Targeting the chromatin binding of exportin-1 disrupts NFAT and T cell activation.

Exportin-1 (XPO1/CRM1) plays a central role in the nuclear-to-cytoplasmic transport of hundreds of proteins and contributes to other cellular processes, such as centrosome duplication. Small molecules targeting XPO1 induce cytotoxicity, and selinexor was approved by the Food and Drug Administration in 2019 as a cancer chemotherapy for relapsed multiple myeloma. Here, we describe a cell-type-dependent chromatin-binding function for XPO1 that is essential for the chromatin occupancy of NFAT transcription factors and thus the appropriate activation of T cells. Additionally, we establish a class of XPO1-targeting small molecules capable of disrupting the chromatin binding of XPO1 without perturbing nuclear export or inducing cytotoxicity. This work defines a broad transcription regulatory role for XPO1 that is essential for T cell activation as well as a new class of XPO1 modulators to enable therapeutic targeting of XPO1 beyond oncology including in T cell-driven autoimmune disorders.

The selective serotonin reuptake inhibitor sertraline alters learning from aversive reinforcements in patients with depression: evidence from a randomized controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological treatments for depression and anxiety. However, little is known about how pharmacological action is related to cognitive and affective processes. Here, we examine whether specific reinforcement learning processes mediate the treatment effects of SSRIs. METHODS: The PANDA trial was a multicentre, double-blind, randomized clinical trial in UK primary care comparing the SSRI sertraline with placebo for depression and anxiety. Participants (N = 655) performed an affective Go/NoGo task three times during the trial and computational models were used to infer reinforcement learning processes. RESULTS: There was poor task performance: only 54% of the task runs were informative, with more informative task runs in the placebo than in the active group. There was no evidence for the preregistered hypothesis that Pavlovian inhibition was affected by sertraline. Exploratory analyses revealed that in the sertraline group, early increases in Pavlovian inhibition were associated with improvements in depression after 12 weeks. Furthermore, sertraline increased how fast participants learned from losses and faster learning from losses was associated with more severe generalized anxiety symptoms. CONCLUSIONS: The study findings indicate a relationship between aversive reinforcement learning mechanisms and aspects of depression, anxiety, and SSRI treatment, but these relationships did not align with the initial hypotheses. Poor task performance limits the interpretability and likely generalizability of the findings, and highlights the critical importance of developing acceptable and reliable tasks for use in clinical studies. FUNDING: This article presents research supported by NIHR Program Grants for Applied Research (RP-PG-0610-10048), the NIHR BRC, and UCL, with additional support from IMPRS COMP2PSYCH (JM, QH) and a Wellcome Trust grant (QH).

Differences in quality of life and patient satisfaction between complete denture occlusion schemes: A parallel randomized control trial.

STATEMENT OF PROBLEM: Bilateral balanced occlusion has been advocated over nonbalanced occlusion for improved removable complete denture stability and function. However, assessments of quality of life and patient satisfaction studies between the 2 occlusion schemes are lacking. PURPOSE: The objective of this parallel randomized control trial was to determine the difference in quality of life and patient satisfaction between the nonbalanced and bilaterally balanced occlusal schemes. MATERIAL AND METHODS: Sixty participants were included in the parallel randomized control trial of nonbalanced and bilaterally balanced complete dentures. Thirty were recruited into each group with definitive inclusion and exclusion criteria as per the Consolidated Standards of Reporting Trials (CONSORT) guidelines. Quality of life was estimated from the oral health quality of life (Oral Health Impact profile) for edentulous patients questionnaire, and patient satisfaction was analyzed from a visual analog scale. The estimation was made at 0, 3, and 6 months after denture insertion. The data were statistically analyzed with the Friedman, Mann-Whitney, and t test (α=.05). RESULTS: The mean ±standard deviation Oral Health Impact profile score was 60.81 ±8.87 for nonbalanced dentures and 64.12 ±8.98 for bilaterally balanced dentures. The mean ±standard deviation visual analog scale score was 2.84 ±0.28 for nonbalanced dentures and 2.90 ±0.31 for bilaterally balanced dentures. The Mann-Whitney and t test indicated nonsignificant differences between the 2 groups and at different time intervals for Oral Health Impact profile and visual analog scale scores (P>.05). CONCLUSIONS: The study detected no significant differences between the 2 occlusal schemes in quality of life or patient satisfaction.

