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Fibrosis is a common pathological response to inflammation in many peripheral tissues and can prevent tissue regeneration and repair. Here, we identified persistent fibrotic scarring in the CNS following immune cell infiltration in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Using lineage tracing and single-cell sequencing in EAE, we determined that the majority of the fibrotic scar is derived from proliferative CNS fibroblasts, not pericytes or infiltrating bone marrow-derived cells. Ablating proliferating fibrotic cells using cell-specific expression of herpes thymidine kinase led to an increase in oligodendrocyte lineage cells within the inflammatory lesions and a reduction in motor disability. We further identified that interferon-gamma pathway genes are enriched in CNS fibrotic cells, and the fibrotic cell-specific deletion of Ifngr1 resulted in reduced fibrotic scarring in EAE. These data delineate a framework for understanding the CNS fibrotic response. Dorrier et al. identified fibrotic scarring in a mouse model of multiple sclerosis that arises from the proliferation of fibroblasts in the meninges and surrounding blood vessels, and determine that reducing scarring decreases motor symptom severity.

Current Aβ-targeting therapeutics for Alzheimer’s disease (AD) only slow cognitive decline due to poor understanding of AD pathogenesis. Here we describe a mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of hippocampal proteins associated with AD pathology. Correspondingly, we developed a brain-penetrant inhibitor of G9a, MS1262, which restored both age-related learning & memory and noncognitive functions in multiple AD mouse models. Further, comparison of AD pathology-correlated mouse proteomes with those of AD patients found G9a regulates pathological pathways that promote Aβ and neurofibrillary tangles. This mouse-to-human overlap of G9a regulated AD-associated pathologic proteins supports at the molecular level the efficacy of targeting G9a translational mechanism for treating AD patients. Additionally, MS1262 treatment reversed the AD-characteristic expression or phosphorylation of multiple clinically validated biomarkers of AD that have the potential to be used for early-stage AD diagnosis and companion diagnosis of individualized drug effects. The authors describe a new mechanism of AD pathogenesis in which the histone methylase G9a regulates translation of hippocampal proteins associated with AD pathology. Targeting this mechanism with a brain-penetrant inhibitor of G9a helped rescue brain pathology in AD mouse models.

Background Artificial intelligence (AI) holds transformative potential for graduate medical education (GME), yet, a comprehensive exploration of AI’s applications, perceptions, and limitations in GME is lacking. Objective To map the current literature on AI in GME, identifying prevailing perceptions, applications, and research gaps to inform future research, policy discussions, and educational practices through a scoping review. Methods Following the Joanna Briggs Institute guidelines and the PRISMA-ScR checklist a comprehensive search of multiple databases up to February 2024 was performed to include studies addressing AI interventions in GME. Results Out of 1734 citations, 102 studies met the inclusion criteria, conducted across 16 countries, predominantly from North America (72), Asia (14), and Europe (6). Radiology had the highest number of publications (21), followed by general surgery (11) and emergency medicine (8). The majority of studies were published in 2023. Several key thematic areas emerged from the literature. Initially, perceptions of AI in graduate medical education (GME) were mixed, but have increasingly shifted toward a more favorable outlook, particularly as the benefits of AI integration in education become more apparent. In assessments, AI demonstrated the ability to differentiate between skill levels and offer meaningful feedback. It has also been effective in evaluating narrative comments to assess resident performance. In the domain of recruitment, AI tools have been applied to analyze letters of recommendation, applications, and personal statements, helping identify potential biases and improve equity in candidate selection. Furthermore, large language models consistently outperformed average candidates on board certification and in-training examinations, indicating their potential utility in standardized assessments. Finally, AI tools showed promise in enhancing clinical decision-making by supporting trainees with improved diagnostic accuracy and efficiency. Conclusions This scoping review provides a comprehensive overview of applications and limitations of AI in GME but is limited with potential biases, study heterogeneity, and evolving nature of AI.

