for preparing college students for participation in an equitable and just society, since this coursework holds a unique position at many institutions to expose college students to issues of difference and inequality. This study synthesizes research on the relationship between university/college instruction explicitly using the word course and the root divers and student outcomes over the span of 25 years. Within a meta-analytic sample of 355 effect sizes, from 73 publications, and 47 distinct samples representing 116,092 undergraduate students the results indicate an overall small positive association between diversity coursework and various outcomes. Additional results highlighted the ways in which this relationship is moderated by various characteristics of the courses, outcome measures, and study design.

Purpose: The purpose of this mixed-methods study was to: (a) evaluate the effectiveness of a required Health-Related Fitness (HRF) course in changing dietary behaviors among community college (CC) students, and (b) explore student perceptions about the effectiveness of HRF curriculum activities in changing behaviors. Methods: Pre- and post-semester data were gathered from 76 CC students (aged 18-34) enrolled in four HRF courses on a CC campus in Texas. Pre- and post-survey questions included demographic and dietary behavior questions from the College Student Health Survey. Descriptive statistics were used for demographic data, while repeated measures Multivariate Analysis of Variance (MANOVA) analyses were used to analyze dietary behaviors. Dietary behaviors were measured by fruit and vegetable (FV) consumption, meal patterns (breakfast, fast food, restaurant eating), and sugar sweetened beverage intake (soda, diet soda, fruit drinks, sports drinks, coffee drinks, and other sweetened beverages). Frequency statistics were conducted on themes emerging from open-ended questions (post-survey). Results: No significant changes were found in FV consumption. There were meaningful changes in dietary patterns, including significant increases in breakfast eating, significant decreases in sports drink consumption, and decreases in other sugar-sweetened beverage categories. Most students (96.1%) reported that the HRF course was beneficial. Participants' curriculum recommendations included additional instructional time regarding selection and preparation of healthier foods. Sustainability suggestions included tracking, motivation, support, and continuing education. Conclusions: Significant changes among meal patterns and sugar-sweetened beverages represent positive shifts, yet additional instructional time and course activities may be warranted to increase FV consumption. The HRF course appears to be a valuable intervention for teaching healthy lifestyle behaviors to the young adult population. Recommendations: Additional research is needed to compare different age groups, gender and ethnic differences, and four-year vs. CC students. Longitudinal studies can be helpful in determining long-term influences of HRF courses on students' health behaviors. Focus groups can also be implemented to capture additional information regarding students' perceptions about the HRF course and modifications to enhance learning and promote lasting healthy behavior change. Additionally, experiential learning activities can be integrated to enhance retention of learning and develop students' self-efficacy for adopting healthy dietary behaviors.

BackgroundMinority groups of African descent experience disproportionately greater asthma morbidity compared with other racial groups, suggesting that genetic variation from a common ancestry could influence exacerbation risk.ObjectiveWe evaluated clinical trial measures in the context of self-reported race and genetic ancestry to identify risk factors for asthma exacerbations.MethodsOne thousand eight hundred forty multiethnic subjects from 12 Asthma Clinical Research Network and AsthmaNet trials were analyzed for incident asthma exacerbations with Poisson regression models that included clinical measures, self-reported race (black, non-Hispanic white, and other), and estimates of global genetic African ancestry in a subgroup (n = 760).ResultsTwenty-four percent of 1840 subjects self-identified as black. Black and white subjects had common risk factors for exacerbations, including a history of 2 or more exacerbations in the previous year and FEV1 percent predicted values, whereas chronic sinusitis, allergic rhinitis, and gastroesophageal reflux disease were only associated with increased exacerbation risk in black subjects. In the combined multiethnic cohort, neither race (P = .30) nor percentage of genetic African ancestry as a continuous variable associated with exacerbation risk (adjusted rate ratio [RR], 1.26 [95% CI, 0.94-1.70; P = .13]; RR per 1-SD change [32% ancestry], 0.97 [95% CI, 0.78-1.19; P = .74]). However, in 161 black subjects with genetic data, those with African ancestry greater than the median (≥82%) had a significantly greater risk of exacerbation (RR, 3.06 [95% CI, 1.09-8.6; P = .03]).ConclusionBlack subjects have unique risk factors for asthma exacerbations, of which global African genetic ancestry had the strongest effect.

