Hif1α and Wnt are required for posterior gene expression during Xenopus tropicalis tail regeneration.

Regeneration of complex tissues is initiated by an injury-induced stress response, eventually leading to activation of developmental signaling pathways such as Wnt signaling. How early injury cues are interpreted and coupled to activation of these developmental signals and their targets is not well understood. Here, we show that Hif1α, a stress induced transcription factor, is required for tail regeneration in Xenopus tropicalis. We find that Hif1α is required for regeneration of differentiated axial tissues, including axons and muscle. Using RNA-sequencing, we find that Hif1α and Wnt converge on a broad set of genes required for posterior specification and differentiation, including the posterior hox genes. We further show that Hif1α is required for transcription via a Wnt-responsive element, a function that is conserved in both regeneration and early neural patterning. Our findings indicate that Hif1α has regulatory roles in Wnt target gene expression across multiple tissue contexts.

Is Contrast-Enhanced Computed Tomography Redundant for Suspected Intracranial Infection in the Emergency Setting?

OBJECTIVE: There are currently no guidelines for when to use intravenous contrast with head computed tomography (CT) when there is suspected acute intracranial infection. The purpose of our study was to determine the proportion of cases with enhancing findings on CT that also have conspicuous correlating associated findings on noncontrast CT, which would have on their own merited further evaluation with magnetic resonance imaging, the criterion standard for evaluating central nervous system pathology. METHODS: A retrospective keyword search of the history and clinical information fields in radiology reports for CT examinations of the head without and with contrast from the period January 1, 2004, to October 31, 2021 was performed. Patients with prior head surgery or a history of cancer were excluded. For remaining patients, the noncontrast CT was reviewed for vasogenic edema or mass effect as markers of a possible acute infection, and the presence of background hypodense white matter changes was noted and graded as either absent, mild/scattered, or confluent. Subsequently, the companion contrast-enhanced CT was reviewed for an enhancing abnormality. Chart review was performed to confirm that an infectious process was the ultimate clinical diagnosis in patients with enhancing abnormalities. RESULTS: Of 343 patients meeting study inclusion/exclusion criteria, 39 had acute infections with an enhancing abnormality on CT (prevalence 11.3%). Thirty-two of these 39 patients also had correlative findings on the noncontrast CT. Noncontrast CT had a positive predictive value of 100%, negative predictive value of 97.7%, sensitivity of 82.1%, specificity of 100%, and accuracy of 98.0% for detecting markers (vasogenic edema and/or mass effect) associated with an enhancing abnormality. Vasogenic edema was the most common noncontrast CT finding in patients who had an infectious enhancing lesion (32 of 39), followed by mass effect (22 of 39). The 7 cases where the acute infection was occult on noncontrast CT were due to leptomeningitis (n = 3), confluent background white matter changes masking the vasogenic edema surrounding intra-axial lesions (n = 3), and a small 0.5 cm extra-axial abscess. CONCLUSIONS: Most acute intracranial infections with an enhancing CT finding also have a correlative conspicuous noncontrast finding that on its own would merit further evaluation with magnetic resonance imaging, the criterion standard for investigating central nervous system disease, and therefore, in the setting of suspected intracranial infection, contrast-enhanced CT is redundant in most cases. Contrast-enhanced CT primarily provides diagnostic benefit in patients with confluent background white matter changes that may mask vasogenic edema on noncontrast CT.

Can Anterior Osteophyte Fractures Be Distinguished From Fracture Mimics in the Subaxial Cervical Spine? A Retrospective Analysis Evaluating Reported Fractures With Clinical Management Correlation.