Risk-taking to obtain reward: sex differences and associations with emotional and depressive symptoms in a nationally representative cohort of UK adolescents.

BACKGROUND: Cognitive mechanisms that characterize or precede depressive symptoms are poorly understood. We investigated cross-sectional and longitudinal associations between risk taking to obtain reward and adolescent depressive symptoms in a large prospective cohort, using the Cambridge Gambling Task (CGT). We also explored sex differences. METHODS: The Millennium Cohort Study (MCS) is an ongoing UK study, following the lives of 19 000 individuals born 2000/02. The CGT was completed at ages 11 (n = 12 355) and 14 (n = 10 578). Our main exposure was the proportion of points gambled, when the odds of winning were above chance (risk-taking to obtain reward). Outcomes were emotional symptoms (Strengths and Difficulties Questionnaire, SDQ) at age 11 and depressive symptoms (short Mood and Feelings Questionnaire, sMFQ) at age 14. We calculated cross-sectional and longitudinal associations, using linear regressions. RESULTS: In univariable models, there was evidence of cross-sectional associations between risk-taking and SDQ/sMFQ scores, but these associations disappeared after we adjusted for sex. Longitudinally, there was weak evidence of an association between risk-taking and depressive symptoms in females only [a 20-point increase in risk-taking at age 11 was associated with a reduction of 0.31 sMFQ points at age 14 (95% CI -0.60 to -0.02)]. At both time-points, females were less risk-taking than males. CONCLUSIONS: We found no convincing evidence of a relationship between risk-taking to obtain reward and depressive symptoms. There were large sex differences in risk-taking, but these do not appear to contribute to the female preponderance of depressive symptoms in adolescence.

Computer-Aided Detection AI Reduces Interreader Variability in Grading Hip Abnormalities With MRI.

BACKGROUND: Accurate interpretation of hip MRI is time-intensive and difficult, prone to inter- and intrareviewer variability, and lacks a universally accepted grading scale to evaluate morphological abnormalities. PURPOSE: To 1) develop and evaluate a deep-learning-based model for binary classification of hip osteoarthritis (OA) morphological abnormalities on MR images, and 2) develop an artificial intelligence (AI)-based assist tool to find if using the model predictions improves interreader agreement in hip grading. STUDY TYPE: Retrospective study aimed to evaluate a technical development. POPULATION: A total of 764 MRI volumes (364 patients) obtained from two studies (242 patients from LASEM [FORCe] and 122 patients from UCSF), split into a 65-25-10% train, validation, test set for network training. FIELD STRENGTH/SEQUENCE: 3T MRI, 2D T2 FSE, PD SPAIR. ASSESSMENT: Automatic binary classification of cartilage lesions, bone marrow edema-like lesions, and subchondral cyst-like lesions using the MRNet, interreader agreement before and after using network predictions. STATISTICAL TESTS: Receiver operating characteristic (ROC) curve, area under curve (AUC), specificity and sensitivity, and balanced accuracy. RESULTS: For cartilage lesions, bone marrow edema-like lesions and subchondral cyst-like lesions the AUCs were: 0.80 (95% confidence interval [CI] 0.65, 0.95), 0.84 (95% CI 0.67, 1.00), and 0.77 (95% CI 0.66, 0.85), respectively. The sensitivity and specificity of the radiologist for binary classification were: 0.79 (95% CI 0.65, 0.93) and 0.80 (95% CI 0.59, 1.02), 0.40 (95% CI -0.02, 0.83) and 0.72 (95% CI 0.59, 0.86), 0.75 (95% CI 0.45, 1.05) and 0.88 (95% CI 0.77, 0.98). The interreader balanced accuracy increased from 53%, 71% and 56% to 60%, 73% and 68% after using the network predictions and saliency maps. DATA CONCLUSION: We have shown that a deep-learning approach achieved high performance in clinical classification tasks on hip MR images, and that using the predictions from the deep-learning model improved the interreader agreement in all pathologies. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 1 J. Magn. Reson. Imaging 2020;52:1163-1172.

