Replay Comes of Age.

Hippocampal place cells take part in sequenced patterns of reactivation after behavioral experience, known as replay. Since replay was first reported, nearly 20 years ago, many new results have been found, necessitating revision of the original interpretations. We review some of these results with a focus on the phenomenology of replay.

Pharmacokinetic-pharmacodynamic modelling and simulation of methotrexate dosing in patients with rheumatoid arthritis.

AIMS: To develop a non-linear mixed-effects population pharmacokinetic and pharmacodynamic (PK-PD) model describing the change in the concentration of methotrexate polyglutamates in erythrocytes (ery-MTX-PGn with "n" number of glutamate, representing PK component) and how this relates to modified 28-joint Disease Activity Score incorporating erythrocyte sedimentation rate (DAS-28-3) for rheumatoid arthritis (RA), representing PD component. METHODS: An existing PK model was fitted to data from a study consisting of 117 RA patients. The estimation of population PK-PD parameters was performed using stochastic approximation expectation maximisation algorithm in Monolix 2021R2. The model was used to perform Monte Carlo simulations of a loading dose regimen (50mg subcutaneous methotrexate as loading doses, then 20mg weekly oral methotrexate) compared to a standard dosing regimen (10mg weekly oral methotrexate for 2 weeks, then 20mg weekly oral methotrexate). RESULTS: Every 40 nmol/L increase in ery-MTX-PG3-5 total concentration correlated with 1-unit reduction in DAS-28-3. Significant covariate effects on the therapeutic response of methotrexate included the use of prednisolone in the first 4 weeks (positive use correlated with 25% reduction in DAS-28-3 when other variables were constant) and patient age (every 10-year increase in age correlated with 3.4% increase in DAS-28-3 when other variables were constant). 4 methotrexate loading doses led to a higher percentage of patients achieving a good/moderate response compared to the standard regimen (Week 4: 87.6% vs. 39.8%; Week 10: 64.7% vs. 57.0%). CONCLUSIONS: A loading dose regimen was more likely to achieve higher ery-MTX-PG concentration and better therapeutic response after 4 weeks of methotrexate treatment.

Where does the carbon go? Long-term effects of forest management on the carbon budget of a temperate-forest water-supply watershed.

While forest management commonly seeks to increase carbon (C) capture and sequestration, in some settings, a high density of C storage may be detrimental to other land uses and ecosystem services. We study a forested, drinking-water-supply watershed to determine the effects of forest management on C storage with the implicit understanding that greater storage of C will lead to increased quantity of carbon exported hydrologically into a source-water reservoir. Using a custom implementation of CBM-CFS3, a Canadian model to simulate C transformations and movement in forested systems, and a custom forest disturbance and management model, we simulate various management scenarios and their C outcomes. The largest forest C pool, mineral soils, is very slow to change and manipulating DOC export through this pool would likely not be feasible within human management timescales. Other pools, in which C has lower residence time and from which C is more readily mobilized, are a more promising area for future research into hydrologic DOC export under varying management regimes. Our findings indicate that management activities can serve to reduce forest C storage, but further research is required to connect these outcomes to hydrologic export.

Misidentifying illuminant changes in natural scenes due to failures in relational colour constancy.

The colours of surfaces in a scene may not appear constant with a change in the colour of the illumination. Yet even when colour constancy fails, human observers can usually discriminate changes in lighting from changes in surface reflecting properties. This operational ability has been attributed to the constancy of perceived colour relations between surfaces under illuminant changes, in turn based on approximately invariant spatial ratios of cone photoreceptor excitations. Natural deviations in these ratios may, however, lead to illuminant changes being misidentified. The aim of this work was to test whether such misidentifications occur with natural scenes and whether they are due to failures in relational colour constancy. Pairs of scene images from hyperspectral data were presented side-by-side on a computer-controlled display. On one side, the scene underwent illuminant changes and on the other side, it underwent the same changes but with images corrected for any residual deviations in spatial ratios. Observers systematically misidentified the corrected images as being due to illuminant changes. The frequency of errors increased with the size of the deviations, which were closely correlated with the estimated failures in relational colour constancy.