OBJECTIVE: This study aimed to retrospectively distinguish true- from false-positive fractures of anterior subaxial cervical osteophytes, which were reported on noncontrast computed tomography reports, and to correlate the imaging findings with patient symptoms and analyze the downstream impact on management of both true and false positive fractures. METHODS: A total of 127 patients had computed tomography reports of anterior osteophyte fractures. Radiology reports and imaging studies were evaluated to distinguish true fractures from fracture mimics. We analyzed imaging features including rigid spine (RS), prevertebral soft tissue swelling (PVSTS), and instability. We categorized symptoms and examination findings into 3 groups (0, asymptomatic; 1, neck pain; 2, neurological symptoms). Management was categorized into 3 groups (0, no treatment; 1, external bracing; 2, surgery). Associations between imaging features, fracture classification, clinical symptoms, magnetic resonance imaging utilization, and management were calculated using χ2 with Cramer V test to determine effect size. RESULTS: Eighty patients had false-positive fractures, and 47 were true positive. There were significant associations between magnetic resonance imaging utilization and fracture classification (P ≤ 0.001), PVSTS (P ≤ 0.005), patient symptoms (P ≤ 0.001), and patient management (P ≤ 0.001). There were significant associations between patient management and fracture classification (P ≤ 0.001), patient symptoms (P ≤ 0.001), PVSTS (P ≤ 0.001), imaging findings of instability (P ≤ 0.001), and RS (P ≤ 0.021). There were significant associations between fracture classification and patient symptoms (P ≤ 0.045), and RS (P ≤ 0.006). CONCLUSIONS: Subaxial isolated anterior osteophyte fractures fell into 3 major categories. By our methodology, if a suspected fracture was determined to be a fracture mimic in an asymptomatic patient, it was unlikely to be clinically significant. Isolated anterior osteophyte fractures without neurological symptoms or more concerning imaging findings can be treated conservatively. Finally, fractures that demonstrate indirect signs of instability or are associated with RS are more associated with surgical management.

Nutrient availability contributes to a graded refractory period for regeneration in Xenopus tropicalis.

Xenopus tadpoles are a unique model for regeneration in that they exhibit two distinct phases of age-specific regenerative competence. In Xenopus laevis, young tadpoles fully regenerate following major injuries such as tail transection, then transiently lose regenerative competence during the "refractory period" from stages 45-47. Regenerative competence is then regained in older tadpoles before being permanently lost during metamorphosis. Here we show that a similar refractory period exists in X. tropicalis. Notably, tadpoles lose regenerative competence gradually in X. tropicalis, with full regenerative competence lost at stage 47. We find that the refractory period coincides closely with depletion of maternal yolk stores and the onset of independent feeding, and so we hypothesized that it might be caused in part by nutrient stress. In support of this hypothesis, we find that cell proliferation declines throughout the tail as the refractory period approaches. When we block nutrient mobilization by inhibiting mTOR signaling, we find that tadpole growth and regeneration are reduced, while yolk stores persist. Finally, we are able to restore regenerative competence and cell proliferation during the refractory period by abundantly feeding tadpoles. Our study argues that nutrient stress contributes to lack of regenerative competence and introduces the X. tropicalis refractory period as a valuable new model for interrogating how metabolic constraints inform regeneration.

Gradient expectations: Revisiting Charles Manning Child's theory of metabolic regionalisation in developmental patterning and regeneration.

Charles Manning Child introduced one of several early models to explain how an organism can both establish and re-establish positional identity during embryogenesis and regeneration. In his gradient theory model, tissues along an axis exhibit graded levels of metabolic activity demonstrated through their differential susceptibility to metabolic inhibitors. While Child's work was difficult to place in a mechanistic framework in his own time, technological advances and recent discoveries in both embryos and regenerating organisms make his early work on redox signalling as a positional cue newly pertinent.

Chromatin accessibility analysis reveals distinct functions for HDAC and EZH2 activities in early appendage regeneration.

Xenopus tropicalis tadpoles have the capacity for scarless regeneration of appendages including the limb and tail. Following injury, transcriptional programs must be activated and inactivated with high spatial and temporal resolution to result in a properly patterned appendage. Functional studies have established that histone-modifying enzymes that act to close chromatin are required for regeneration, but the genomic regions sensitive to these activities are not fully established. Here we show that early inhibition of HDAC or EZH2 activity results in incomplete tail regeneration. To identify how each of these perturbations impacts chromatin accessibility, we applied an assay for transposase-accessible chromatin (ATAC-seq) to HDAC or EZH2-inhibited regenerating tadpoles. We find that neither perturbation results in a global increase in chromatin accessibility, but that both inhibitors have targeted effects on chromatin accessibility and gene expression. Upon HDAC inhibition, regulatory regions neighbouring genes associated with neuronal regeneration are preferentially accessible, whereas regions associated with immune response and apoptosis are preferentially accessible following EZH2 inhibition. Together, these results suggest distinct roles for these two chromatin-closing activities in appendage regeneration.

The incidence of brainstem toxicity following high-dose conformal proton therapy for adult skull-base malignancies.