Detection of Lumbar Spine Osseous Metastases Using Dual-Energy CT: Phantom Results and Preliminary Clinical Validation.

OBJECTIVE: The purpose of this study was to evaluate the sensitivity, tumor conspicuity, and image quality of different material decomposition images of phantoms and patients with nearly isodense bone metastases using rapid-kilovoltage-switching dual-energy CT (DECT). MATERIALS AND METHODS: Fifty-one semianthropomorphic lumbar spine phantoms embedded with 75 simulated tumors were scanned without and with outer torso-attenuating encasement under the same scan settings. Two radiologists independently reviewed the 70-keV virtual monochromatic and material decomposition images (hydroxyapatite-water, water-hydroxyapatite, cortical bone-water, water-cortical bone). The sensitivity of tumor detection, tumor conspicuity (on a 3-point scale), and image quality (on a 3-point scale) were recorded by two independent readers. McNemar and Wilcoxon signed rank tests were used to compare results between the image reconstructions. Six clinical abdominopelvic DECT scans (three men, three women; mean age, 52 years) with nine nearly isodense lumbar spine tumors missed in the clinical report but confirmed on other scans were also evaluated. RESULTS: The hydroxyapatite-water material decomposition algorithm showed improved sensitivity for isodense lesion detection (without torso phantom encasement, 94% vs 82%, p = 0.031; with torso phantom encasement, 38% vs 18%, p = 0.013), and higher tumor conspicuity scores (p < 0.0001) compared with 70-keV virtual monoenergetic images. Artifacts were more prevalent with all material decomposition images than with 70-keV virtual monoenergetic images. Similar results were seen in the patient study. CONCLUSION: Dual-energy CT with hydroxyapatite-water material decomposition may improve the detection of bone marrow metastases, especially for subtle isodense tumors. Further study in prospective clinical scans is warranted.

Knee Imaging Following Anterior Cruciate Ligament Reconstruction: The Surgeon's and Radiologist's Perspectives.

Anterior cruciate ligament (ACL) tears are common injuries that if left untreated can result in chronic instability, cartilage damage, meniscal tears, and ligamentous injuries, eventually leading to early osteoarthritis. ACL reconstruction surgeries are therefore increasingly being performed. Despite the fact that most patients achieve excellent postoperative results, patients can present with recurrent instability and pain. These patients often undergo imaging with radiographs, magnetic resonance imaging, and/or computed tomography. An understanding of the imaging appearance of the normal ACL reconstruction and common causes of failure is therefore essential for the interpreting radiologist. This article reviews surgical techniques for ACL reconstruction, highlighting recent technical advances, the normal imaging appearance after ACL reconstruction, etiologies for reconstruction failure, and the diagnosis of these with the aid of imaging.

Clinicians' perception of the preventability of inpatient mortality.