Core outcome domains for lichen sclerosus: a CORALS initiative consensus statement.

BACKGROUND: Lichen sclerosus (LS) is a chronic inflammatory condition mainly affecting genital skin. It causes distressing symptoms that impact daily quality of life (QoL). It causes progressive anatomical changes and a potential risk of cancer. Published randomized controlled trials are of varying methodological quality and difficult to combine in meta-analyses. This is partly due to lack of agreed outcome measures to assess treatment response. Identification of core outcome sets (COSs), which standardize key outcomes to be measured in all future trials, is a solution to this problem. OBJECTIVES: To obtain international agreement on which outcome domains should be measured in interventional trials of genital LS. METHODS: Recommended best practice for COS domain development was followed: (i) identification of potential outcome domains: a long list was generated through an up-to-date LS literature search, including information collected during the LS priority-setting partnership; (ii) provisional agreement of outcome domains: a three-stage multi-stakeholder international electronic-Delphi (e-Delphi) consensus study; (iii) final agreement of outcome domains: online consensus meeting with international stakeholders including anonymized voting. RESULTS: In total, 123 participants (77 patients, 44 health professionals, 2 researchers) from 20 countries completed three rounds of the e-Delphi study. Eleven outcome domains were rated as 'critical' and were discussed at the online consensus meetings. The first set of consensus meetings involved 42 participants from 12 countries. Consensus was met for 'symptoms' (100% agreed) and 'QoL - LS-specific' (92% agreed). After the second set of meetings, involving 29 participants from 12 countries, 'clinical (visible) signs' also met consensus (97% agreed). CONCLUSIONS: The international community has agreed on three key outcome domains to measure in all future LS clinical trials. We recommend that trialists and systematic reviewers incorporate these domains into study protocols with immediate effect. CORALS will now work with stakeholders to select an outcome measurement instrument per prioritized core domain.

Prefrontal cortical neurons are selective for non-local hippocampal representations during replay and behavior.

Diverse functions such as decision-making and memory consolidation may depend upon communication between neurons in hippocampus (HP) and prefrontal cortex (PFC). HP replay is a candidate mechanism to facilitate this communication, however details remain largely unknown due to the technical challenges of recording sufficient numbers of HP neurons for replay while also recording PFC neurons. Here we implanted male rats with 40-tetrode drives, split between HP and PFC, during learning of a Y-maze spatial memory task. Surprisingly, we found that in contrast to their non-selectivity for maze arm during movement, a portion of PFC neurons were highly selective for HP replay of different arms. Moreover, PFC neurons' selectivity to HP non-local arm representation during running tended to match their replay arm selectivity and was predictive of future choice. Thus, PFC activity that is tuned to HP activity is best explained by non-local HP position representations rather than HP representation of actual position, providing a new potential mechanism of HP-PFC coordination during HP replay.SIGNIFICANCE STATEMENTThe hippocampus is implicated in spatial learning while the prefrontal cortex is implicated in decision-making. The question of how the two areas interact has been of great interest. A specific activity type in hippocampus called replay is particularly interesting because it resembles internal exploration of non-local experiences, but is technically challenging to study, requiring recordings from large numbers of hippocampus neurons simultaneously. Here we combined replay recordings from hippocampus with prefrontal recordings, to reveal a surprising degree of selectivity for replay, and a pattern of coordination that supports some conceptions of hippocampocortical interaction and challenges others.

Colour constancy failures expected in colourful environments.

Colour constancy refers to the constant perceived or apparent colour of a surface despite changes in illumination spectrum. Laboratory measurements have often found it imperfect. The aim here was to estimate the frequency of constancy failures in natural outdoor environments and relate them to colorimetric surface properties. A computational analysis was performed with 50 hyperspectral reflectance images of outdoor scenes undergoing simulated daylight changes. For a chromatically adapted observer, estimated colour appearance changed noticeably for at least 5% of the surface area in 60% of scenes, and at least 10% of the surface area in 44% of scenes. Somewhat higher frequencies were found for estimated changes in perceived colour relations represented by spatial ratios of cone-photoreceptor excitations. These estimated changes correlated with surface chroma and saturation. Outdoors, the colour constancy of some individual surfaces seems likely to fail, particularly if those surfaces are colourful.