Background & aimsThere are few serum biomarkers to identify patients with Crohn's disease (CD) who are at risk for stricture development. The extracellular matrix components, collagen type III alpha 1 chain (COL3A1) and cartilage oligomeric matrix protein (COMP), could contribute to intestinal fibrosis. We investigated whether children with inflammatory CD (B1) who later develop strictures (B2) have increased plasma levels of COL3A1 or COMP at diagnosis, compared with children who remain B1. We compared results with previously studied biomarkers, including autoantibodies against colony-stimulating factor 2 (CSF2).MethodsWe selected 161 subjects (mean age, 12.2 y; 62% male) from the Risk Stratification and Identification of Immunogenic and Microbial Markers of Rapid Disease Progression in Children with Crohn's cohort, completed at 28 sites in the United States and Canada from 2008 through 2012. The children underwent colonoscopy and upper endoscopy at diagnosis and were followed up every 6 months for 36 months; plasma samples were collected at baseline. Based on CD phenotype, children were separated to group 1 (B1 phenotype at diagnosis and follow-up evaluation), group 2 (B2 phenotype at diagnosis), or group 3 (B1 phenotype at diagnosis who developed strictures during follow-up evaluation). Plasma samples were collected from patients and 40 children without inflammatory bowel disease (controls) at baseline and analyzed by enzyme-linked immunosorbent assay to measure COL3A1 and COMP. These results were compared with those from a previous biomarker study. The Kruskal-Wallis test and the pairwise Dunn test with Bonferroni correction were used to compare differences among groups.ResultsThe median baseline concentration of COL3A1 was significantly higher in plasma from group 3 vs group 1 (P < .01) and controls (P = .01). Median baseline plasma concentrations of COMP did not differ significantly among groups. A model comprising baseline concentrations of COL3A1 and anti-CSF2 identified patients with B2 vs B1 CD with an area under the curve of 0.80 (95% CI, 0.71-0.89); the combined concentration identified patients with strictures with a sensitivity value of 0.70 (95% CI, 0.55-0.83) and a specificity value of 0.83 (95% CI, 0.67-0.93).ConclusionsWe found median plasma concentrations of COL3A1, measured by enzyme-linked immunosorbent assay at diagnosis, to be significantly higher in patients with CD who later developed strictures than in patients without strictures. The combination of concentrations of COL3A1 and anti-CSF2 might be used to identify pediatric patients at CD diagnosis who are at risk for future strictures.Clinical trial registrationClinicalTrials.gov identifier: NCT00790543.

Background & aimsCrohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression.MethodsWe obtained blood samples from 164 pediatric patients (1-17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1-3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease.ResultsWe identified 1189 5'-cytosine-phosphate-guanosine-3' (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease.ConclusionsMethylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.

Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.

BACKGROUND:Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS:In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS:Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION:Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING:US National Institutes of Health.

Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer's patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.

BACKGROUND:Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. METHODS:Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. RESULTS:We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P < 0.0001). CONCLUSIONS:Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.

In the United States, approximately 5% of individuals with inflammatory bowel disease (IBD) are younger than 20 years old. Studies of pediatric cohorts can provide unique insights into genetic architecture of IBD, which includes Crohn's disease (CD) and ulcerative colitis (UC). Large genome-wide association studies have found more than 200 IBD-associated loci but explain a minority of disease variance for CD and UC. We sought to characterize the contribution of rare variants to disease development, comparing exome sequencing of 368 pediatric IBD patients to publicly available exome sequencing (dbGaP) and aggregate frequency data (ExAC). Using dbGaP data, we performed logistic regression for common variants and optimal unified association tests (SKAT-O) for rare, likely-deleterious variants. We further compared rare variants to ExAC counts with Fisher's exact tests. We did pathway enrichment analysis on the most significant genes from each comparison. Many variants overlapped with known IBD-associated genes (e.g. NOD2). Rare variants were enriched in CD-associated loci (p = 0.009) and showed suggestive enrichment in neutrophil function genes (p = 0.05). Pathway enrichment implicated immune-related pathways, especially cell killing and apoptosis. Variants in extracellular matrix genes also emerged as an important theme in our analysis.