BACKGROUND: Dose escalation for skull-based malignancies often presents risks to critical adjacent neural structures, including the brainstem. We report the incidence of brainstem toxicity following fractionated high-dose conformal proton therapy and associated dosimetric parameters. MATERIAL AND METHODS: We performed a single-institution review of patients with skull-base chordoma or chondrosarcoma who were treated with proton therapy between February 2007 and January 2020 on a prospective outcomes-tracking protocol. The primary endpoint was grade ≥2 brainstem toxicity. No patients received concurrent chemotherapy, and brainstem toxicity was censored for analysis if it coincided with local disease progression. RESULTS: We analyzed 163 patients who received a minimum of 45 GyRBE to 0.03 cm3 of the brainstem. Patients were treated to a median total dose of 73.8 (range 64.5-74.4) GyRBE at 1.8 GyRBE per fraction with 17 patients undergoing twice-daily treatment at 1.2 GyRBE per fraction. With a median follow-up of 4 years, the 5-year cumulative incidence of grade ≥2 brainstem injury was 1.3% (95% CI 0.25-4.3%). There was one grade 2, one grade 3, and no grade 4 or 5 events, with all patients recovering function with medical management. CONCLUSION: In delivering curative-intent radiotherapy for skull-base chordoma and chondrosarcoma in adults, small volumes of the brainstem can safely receive at least 64 GyRBE with minimal risk of serious brainstem injury.

Imaging of dental infections.

Dental infections are a common presentation in the emergency department (ED). To help guide clinical management for these infections, the radiologist must be familiar with the anatomy of the oral cavity and neighboring structures, the range of appearance of dental infections, and the routes along which they may spread. Computed tomography (CT) is often performed when severe dental infections are suspected. This pictorial essay reviews the anatomy pertinent to the imaging evaluation of dental infections and depicts a spectrum of pathology that may be encountered, ranging from simple dentoalveolar infections to complex multispatial infections.

IgG4-Related Disease: A Clinical Case Series From a Tertiary Care Center in India.

AIM: Immunoglobulin G4-related disease (IgG4-RD) is often an unrecognized, rare fibroinflammatory condition that can involve various organ systems. This study aimed to identify the different clinical patterns of this disease in a single center in North India. METHODS: Patients were diagnosed on the basis of published diagnostic criteria for IgG4-RD. Patients' presenting complaints; epidemiologic profiles; and laboratory, radiologic, and histologic findings along with the treatment and outcomes were collected and analyzed. RESULTS: In total, 70 patients were diagnosed with the disease. The female-to-male ratio was 0.94:1, and it increased with multiorgan involvement. The mean age of patients was 41.4 years, and the majority of the patients (65.7%) were younger than 50 years. Patients were diagnosed as possible (38.57%), probable (32.85%), and definite (28.57%) IgG4-RD. The incidence of the involvement of orbital and periorbital tissues was the highest (52.9%); however, 13% of the patients had multiple organ involvement. Patients with involvement of the retroperitoneal tissues and the lymph nodes were 8.5% and 5.7%, respectively. Increased serum IgG4 levels were found in 74.3% of the patients with single-organ involvement, whereas all patients with multiorgan involvement had increased IgG4 levels. The majority of patients (94.3%) required immunosuppressive medications along with corticosteroids. Azathioprine was the most commonly used (72.8%) immunosuppressive medication. Rituximab was used in 17.1% of the patients, of whom only one had multisystem involvement. CONCLUSIONS: This study depicts the most common patterns of organ involvement, along with the epidemiologic, laboratory, histologic, and radiologic data and response to treatment, in IgG4-RD, with a definite ophthalmology referral bias.

Pediatric Retroclival Epidural Hematoma in the Acute Trauma Setting: A Sign of Tectorial Membrane Stripping Injury.