Information gains from commercial spectral filters in anomalous trichromacy.

Red-green color discrimination is compromised in anomalous trichromacy, the most common inherited color vision deficiency. This computational analysis tested whether three commercial optical filters with medium-to-long-wavelength stop bands increased information about colored surfaces. The surfaces were sampled from 50 hyperspectral images of outdoor scenes. At best, potential gains in the effective number of surfaces discriminable solely by color reached 9% in protanomaly and 15% in deuteranomaly, much less than with normal trichromacy. Gains were still less with lower scene illumination and more severe color vision deficiency. Stop-band filters may offer little improvement in objective real-world color discrimination.

Population pharmacokinetic modelling of febuxostat in healthy subjects and people with gout.

AIMS: To investigate and characterise the pharmacokinetics of febuxostat and the effect of the covariates of renal function and body size descriptors on the pharmacokinetics of the drug. METHODS: Blood samples (n = 239) were collected using sparse and rich sampling strategies from healthy (n = 9) and gouty (n = 29) subjects. Febuxostat plasma concentrations were measured by a validated high-performance liquid chromatography method. Population pharmacokinetic analysis was performed using NONMEM. A common variability on bioavailability (FVAR) approach was used to test the effect of fed status on absorption parameters. Covariates were modelled using a power model. RESULTS: The time course of the plasma concentrations of febuxostat is best described by a two-compartment model. In the final model, the population mean for apparent clearance (CL/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption rate constant (ka) and apparent intercompartmental clearance (Q/F) were 6.91 l h-1 , 32.8 l, 19.4 l, 3.6 h-1 and 1.25 l h-1 , respectively. The population parmater variability (coefficient of variation) for CL/F, Vc/F and Vp/F were 13.6, 22 and 19.5%, respectively. Food reduced the relative biovailability and ka by 67% and 87%, respectively. Renal function, as assessed by creatinine clearance, was a significant covariate for CL/F while body mass index was a significant covariate for Vc/F. CONCLUSIONS: Renal function and body mass index were significant covariates. Further work is warranted to investigate the clinical relevance of these results, notably as renal impairment and obesity are common occurrences in people with gout.

First North American fossil monkey and early Miocene tropical biotic interchange.

New World monkeys (platyrrhines) are a diverse part of modern tropical ecosystems in North and South America, yet their early evolutionary history in the tropics is largely unknown. Molecular divergence estimates suggest that primates arrived in tropical Central America, the southern-most extent of the North American landmass, with several dispersals from South America starting with the emergence of the Isthmus of Panama 3-4 million years ago (Ma). The complete absence of primate fossils from Central America has, however, limited our understanding of their history in the New World. Here we present the first description of a fossil monkey recovered from the North American landmass, the oldest known crown platyrrhine, from a precisely dated 20.9-Ma layer in the Las Cascadas Formation in the Panama Canal Basin, Panama. This discovery suggests that family-level diversification of extant New World monkeys occurred in the tropics, with new divergence estimates for Cebidae between 22 and 25 Ma, and provides the oldest fossil evidence for mammalian interchange between South and North America. The timing is consistent with recent tectonic reconstructions of a relatively narrow Central American Seaway in the early Miocene epoch, coincident with over-water dispersals inferred for many other groups of animals and plants. Discovery of an early Miocene primate in Panama provides evidence for a circum-Caribbean tropical distribution of New World monkeys by this time, with ocean barriers not wholly restricting their northward movements, requiring a complex set of ecological factors to explain their absence in well-sampled similarly aged localities at higher latitudes of North America.

Predictable hydrological and ecological responses to Holocene North Atlantic variability.