Abstract Objective The impact of comorbidities and biomarkers on COVID-19 severity vary by sex but have not yet been verified in population-based studies. We examined the association of comorbidities, inflammatory biomarkers, and severe outcomes in men and women hospitalized for COVID-19. Design This is a retrospective cohort analysis based on the National COVID Cohort Collaborative (N3C). We included 574,391 adult patients admitted for COVID-19 at hospitals or emergency rooms between 01/01/2020 and 12/31/2021. Methods We defined comorbidities at or before the first admission for COVID-19 by Charlson Comorbidity Index (CCI) and CCI components. We used the averaged lab values taken within 15 days before or after the admission date to measure biomarkers including c-reactive protein (CRP), ferritin, procalcitonin, N-terminal pro b-type natriuretic peptide (NT proBNP), d-dimer, absolute lymphocyte counts, absolute neutrophil counts, and platelets. Our primary outcome was all-cause mortality; secondary outcomes were invasive mechanical ventilation (IMV) and hospital length of stay (LOS). We used logistic regression adjusted for age, race, ethnicity, visit type, and medications to assess the association of comorbidities, biomarkers, and mortality disaggregating by sex. Results Moderate to severe liver disease, renal disease, metastatic solid tumor, and myocardial infarction were the top four fatal comorbidities among patients who were hospitalized for COVID-19 (adjusted odds ratio [aOR] > 2). These four comorbid conditions remained the most lethal in both sexes, with a higher magnitude of risk in women than in men (p-interaction 2). The association between the abnormal biomarkers and death was stronger in women than in men (p-interaction

IntroductionAberrant activation of Extracellular Signal-Regulated Kinase (ERK) signaling is associated with Alzheimer’s disease (AD) pathogenesis. For example, enhanced ERK signal activation mediated by Apolipoprotein E4 (APOE4), which is a critical genetic risk factor for AD, increases the transcription of amyloid precursor protein (APP). We hypothesize that O-linked N-acetylglucosamine (O-GlcNAc) regulates the phosphorylation and activation of ERK. O-GlcNAc is a single sugar post-translational modification that dynamically cycles on and off proteins in response to nutrient changes by the action of the enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. However, O-GlcNAc quickly returns to a baseline level after stimulus removal (called O-GlcNAc homeostasis).MethodsWe did a serum reactivation time-course followed by western blot in SH-SY5Y neuroblastoma cells after long-term O-GlcNAcase (OGA) inhibition by Thiamet-G (TMG) treatment, O-GlcNAc transferase (OGT) knock-down (KD) and OGA KD. Brain tissues of C57BL6/J mice and 5XFAD Alzheimer’s disease mice intra-peritoneally injected with TMG for 1 month and C57BL6/J mice intra-peritoneally injected with TMG for 6 months were also used for western blot.ResultsWe found that ERK1/2 phosphorylation at Thr 202/Tyr204 and Thr183/Tyr185 (p-ERK) are amplified and hence ERK1/2 are activated after long-term OGA inhibition in SH-SY5Y cells. In addition to pharmacological treatment, genetic disruption of O-GlcNAc by OGT KD and OGA KD also increased p-ERK in SH-SY5Y cells suggesting O-GlcNAc homeostasis controls ERK signaling. To determine how O-GlcNAc regulates p-ERK, we probed the expression of phosphorylated mitogen-activated protein kinase-kinase (p-MEK) which phosphorylates and activates ERK and Dual specificity phosphatase-4 (DUSP4) which dephosphorylates and inactivates ERK in SH-SY5Y cells. p-MEK increases in TMG treated and OGT KD cells whereas total DUSP4 decreases in OGT KD and OGA KD cells with serum reactivation time course. Next, we probed the role of OGA inhibition in regulating ERK activation using mice brain-tissue samples. Interestingly, 6-month intra-peritoneal TMG injection in C57BL/6J mice showed an increase in amplitude of p-ERK and APP protein levels, indicating long-term OGA inhibition potentially contributes to AD progression. Furthermore, 1-month TMG injection was sufficient to increase the amplitude of p-ERK in 5XFAD AD mice brains suggesting AD phenotype contributes to the acceleration of ERK activation mediated by OGA inhibition.ConclusionTogether, these results indicate that disruptions to O-GlcNAc homeostasis amplify ERK signal activation in AD.