Practice questions are highly sought out for use as a study tool among medical students in undergraduate medical education. At the same time, it remains unknown how medical students use and incorporate practice questions and their rationales into their studies. To explore this heavily relied upon study strategy, semi-structured interviews were conducted with second-year medical students to assess how they approach using practice questions. Qualitative thematic analysis revealed several recurrent themes: (1) Medical students use practice questions for primary learning, (2) Medical students place more importance on the rationale of a practice question versus selecting the right answer, and (3) Medical students view practice questions as being designed to be used once or having a single-use. Together, these themes provide insight into how medical students use practice questions to study, which may guide medical educators in their creation of practice questions with appropriate rationales and provide foundational data for future mixed methods analyses seeking to generalize these findings.

Aryl hydrocarbon receptor (AHR) agonists such as dioxin have been associated with obesity and the development of diabetes. Whole-body Ahr knockout mice on high-fat diet (HFD) have been shown to resist obesity and hepatic steatosis. Tissue-specific knockout of Ahr in mature adipocytes via adiponectin-Cre exacerbates obesity while knockout in liver increases steatosis without having significant effects on obesity. Our previous studies demonstrated that treatment of subcutaneous preadipocytes with exogenous or endogenous AHR agonists disrupts maturation into functional adipocytes in vitro. Here, we used platelet-derived growth factor receptor alpha (Pdgfrα)-Cre mice, a Cre model previously established to knock out genes in preadipocyte lineages and other cell types, but not liver cells, to further define AHR’s role in obesity. We demonstrate that Pdgfrα-Cre Ahr-floxed (Ahrfl/fl) knockout mice are protected from HFD-induced obesity compared to non-knockout Ahrfl/fl mice (control mice). The Pdgfrα-Cre Ahrfl/fl knockout mice were also protected from increased adiposity, enlargement of adipocyte size, and liver steatosis while on the HFD compared to control mice. On a regular control diet, knockout and non-knockout mice showed no differences in weight gain, indicating the protective phenotype arises only when animals are challenged by a HFD. At the cellular level, cultured cells from brown adipose tissue (BAT) of Pdgfrα-Cre Ahrfl/fl mice were more responsive than cells from controls to transcriptional activation of the thermogenic uncoupling protein 1 (Ucp1) gene by norepinephrine, suggesting an ability to burn more energy under certain conditions. Collectively, our results show that knockout of Ahr mediated by Pdgfrα-Cre is protective against diet-induced obesity and suggest a mechanism by which enhanced UCP1 activity within BAT might confer these effects.

National licensing exams (NLEs) including the Comprehensive Osteopathic Medical Licensing Examination (COMLEX) Level 1 evaluate student achievement. Scores have historically been utilized to stratify medical student applicants for residency. Grade point average (GPA), number of practice questions completed, and performance on practice exams have been shown to be predictive of NLE performance. Test anxiety and acute stress have been shown to negatively impact NLE performance. The role of study behaviors and other nonacademic factors in COMLEX Level 1 performance is unknown. This study aims to evaluate academic and nonacademic factors and to correlate them with COMLEX Level 1 performance. Additional analysis is conducted to associate COMLEX Level 1 performance with academic and nonacademic factors when controlling for GPA. An anonymous online survey was administered to third- (OMS III) and fourth-year (OMS IV) osteopathic medical students at Kansas City University that had completed the COMLEX Level 1 examination. In total, 72 students responded to the survey. Survey results were linked to student records of GPA and COMLEX Level 1 scores, resulting in 59 complete responses for analysis. Independent-sample t-tests and linear ordinary least squares regression were utilized to analyze the results. The majority of participants are male (62.7%) and OMS III (98.3%) with an average age of 27.14 ± 2.58 (mean ± standard deviation). Further demographic data reveal hours per week spent for personal time during dedicated study (n=46, 19.7 ± 18.53), hours of sleep per night during dedicated study (7.34 ± 0.92), and money spent on board preparation ($1,319.12 ± $689.17). High ($1,600-$3,000), average ($1,000-$1,500), and low ($100-$900) spenders do not statistically differ and COMLEX Level 1 performance is not related to the number of resources utilized ( statistics <1; p>0.05). Pearson correlations reveal a statistically significant relationship between COMLEX Level 1 scores with GPA (0.73, p<0.001), number of practice exams completed (0.39, p<0.001), number of questions completed (0.46, p<0.001), number of weeks of study (0.55, p<0.001), and preparation cost (0.28, p<0.05). The regression analysis revealed that money spent on board preparation, number of questions completed, and time spent studying accounted for 75.8% of the variance in COMLEX Level 1 scores after controlling for GPA. The data show the association of money spent on board preparation, numbers of questions competed, and time spent studying with a student's COMLEX Level 1 score. Additionally, these results highlight the amount of money students spend on extracurricular materials to prepare for COMLEX Level 1, yet the data show that the number of resources that students utilized is not related to a student's COMLEX Level 1 performance.