Climate variations in the North Atlantic region can substantially impact surrounding continents. Notably, the Younger Dryas chronozone was named for the ecosystem effects of abrupt changes in the region at circa (ca.) 12.9-11.7 ka (millennia before 1950 AD). Holocene variations since then, however, have been hard to diagnose, and the responsiveness of terrestrial ecosystems continues to be debated. Here, we show that Holocene climate variations had spatial patterns consistent with changes in Atlantic overturning and repeatedly steepened the temperature gradient between Nova Scotia and Greenland since >8 ka. The multicentury changes correlated with hydrologic and vegetation changes in the northeast United States, including when an enhanced temperature gradient coincided with subregional droughts indicated by water-level changes at multiple coastal lakes at 4.9-4.6, 4.2-3.9, 2.8-2.1, and 1.3-1.2 ka. We assessed the variability and its effects by replicating signals across sites, using converging evidence from multiple methods, and applying forward models of the systems involved. We evaluated forest responses in the northeast United States and found that they tracked the regional climate shifts including the smallest magnitude (∼5% or 50 mm) changes in effective precipitation. Although a long-term increase in effective precipitation of >45% (>400 mm) could have prevented ecological communities from equilibrating to the continuously changing conditions, our comparisons confirm stable vegetation-climate relationships and support the use of fossil pollen records for quantitative paleoclimate reconstruction. Overall, the network of records indicates that centennial climate variability has repeatedly affected the North Atlantic region with predictable consequences.

Phosphatidic acid drives mTORC1 lysosomal translocation in the absence of amino acids.

Mammalian target of rapamycin complex 1 (mTORC1) promotes cell growth and proliferation in response to nutrients and growth factors. Amino acids induce lysosomal translocation of mTORC1 via the Rag GTPases. Growth factors activate Ras homolog enriched in brain (Rheb), which in turn activates mTORC1 at the lysosome. Amino acids and growth factors also induce the phospholipase D (PLD)-phosphatidic acid (PA) pathway, required for mTORC1 signaling through mechanisms that are not fully understood. Here, using human and murine cell lines, along with immunofluorescence, confocal microscopy, endocytosis, PLD activity, and cell viability assays, we show that exogenously supplied PA vesicles deliver mTORC1 to the lysosome in the absence of amino acids, Rag GTPases, growth factors, and Rheb. Of note, pharmacological or genetic inhibition of endogenous PLD prevented mTORC1 lysosomal translocation. We observed that precancerous cells with constitutive Rheb activation through loss of tuberous sclerosis complex subunit 2 (TSC2) exploit the PLD-PA pathway and thereby sustain mTORC1 activation at the lysosome in the absence of amino acids. Our findings indicate that sequential inputs from amino acids and growth factors trigger PA production required for mTORC1 translocation and activation at the lysosome.

Opioid prescribing and health outcomes in opioid-naive patients: Analysis of a statewide health information exchange.

BACKGROUND: Widespread use of prescription opioids is associated with adverse outcomes. OBJECTIVE: To identify factors associated with adverse health outcomes and health care use using a statewide health information exchange. METHODS: This is a retrospective cohort study using the Indiana Network for Patient Care. Adult opioid-naive patients who received an opioid prescription between January 2012 and December 2017 were included. The outcomes included (1) a composite outcome of any combination of opioid abuse, dependence, or overdose, (2) all-cause mortality, and (3) health care use. Independent variables included opioid dosage, dispensed amount, days supply, concurrent use of short-acting (SA) and long-acting (LA) opioids, and concurrent use with benzodiazepine or gabapentinoids. Additional variables included patients' age, sex, race, modified Charlson Comorbidity Index score, mental health conditions, and medications for opioid use disorders. Factors associated with composite outcome and mortality were identified using Cox proportional hazards and reported as adjusted hazard ratio (aHR) and 95% CI. Factors associated with health care use were identified using Poisson regression and reported as adjusted incidence rate ratio (aIRR) and 95% CI. RESULTS: 1,328,287 opioid prescriptions were identified for 341,722 patients. Opioid-related factors associated with the composite outcome, mortality, and hospitalizations, respectively, included opioid dosage (aHR 1.003 [95% CI 1.001-1.006]; aHR not applicable; aIRR 1.07 [1.06-1.08]), opioid days supply (aHR 1.03 [1.02-1.03]; aHR 1.009 [1.005-1.014]; aIRR 0.94 [0.92-0.96]), concurrent SA/LA opioids (aHR 2.12 [1.78-2.54]; aHR 1.40 [1.14-1.70]; aIRR 1.40 [1.37-1.42]), and use of benzodiazepines/gabapentinoids (aHR 1.68 [1.38-2.04]; aHR 1.23 [1.01-1.51]; aIRR 1.25 [1.23-1.27]). CONCLUSION: Many factors are associated with poor health outcomes, especially concurrent use of SA and LA opioids and overlapping prescriptions of opioids with benzodiazepines or gabapentinoids. Identification of factors associated with adverse outcomes may help identify patients at risk for poor outcomes and could inform possible interventions.