OBJECTIVE. A traumatic retroclival epidural hematoma is a rare imaging finding of severe cervical flexion-extension injury in the pediatric population. The purpose of our study was to identify pediatric patients with a retroclival epidural hematoma, record the hematoma size and extent, and examine the major craniocervical ligaments for injury. MATERIALS AND METHODS. Pediatric patients who suffered a retroclival epidural hematoma were identified retrospectively using the keywords "clivus," "epidural hematoma," and "retroclival" included in head CT reports between 2012 and 2019. The cervical and brain MRI examinations for these patients were reviewed for craniocervical ligament injury by two certified neuroradiologists. Detailed descriptions of patient injuries were recorded along with demographic information, clinical history, patient management, and outcome. RESULTS. Eleven pediatric patients were identified with an acute posttraumatic retroclival epidural hematoma with a mean anteroposterior dimension of 4.4 mm and craniocaudal dimension of 4.3 cm. All patients with a retroclival epidural hematoma who underwent subsequent cervical MRI had a stripping injury of the tectorial membrane (TM). Disruption of additional major craniocervical ligaments on MRI (alar ligament, transverse ligament, longitudinal ligaments, and ligamentum flavum) was relatively rare with the most common associated ligamentous injuries involving the anterior atlantooccipital membrane, apical ligament, and interspinous ligaments. None of the patients suffered a cervical cord or severe intracranial injury. The majority of the patients were managed conservatively with excellent clinical outcomes. CONCLUSION. A posttraumatic retroclival epidural hematoma in the pediatric population is a rare injury often identified initially by head CT and easily overlooked by the radiologist. We propose that a retroclival epidural hematoma in the pediatric population is a direct result of a significant flexion-extension force, with a subsequent stripping injury of the TM from the posterior clivus. Pediatric patients with a posttraumatic retroclival epidural hematoma on initial head CT should undergo a cervical MRI to evaluate the integrity of the TM and other craniocervical ligaments.

"Supradental space sign" on cervical spine CT-a sign of tectorial membrane injury in adults trauma patients.

BACKGROUND AND PURPOSE: The supradental space is a small, predominantly fat-filled recess superior to the atlanto-axial joint and inferior to the basion of the clivus that contains a small venous plexus. The posterior boundary of the supradental space is formed by the tectorial membrane, a stabilizing ligament of the craniocervical junction. The purpose of our study was to examine the imaging appearance of the supradental space in patients with tectorial membrane injury. MATERIALS AND METHODS: Adult patients with tectorial membrane injury were identified utilizing keyword searches of radiology reports using Nuance mPower software. Age-matched positive and negative control groups were obtained. Two CAQ-certified neuroradiologists evaluated the cervical CT exams of these patients for supradental fat pad effacement from hematoma formation. The integrity of the osteoligamentous structures of the craniocervical junction was recorded on CT and MRI exams along with demographic information, clinical history, surgical management, and global outcome. Statistical analysis was performed. RESULTS: Sixteen adults were diagnosed with tectorial membrane injury on cervical MRI. All patients with a visible supradental space demonstrated fat pad effacement and Hounsfield units consistent with hematoma formation. The positive and negative control groups demonstrated supradental fat pad effacement in 2/16 and 1/16 patients, respectively. A p-value of < 0.001 was obtained. CONCLUSION: The "supradental space sign," defined as hematoma formation in the supradental space with effacement of the supradental fat pad is associated with tectorial membrane injury in adult trauma patients with sensitivity of 93.75% (95% confidence interval 69.77 to 99.84%) and specificity of 90.62% (95% confidence interval 74.98 to 98.02%).

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development.

Oral epithelia protect against constant challenges by bacteria, viruses, toxins and injury while also contributing to the formation of ectodermal appendages such as teeth, salivary glands and lingual papillae. Despite increasing evidence that differentiation pathway genes are frequently mutated in oral cancers, comparatively little is known about the mechanisms that regulate normal oral epithelial development. Here, we characterize oral epithelial stratification and describe multiple distinct functions for the mitotic spindle orientation gene LGN (Gpsm2) in promoting differentiation and tissue patterning in the mouse oral cavity. Similar to its function in epidermis, apically localized LGN directs perpendicular divisions that promote stratification of the palatal, buccogingival and ventral tongue epithelia. Surprisingly, however, in dorsal tongue LGN is predominantly localized basally, circumferentially or bilaterally and promotes planar divisions. Loss of LGN disrupts the organization and morphogenesis of filiform papillae but appears to be dispensable for embryonic hair follicle development. Thus, LGN has crucial tissue-specific functions in patterning surface ectoderm and its appendages by controlling division orientation.

Cogan syndrome: An autoimmune eye and ear disease with systemic manifestations.