In 2019, an online survey of 2,015 Australian residents examined the extent of trust of various groups and institutions. A Latent Class Analysis (LCA) of the results generated a typology of trust in Australia. The LCA uncovered four classes based on levels of trust as well as associated demographic profiles and attitudes. The four groups were: those that are very distrusting (15%); those that are largely unsure about how much they can trust various groups and institutions (17%); those that are somewhat trusting (42%); and those that are largely trusting (26%). The largely trusting group was differentiated by their holistic trust in institutions and trust in other Australians (no matter their background). Discomfort with cultural difference was a defining characteristic of the very distrusting class. Examination of these four groups helps understand concerns of Australians and enable the development of strategies to address institutional and interpersonal distrust.

Ulcerative colitis (UC), Crohn’s disease (CD), and celiac disease are prevalent intestinal inflammatory disorders with nonsatisfactory therapeutic interventions. Analyzing patient data-driven cohorts can highlight disease pathways and new targets for interventions. Long noncoding RNAs (lncRNAs) are attractive candidates, since they are readily targetable by RNA therapeutics, show relative cell-specific expression, and play key cellular functions. Uniformly analyzing gut mucosal transcriptomics from 696 subjects, we have highlighted lncRNA expression along the gastrointestinal (GI) tract, demonstrating that, in control samples, lncRNAs have a more location-specific expression in comparison with protein-coding genes. We defined dysregulation of lncRNAs in treatment-naive UC, CD, and celiac diseases using independent test and validation cohorts. Using the Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT) inception UC cohort, we defined and prioritized lncRNA linked with UC severity and prospective outcomes, and we highlighted lncRNAs linked with gut microbes previously implicated in mucosal homeostasis. HNF1A-AS1 lncRNA was reduced in all 3 conditions and was further reduced in more severe UC form. Similarly, the reduction of HNF1A-AS1 ortholog in mice gut epithelia showed higher sensitivity to dextran sodium sulfate–induced colitis, which was coupled with alteration in the gut microbial community. These analyses highlight prioritized dysregulated lncRNAs that can guide future preclinical studies for testing them as potential targets.

Abstract Excitotoxicity is the underlying mechanism for all acute neuronal injury, from cerebral ischemia, status epilepticus, traumatic CNS injury, and hypoglycemia. It causes morphological neuronal necrosis, and it triggers a programmed cell death program. Excessive calcium entry through the NMDA‐receptor‐operated cation channel activates two key enzymes—calpain I and neuronal nitric oxide synthase (nNOS). Calpain I, a cytosolic enzyme, translocates to mitochondrial and lysosomal membranes, causing release of cytochrome c, endonuclease G, and apoptosis‐inducing factor (AIF) from mitochondria and DNase II and cathepsins B and D from lysosomes. These all translocate to neuronal nuclei, creating DNA damage, which activates poly(ADP) ribose polymerase‐1 (PARP‐1) to form excessive amounts of poly(ADP) ribose (PAR) polymers, which translocate to mitochondrial membranes, causing release of truncated AIF (tAIF). The free radicals that are released from mitochondria and peroxynitrite, formed from nitric oxide (NO) from nNOS catalysis of L‐arginine to L‐citrulline, damage mitochondrial and lysosomal membranes and DNA. The end result is the necrotic death of neurons. Another programmed necrotic pathway, necroptosis, occurs through a parallel pathway. As investigators of necroptosis do not recognize the excitotoxic pathway, it is unclear to what extent each contributes to programmed neuronal necrosis. We are studying the extent to which each contributes to acute neuronal necrosis and the extent of cross‐talk between these pathways.