Adoption of Lean management and hospital performance: Results from a national survey.

BACKGROUND: Despite being adopted by a large number of hospitals, the relationship between Lean management and hospital performance is mixed and not well understood. PURPOSE: We examined the relationships between Lean and hospital financial performance, patient outcomes, and patient satisfaction in a large national sample of hospitals, controlling for relevant organizational and market factors. METHODOLOGY/APPROACH: A mixed effects linear regression analysis was performed to assess the relationships between adoption of Lean and 10 measures of hospital performance using data from 1,152 hospitals that responded to the 2017 National Survey of Lean/Transformational Performance Improvement in Hospitals. Hospital performance, organizational, and market data over the period 2011-2015 come from the 2015 American Hospital Association Annual Hospital Survey and the respective annual Centers for Medicare & Medicaid Services (CMS) Medicare Cost Report, CMS Hospital Compare, CMS MEDPAR, and the CMS Hospital Service Area File. RESULTS: Lean adoption was significantly associated at alpha < .05, with lower Medicare spending per beneficiary (b = -.005, p = .027). None of the other nine associations were statistically significant, although eight of them were in the predicted direction. CONCLUSION: Lean adoption is not associated with most measures of hospital performance. It is likely Lean implementation varies greatly across hospitals. Future research should examine the relationships among the various dimensions of Lean implementation and performance. PRACTICE IMPLICATIONS: If Lean management is to contribute to hospital performance improvement, leaders must be highly cognizant of what "adoption of Lean" actually means in their hospital. Although limited, single-unit Lean initiatives in an emergency room or other patient care unit may improve performance on some unit-specific measures, improvement on hospital-wide measures of performance requires a broad, sustained commitment to the implementation of Lean practices and tools.

Phospholipase D-dependent mTOR complex 1 (mTORC1) activation by glutamine.

Glutamine is a key nutrient required for sustaining cell proliferation, contributing to nucleotide, protein, and lipid synthesis. The mTOR complex 1 (mTORC1) is a highly conserved protein complex that acts as a sensor of nutrients, relaying signals for the shift from catabolic to anabolic metabolism. Although glutamine plays an important role in mTORC1 activation, the mechanism is not clear. Here we describe a leucine- and Rag-independent mechanism of mTORC1 activation by glutamine that depends on phospholipase D and the production of phosphatidic acid, which is required for the stability and activity of mTORC1. The phospholipase D-dependent activation of mTORC1 by glutamine depended on the GTPases ADP ribosylation factor 1 (Arf1), RalA, and Rheb. Glutamine deprivation could be rescued by α-ketoglutarate, a downstream metabolite of glutamine. This mechanism represents a distinct nutrient input to mTORC1 that is independent of Rag GTPases and leucine.

Effect of gabapentin on sexual function in vulvodynia: a randomized, placebo-controlled trial.