Cogan syndrome (CS) is a rare vasculitis seen primarily in young adults. It predominantly affects eyes, ears and the heart with characteristic findings of interstitial keratitis, sensorineural hearing loss and vestibular dysfunction. A high index of suspicion is required to diagnose this rare disorder. It is one of the few vasculitis which can involve vessels of all sizes: small, medium and large. Coexistence of inflammatory bowel disease (IBD) in Cogan syndrome has been described in the literature. Immunosuppressive agents such as corticosteroids with or without steroid sparing agents are the standard of care. Early diagnosis and treatment are the cornerstone of treatment to prevent permanent damage to the ears and eyes. We describe a patient with Cogan syndrome with large vessel vasculitis and IBD. Our patient was treated with glucocorticoids and methotrexate.

Repeatability of diagnostic features and scoring systems for hepatocellular carcinoma by using MR imaging.

PURPOSE: To determine for expert and novice radiologists repeatability of major diagnostic features and scoring systems (ie, Liver Imaging Reporting and Data System [LI-RADS], Organ Procurement and Transplantation Network [OPTN], and American Association for the Study of Liver Diseases [AASLD]) for hepatocellular carcinoma (HCC) by using magnetic resonance (MR) imaging. MATERIALS AND METHODS: Institutional review board approval was obtained and patient consent was waived for this HIPAA-compliant, retrospective study. The LI-RADS discussed in this article refers to version 2013.1. Ten blinded readers reviewed 100 liver MR imaging studies that demonstrated observations preliminarily assigned LI-RADS scores of LR1-LR5. Diameter and major HCC features (arterial hyperenhancement, washout appearance, pseudocapsule) were recorded for each observation. LI-RADS, OPTN, and AASLD scores were assigned. Interreader agreement was assessed by using intraclass correlation coefficients and κ statistics. Scoring rates were compared by using McNemar test. RESULTS: Overall interreader agreement was substantial for arterial hyperenhancement (0.67 [95% confidence interval {CI}: 0.65, 0.69]), moderate for washout appearance (0.48 [95%CI: 0.46, 0.50]), moderate for pseudocapsule (0.52 [95% CI: 050, 0.54]), fair for LI-RADS (0.35 [95% CI: 0.34, 0.37]), fair for AASLD (0.39 [95% CI: 0.37, 0.42]), and moderate for OPTN (0.53 [95% CI: 0.51, 0.56]). Agreement for measured diameter was almost perfect (range, 0.95-0.97). There was substantial agreement for most scores consistent with HCC. Experts agreed significantly more than did novices and were significantly more likely than were novices to assign a diagnosis of HCC (P < .001). CONCLUSION: Two of three major features for HCC (washout appearance and pseudocapsule) have only moderate interreader agreement. Experts and novices who assigned scores consistent with HCC had substantial but not perfect agreement. Expert agreement is substantial for OPTN, but moderate for LI-RADS and AASLD. Novices were less consistent and less likely to diagnose HCC than were experts.

In vivo predictors of renal cyst pseudoenhancement at 120 kVp.

OBJECTIVE: The purpose of this article is to assess the effects of various CT, patient, and renal cyst characteristics on the occurrence of pseudoenhancement in in vivo renal mass CT examinations using subtraction MRI as the reference standard. MATERIALS AND METHODS: Adult patients imaged with 120-kVp standard kernel biphasic renal mass protocol CT and dynamic contrast-enhanced MRI of the abdomen from January 1, 2005, through May 4, 2012, were identified. Those with nonenhancing Bosniak categories I and II cysts on MRI were selected (n = 33 patients; 110 cysts). By treating measured cyst enhancement (nephrographic CT attenuation minus unenhanced CT attenuation) as either a continuous or categoric outcome variable, a variety of CT, patient-level, and renal cyst characteristics were assessed using mixed effect multivariate models. RESULTS: On univariate assessment, cysts that exhibited pseudoenhancement (> 10 HU) were significantly more endophytic (p = 0.02), significantly smaller (p = 0.0004), and adjacent to significantly higher attenuation renal parenchyma in the nephrographic phase (p = 0.02). On multivariate assessment, cyst diameter (p < 0.0001) and background nephrographic phase parenchymal attenuation (p = 0.003) were the strongest in vivo predictors of pseudoenhancement. The odds of pseudoenhancement occurring increased by 2.14 (95% CI, 1.41-3.23) for every 5-mm decrease in renal cyst diameter and increased by 2.45 (95% CI, 1.41-4.26) for every 25-HU increase in enhanced renal parenchymal attenuation. Endophytic growth was not significant in the multivariate analyses (p = 0.07). CONCLUSION: Renal cyst size and enhanced renal parenchymal attenuation are better in vivo predictors of pseudoenhancement than is endophytic growth pattern.