Purpose The purpose of this paper is to assess whether clinicians have an accurate perception of the preventability of their patients' mortality. Case note review estimates that approximately 5 percent of inpatient deaths are preventable. Design/methodology/approach The design involved in the study is a prospective audit of inpatient mortality in a single NHS hospital trust. The case study includes 979 inpatient mortalities. A number of outcome measures were recorded, including a Likert scale of the preventability of death- and NCEPOD-based grading of care quality. Findings Clinicians assessed only 1.4 percent of deaths as likely to be preventable. This is significantly lower than previously published values ( p<0.0001). Clinicians were also more likely to rate the quality of care as "good," and less likely to identify areas of substandard clinical or organizational management. Research limitations/implications The implications of objective assessment of the preventability of mortality are essential to drive quality improvement in this area. Practical implications There is a wide disparity between independent case note review and clinicians assessing the care of their own patients. This may be due to a "knowledge gap" between reviewers and treating clinicians, or an "objectivity gap" meaning clinicians may not recognize preventability of death of patients under their care. Social implications This study gives some insight into deficiencies in clinical governance processes. Originality/value No similar study has been performed. This has significant implications for the idea of the preventability of mortality.

The Hallucal-Sesamoid Complex: Normal Anatomy, Imaging, and Pathology.

The first metatarsophalangeal joint and hallucal-sesamoid complex are critical structures in weightbearing and susceptible to several pathologies including turf toe, sesamoiditis, degenerative or inflammatory arthritides, infection, and avascular necrosis. This review article summarizes the complex anatomy of the region, covers common pathologies while clarifying terms such as turf toe and sesamoiditis, reviews imaging techniques, and discusses management.

Mechanism and Dynamics of Intramolecular C-H Insertion Reactions of 1-Aza-2-azoniaallene Salts.

The 1-aza-2-azoniaallene salts, generated from α-chloroazo compounds by treatment with halophilic Lewis acids, undergo intramolecular C-H amination reactions to form pyrazolines in good to excellent yields. This intramolecular amination occurs readily at both benzylic and tertiary aliphatic positions and proceeds at an enantioenriched chiral center with retention of stereochemistry. Competition experiments show that insertion occurs more readily at an electron-rich benzylic position than it does at an electron-deficient one. The C-H amination reaction occurs only with certain tethers connecting the heteroallene cation and the pendant aryl groups. With a longer tether or when the reaction is intermolecular, electrophilic aromatic substitution occurs instead of C-H amination. The mechanism and origins of stereospecificity and chemoselectivity were explored with density functional theory (B3LYP and M06-2X). The 1-aza-2-azoniaallene cation undergoes C-H amination through a hydride transfer transition state to form the N-H bond, and the subsequent C-N bond formation occurs spontaneously to generate the heterocyclic product. This concerted two-stage mechanism was shown by IRC and quasi-classical molecular dynamics trajectory studies.

MRI of lesser metatarsophalangeal joint plantar plate tears and associated adjacent interspace lesions.

OBJECTIVE: To identify the variety of second and third intermetatarsal space (IS) lesions that may coexist with and without adjacent metatarsophalangeal joint (MTP) plantar plate (PP) tears. MATERIALS AND METHODS: One hundred forefoot MRIs in 96 patients with metatarsalgia obtained between 30 September 2011 and 21 July 2012 using 1.5- or 3-T MRI were retrospectively reviewed in consensus by two MSK radiologists and one podiatrist (DPM). MRI was evaluated for second and third MTP PP tear and the presence/nature of second and third IS lesions. Second and third IS neuromas were measured in transverse (trans) dimension. RESULTS: A total of 40 PP tears were identified: 36 at the second and 4 at the third MTP. Second MTP PP tear was identified in 33% of females and 40.5% of males. In the 63 female feet there were 21 second MTP PP tears, all of which also had second IS lesions: pericapsular fibrosis (16), bursitis (4), and ganglion (1). In the 37 male feet there were 15 second MTP PP tears, 14 of which had second IS lesions: pericapsular fibrosis (8), bursitis (5), and ganglion (1). There was no definite second IS neuroma adjacent to any second MTP PP tear. In females without PP tear, there were 24 second (3 mm trans average) and 43 third IS neuromas (4.1 mm trans average). In males without PP tear, there were 9 second (3.4 mm trans average) and 16 third IS neuromas (4.1 mm trans average). CONCLUSIONS: MTP PP tears occurred in 40% of our cases, 90% of which occurred at the second MTP. Almost all coexisted with non-neuromatous second IS lesions.