Hyperactivated AKT/mTOR signaling is a hallmark of pancreatic neuroendocrine tumors (PNETs). Drugs targeting this pathway are used clinically, but tumor resistance invariably develops. A better understanding of factors regulating AKT/mTOR signaling and PNET pathogenesis is needed to improve current therapies. We discovered that RABL6A, a new oncogenic driver of PNET proliferation, is required for AKT activity. Silencing RABL6A caused PNET cell-cycle arrest that coincided with selective loss of AKT-S473 (not T308) phosphorylation and AKT/mTOR inactivation. Restoration of AKT phosphorylation rescued the G1 phase block triggered by RABL6A silencing. Mechanistically, loss of AKT-S473 phosphorylation in RABL6A-depleted cells was the result of increased protein phosphatase 2A (PP2A) activity. Inhibition of PP2A restored phosphorylation of AKT-S473 in RABL6A-depleted cells, whereas PP2A reactivation using a specific small-molecule activator of PP2A (SMAP) abolished that phosphorylation. Moreover, SMAP treatment effectively killed PNET cells in a RABL6A-dependent manner and suppressed PNET growth in vivo. The present work identifies RABL6A as a new inhibitor of the PP2A tumor suppressor and an essential activator of AKT in PNET cells. Our findings offer what we believe is a novel strategy of PP2A reactivation for treatment of PNETs as well as other human cancers driven by RABL6A overexpression and PP2A inactivation.

Schweinfurthins are intriguing natural product chemotherapeutics due to their potent yet selective activity and their unknown mechanism of growth inhibition in cancer. Much progress has been made in characterizing the intracellular effects of the schweinfurthins since they were first isolated from Macaranga schweinfurthii in 1986. Here, the L-type calcium channel and P- glycoprotein (Pgp) inhibitor verapamil has been found to enhance schweinfurthin-induced growth inhibition. Verapamil induces an increase in the intracellular concentration of a fluorescent schweinfurthin. However, the synergistic relationship between the schweinfurthins and verapamil is complex and not obvious in that verapamil fails to increase the intracellular concentration of a schweinfurthin analogue that is a known substrate of Pgp. Schweinfurthins are also found to induce alterations to cholesterol homeostasis by increasing the expression of the cholesterol efflux pump ABCA1 in an apparent liver X receptor- independent fashion. In addition, schweinfurthin treatment blunts epidermal growth factor downstream activation and phosphorylation of Akt. Lastly, a schweinfurthin-resistant cell line has been created and characterized for resistance to schweinfurthin-induced growth inhibition. The variety of intracellular effects characteristic of schweinfurthin treatment described here provide mechanistic framework for identifying the potential target and mechanism of growth inhibition for the schweinfurthins.

Because of the short acquisition time during the landing profile, the Defensive Weapons System (or any future nose-mounted ordnance systems) fails to counter undetected enemy threats. First pass landings is a tactic that also works for mitigating the risk of wave offs, multiple attempts to land in a dust cloud, and the very real threat of rapid engine degradation by dust ingestion.