Imaging of congenital anomalies and defects of the skull base and calvarium.

Congenital anomalies and defects of the skull base and calvarium encompass a broad and complex spectrum of pathologies. The clinical presentation is highly variable, and these anomalies may be discovered incidentally in asymptomatic individuals. Radiological assessment plays a pivotal role in precisely characterizing these abnormalities, facilitating the diagnostic process, and assisting in any preoperative preparation.

Endovascular Mechanical Thrombectomy for Ischemic Stroke Treatment in the Setting of Aortic Dissection: Case Report.

Introduction: Acute ischemic stroke can occur in the setting of aortic dissection. Information concerning the utility of endovascular mechanical thrombectomy as an intervention for patients with aortic dissection who are experiencing an acute stroke due to large vessel occlusion is limited to a few case reports. Case series of patients presenting with this clinical situation are needed to further investigate the potential utility of this procedure when patients with acute ischemic stroke and aortic dissection are encountered. Case Presentation: We report a patient with a chronic Stanford type A aortic dissection with dissection extension into the left common carotid artery and left internal carotid artery who had a good clinical outcome following mechanical thrombectomy for a symptomatic middle cerebral artery occlusion. We also review other cases in which endovascular mechanical thrombectomy was conducted in patients with aortic dissection and acute ischemic stroke and discuss the potential risks and benefits of carotid artery stenting in this clinical situation. Conclusion: The rate of successful arterial recanalization in patients with aortic dissection, large vessel occlusion, and acute ischemic stroke treated with mechanical thrombectomy is high. The intervention has been associated with good neurological outcomes and a low rate of procedure-related complications. Additional case series are needed to help discern if our observations are present in a broader array of patients in order to identify which patients are most likely to benefit from mechanical thrombectomy.

Protocol for tail vein injection in Xenopus tropicalis tadpoles.

Functional studies in post-embryonic Xenopus tadpoles are challenging because embryonic perturbations often lead to developmental consequences, such as lethality. Here, we describe a high-throughput protocol for tail vein injection to introduce fluorescent tracers into tadpoles, which we have previously used to effectively inject morpholinos and molecular antagonists. We describe steps for safely positioning tadpoles onto agarose double-coated plates, draining media, injecting into the ventral tail vein, rehydrating plates, and sorting tadpoles by fluorescence with minimal injury for high-throughput experiments. For complete details on the use and execution of this protocol, please refer to Kakebeen et al.,1 Patel et al.,2 and Patel et al.3.

Identification of Fasnall as a therapeutically effective Complex I inhibitor.

Proliferating cancer cells actively utilize anabolic processes for biomass production, including de novo biosynthesis of amino acids, nucleotides, and fatty acids. The key enzyme of the fatty acid biosynthesis pathway, fatty acid synthase (FASN), is widely recognized as a promising therapeutic target in cancer and other health conditions1,2. Here, we establish a metabolic signature of FASN inhibition using a panel of pharmacological inhibitors (GSK2194069, TVB-2640, TVB-3166, C75, cerulenin, and Fasnall). We find that the activity of commonly used FASN inhibitors is inconsistent with the metabolic signature of FASN inhibition (accumulation of malonate, succinate, malonyl coenzyme A, succinyl coenzyme A, and other metabolic perturbations). Moreover, we show that one of these putative FASN inhibitors, Fasnall, is a respiratory Complex I inhibitor that mimics FASN inhibition through NADH accumulation and consequent depletion of the tricarboxylic acid cycle metabolites. We demonstrate that Fasnall impairs tumor growth in several oxidative phosphorylation-dependent cancer models, including combination therapy-resistant melanoma patient-derived xenografts. Fasnall administration does not reproduce neurological side effects in mice reported for other Complex I inhibitors3,4. Our results have significant implications for understanding the FASN role in human health and disease and provide evidence of therapeutic potential for Complex I inhibitors with fast systemic clearance. Our findings also highlight the continuing need for validation of small molecule inhibitors to distinguish high-quality chemical probes and to expand the understanding of their application.