Changes in Early Childhood Irritability and Its Association With Depressive Symptoms and Self-Harm During Adolescence in a Nationally Representative United Kingdom Birth Cohort.

OBJECTIVE: This study aimed to investigate longitudinal associations between changes in early childhood irritability, and depressive symptoms and self-harm at 14 years. METHOD: We used data from 7,225 children in a UK-based general population birth cohort. Childhood irritability was measured at 3, 5, and 7 years using 4 items from 2 questionnaires (the Children's Social Behaviour Questionnaire [CSBQ] and the Strengths and Difficulties Questionnaire [SDQ]). Participants reported depressive symptoms via the short Mood and Feelings Questionnaire (sMFQ) and self-harm via a single-item question, at 14 years. We used multilevel models to calculate within-child change in irritability between 3 and 7 years and examined associations between irritability, and depressive symptoms and self-harm at 14 years using linear and logistic regression models, respectively. We adjusted for child and family sociodemographic/economic characteristics, mental health difficulties, and child cognitive development. RESULTS: Irritability at ages 5 and 7 years was positively associated with depressive symptoms and self-harm at age 14 years. Irritability that remained high between 3 and 7 years was associated with depressive symptoms and self-harm at 14 years in unadjusted (depressive symptoms: ß coefficient = 0.22, 95 % CI = 0.08-0.37, p = .003; self-harm: odds ratio = 1.09, 95 % CI = 1.01-1.16, p = .019) and adjusted models (depressive symptoms: ß coefficient = 0.31, 95 % CI = 0.17-0.45, p < .001; self-harm: odds ratio = 1.12, 95 % CI = 1.0.4-1.19, p = .004). Results were similar in imputed samples. CONCLUSION: Children with irritability that remains high between 3 and 7 years are more likely to report higher depressive symptoms and self-harm during adolescence. These findings support early intervention for children with high irritability and universal interventions in managing irritability for parents of preschool-aged children.

Effectiveness of anterior repositioning splint versus other occlusal splints in the management of temporomandibular joint disc displacement with reduction: A meta-analysis.

BACKGROUND: Disc displacement with reduction (DDwR) is among the common disc disorders of temporomandibular joint (TMJ), which can be managed conservatively by splint therapy. Anterior repositioning splint (ARS) is the most commonly prescribed splint by dental practitioners, but not getting a normal disc-condyle relationship always and other side effects lead to need of comparing with other occlusal splints. This review will help in informed decision-making by clinicians in choosing an appropriate splint type for patients. AIM: The aim is to compare the effectiveness of ARS in the management of DDwR with other occlusal splints for TMJ and muscle pain, TMJ noise, any adverse effects, regaining normal disc-condyle relationship. MATERIALS AND METHODS: We followed published protocol in the International prospective register of systematic reviews. Databases were searched till May 2023 using different search strategies as per the database. Title and abstract screening, followed by full-text screening and data extraction with risk of bias, was done by two independent reviewers in Covidence. Outcomes were reported as risk ratio (RR) or mean difference (MD) for dichotomous or continuous outcomes, respectively, using RevMan 5.4 (Review Manager 5.4) software. We used a random effect model for statistical analysis. Certainty of evidence was assessed using the Grading of Recommendation, Assessment, Development, and Evaluation Guideline Development Tool (GRADEpro GDT) software. RESULTS: A total of 1145 reports were found from a database search. After screening, four studies were included for systematic reviews. Other occlusal splints reported were sagittal vertical extrusion device and mandibular ARS, full hard stabilization splint of canine or centric stabilization type. Data of only two studies could be used for meta-analysis having 30 participants received ARS and 40 received other occlusal splints. We did not find evidence of any difference between ARS and other occlusal splints for TMJ clicking in short term (RR 1.25, 95% confidence interval [CI] 0.91-1.72) but a small difference in favor of other occlusal splint in long term (RR 2.40, 95% CI 1.04-5.55). No evidence of any difference was found between both treatments for TMJ pain in short term (MD-5.68, 95% CI-17.31-5.95) and long term (MD 0.00, 95% CI-2.86-2.86) and muscle pain in short term. The certainty of evidence for comparison of two treatments for different outcomes was of low or very low level. CONCLUSION: Evidence is uncertain that other occlusal splints reduced TMJ clicking slightly in comparison to ARS. For the remaining outcomes, no evidence of any difference was found between the two splints and it may be biased due to selection bias, inadequate blinding of participants, and outcome assessor.

Ultrasound for differentiation between perforated and nonperforated appendicitis in pediatric patients.

OBJECTIVE: Acute appendicitis is the most common condition requiring emergency surgery in children. Differentiation of perforated from nonperforated appendicitis is important because perforated appendicitis may initially be managed conservatively whereas nonperforated appendicitis requires immediate surgical intervention. CT has been proved effective in identifying appendiceal perforation. The purpose of this study was to determine whether perforated and nonperforated appendicitis in children can be similarly differentiated with ultrasound. MATERIALS AND METHODS: This retrospective study included 161 consecutively registered children from two centers who had acute appendicitis and had undergone ultra-sound and appendectomy. Ultrasound images were reviewed for appendiceal size, appearance of the appendiceal wall, changes in periappendiceal fat, and presence of free fluid, abscess, or appendicolith. The surgical report served as the reference standard for determining whether perforation was present. The specificity and sensitivity of each ultrasound finding were determined, and binary models were generated. RESULTS: The patients included were 94 boys and 67 girls (age range, 1-20 years; mean, 11 ± 4.4 [SD] years) The appendiceal perforation rate was significantly higher in children younger than 8 years (62.5%) compared with older children (29.5%). Sonographic findings associated with perforation included abscess (sensitivity, 36.2%; specificity, 99%), loss of the echogenic submucosal layer of the appendix in a child younger than 8 years (sensitivity, 100%; specificity, 72.7%), and presence of an appendicolith in a child younger than 8 years (sensitivity, 68.4%; specificity, 91.7%). CONCLUSION: Ultrasound is effective for differentiation of perforated from nonperforated appendicitis in children.

The art of managing various ocular defects in different clinical scenarios: A case series.

The absence of eye and irradiation post-enucleation may result in problems like dryness of the eye sockets, itching and crusting. This may lead to poor prosthesis adaptation and a lack of patient acceptance of the prosthesis. To combat the most common problem of dryness, patients are advised artificial tears to use as teardrops or ocular prostheses along with a tear reservoir. This case series describes methods of fabricating ocular prosthesis indicated in different scenarios: the modified stock ocular and a custom-made ocular prosthesis when tearing secretion is enough in the eye socket and an ocular prosthesis with a tear reservoir in cases showing reduced tear secretion. A novel technique of fabricating hollow lightweight ocular prostheses having the sustained prolonged release of artificial tears has been described.

Treatment of an Ill-Fitting Complete Dental Prosthesis with Digital Sensor Device: A Case Report.

Complete edentulism is one of the most common problems encountered by geriatric individuals. With advanced aging, despite attempts made to retain natural dentition, loss of entire teeth is yet observed. For precise denture fabrication, a digital sensor device was used during the making procedure. The use of sensor device aided in better appreciation and more retentiveness of denture.

Mental health impact of autism on families of children with intellectual and developmental disabilities of genetic origin.

Background: Many children with an intellectual or developmental disability (IDD) have associated autism spectrum disorders (ASD), as well as an increased risk of mental health difficulties. In a cohort with IDD of genetic aetiology, we tested the hypothesis that excess risk attached to those with ASD + IDD, in terms of both children's mental health and parental psychological distress. Methods: Participants with a copy number variant or single nucleotide variant (5-19 years) were recruited via UK National Health Service. 1904 caregivers competed an online assessment of child mental health and reported on their own psychological wellbeing. We used regression to examine the association between IDD with and without co-occurring ASD, and co-occurring mental health difficulties, as well as with parental psychological distress. We adjusted for children's sex, developmental level, physical health, and socio-economic deprivation. Results: Of the 1904 participants with IDD, 701 (36.8%) had co-occurring ASD. Children with both IDD and ASD were at higher risk of associated disorders than those with IDD alone (ADHD: OR = 1.84, 95% confidence interval [CI] 1.46-2.32, p < 0.0001; emotional disorders: OR = 1.85, 95%CI 1.36-2.5, p < 0.0001; disruptive behaviour disorders: OR = 1.79, 95%CI 1.36-2.37, p < 0.0001). The severity of associated symptoms was also greater in those with ASD (hyperactivity: B = 0.25, 95%CI 0.07-0.34, p = 0.006; emotional difficulties: B = 0.91, 95%CI 0.67 to 1.14, p < 0.0001; conduct problems: B = 0.25, 95%CI 0.05 to 0.46, p = 0.013). Parents of children with IDD and ASD also reported greater psychological distress than those with IDD alone (ß = 0.1, 95% CI 0.85 to 2.21, p < 0.0001). Specifically, in those with ASD, symptoms of hyperactivity (ß = 0.13, 95% CI 0.29-0.63, p < 0.0001), emotional difficulties (ß = 0.15, 95% CI 0.26-0.51, p < 0.0001) and conduct difficulties (ß = 0.07, 95% CI 0.07-0.37, p < 0.004) all significantly contributed to parental psychological distress. Conclusions: Among children with IDD of genetic aetiology, one third have co-occurring ASD. Not only do those with co-occurring ASD present with a wider range of associated mental health disorders and more severe mental health difficulties than those with IDD alone, but their parents also experience more psychological distress. Our findings suggest that the additional mental health and behavioural symptoms in those with ASD contributed to the degree of parental psychological distress.

Inhibition of SC4MOL and HSD17B7 shifts cellular sterol composition and promotes oligodendrocyte formation.

While the cholesterol biosynthesis pathway has been extensively studied, recent work has forged new links between inhibition of specific sterol pathway enzymes, accumulation of their unique sterol substrates, and biological areas as diverse as cancer, immunology, and neurodegenerative disease. We recently reported that dozens of small molecules enhance formation of oligodendrocytes, a glial cell type lost in multiple sclerosis, by inhibiting CYP51, Sterol 14-reductase, or EBP and inducing cellular accumulation of their 8,9-unsaturated sterol substrates. Several adjacent pathway enzymes also have 8,9-unsaturated sterol substrates but have not yet been evaluated as potential targets for oligodendrocyte formation or in many other biological contexts, in part due to a lack of available small-molecule probes. Here, we show that genetic suppression of SC4MOL or HSD17B7 increases the formation of oligodendrocytes. Additionally, we have identified and optimized multiple potent new series of SC4MOL and HSD17B7 inhibitors and shown that these small molecules enhance oligodendrocyte formation. SC4MOL inhibitor CW4142 induced accumulation of SC4MOL's sterol substrates in mouse brain and represents an in vivo probe of SC4MOL activity. Mechanistically, the cellular accumulation of these 8,9-unsaturated sterols represents a central driver of enhanced oligodendrocyte formation, as exogenous addition of purified SC4MOL and HSD17B7 substrates but not their 8,9-saturated analogs promotes OPC differentiation. Our work validates SC4MOL and HSD17B7 as novel targets for promoting oligodendrocyte formation, underlines a broad role for 8,9-unsaturated sterols as enhancers of oligodendrocyte formation, and establishes the first high-quality small molecules targeting SC4MOL and HSD17B7 as novel tools for probing diverse areas of biology.