BACKGROUND: Sexual dysfunction is common in women with vulvodynia. OBJECTIVE: The purpose of this study was (1) to evaluate whether extended-release gabapentin is more effective than placebo in improving sexual function in women with provoked vulvodynia and whether there is a relationship between treatment outcome and pelvic pain muscle severity that is evaluated by palpation with standardized applied pressure and (2) to evaluate whether sexual function in women with provoked vulvodynia would approach that of control subjects who report no vulvar pain either before or after treatment. STUDY DESIGN: As a secondary outcome in a multicenter double-blind, randomized crossover trial, sexual function that was measured by the Female Sexual Function Index was evaluated with gabapentin (1200-3000 mg/d) compared with placebo. Pain-free control subjects, matched by age and race, also completed Female Sexual Function Index for comparison. RESULTS: From August 2012 to January 2016, 230 women were screened at 3 academic institutions, and 89 women were assigned randomly to treatment. Gabapentin was more effective than placebo in improving overall sexual function (adjusted mean difference, 1.3; 95% confidence interval, 0.4-2.2; P=.008), which included desire (mean difference, 0.2; 95% confidence interval, 0.0-3.3; P=.04), arousal (mean difference, 0.3; 95% confidence interval, 0.1-0.5; P=.004), and satisfaction (mean difference, 0.3; 95% confidence interval, 0.04-0.5; P=.02); however, sexual function remained significantly lower than in 56 matched vulvodynia pain-free control subjects. There was a moderate treatment effect among participants with baseline pelvic muscle pain severity scores above the median on the full Female Sexual Function Index scale (mean difference, 1.6; 95% confidence interval, 0.3-2.8; P=.02) and arousal (mean difference, 0.3; 95% confidence interval, 0.1-0.6; P=.01) and pain domains (mean difference, 0.4; 95% confidence interval, 0.02-0.9; P=.04). CONCLUSION: Gabapentin improved sexual function in this group of women with provoked vulvodynia, although overall sexual function remained lower than women without the disorder. The most statistically significant increase was in the arousal domain of the Female Sexual Function Index that suggested a central mechanism of response. Women with median algometer pain scores >5 improved sexual function overall, but the improvement was more frequent than the pain domain. We hypothesize that gabapentin may be effective as a pharmacologic treatment for those women with provoked vulvodynia and increased pelvic muscle pain on examination.

Population pharmacokinetics of lenalidomide in patients with B-cell malignancies.

AIMS: Lenalidomide is an immunomodulatory imide drug used broadly in the treatment of multiple myeloma and lymphoma. It continues to be evaluated in chronic lymphocytic leukaemia (CLL) at lower doses due to dose-related toxicities including tumour flare and tumour lysis syndrome. This study aimed to develop a population pharmacokinetic model for lenalidomide in multiple cancers, including CLL, to identify any disease-related differences in disposition. METHODS: Lenalidomide concentrations from 4 clinical trials were collated (1999 samples, 125 subjects), covering 4 cancers (multiple myeloma, CLL, acute myeloid leukaemia and acute lymphoblastic leukaemia) and a large dose range (2.5-75 mg). A population pharmacokinetic model was developed with NONMEM and patient demographics were tested as covariates. RESULTS: The data were best fitted by a 1-compartment kinetic model with absorption described by 7 transit compartments. Clearance and volume of distribution were allometrically scaled for fat-free mass. The population parameter estimates for apparent clearance, apparent volume of distribution and transit rate constant were 12 L/h (10.8-13.6), 68.8 L (61.8-76.3), and 13.5 h-1 (11.9-36.8) respectively. Patients with impaired renal function (creatinine clearance <30 mL/min) exhibited a 22% reduction in lenalidomide clearance compared to patients with creatinine clearance of 90 mL/min. Cancer type had no discernible effect on lenalidomide disposition. CONCLUSIONS: This is the first report of a lenalidomide population pharmacokinetic model to evaluate lenalidomide pharmacokinetics in patients with CLL and compare its pharmacokinetics with other B-cell malignancies. As no differences in pharmacokinetics were found between the observed cancer-types, the unique toxicities observed in CLL may be due to disease-specific pharmacodynamics.

Hippocampal place-cell sequences depict future paths to remembered goals.

Effective navigation requires planning extended routes to remembered goal locations. Hippocampal place cells have been proposed to have a role in navigational planning, but direct evidence has been lacking. Here we show that before goal-directed navigation in an open arena, the rat hippocampus generates brief sequences encoding spatial trajectories strongly biased to progress from the subject's current location to a known goal location. These sequences predict immediate future behaviour, even in cases in which the specific combination of start and goal locations is novel. These results indicate that hippocampal sequence events characterized previously in linearly constrained environments as 'replay' are also capable of supporting a goal-directed, trajectory-finding mechanism, which identifies important places and relevant behavioural paths, at specific times when memory retrieval is required, and in a manner that could be used to control subsequent navigational behaviour.

Hyperspectral imaging in color vision research: tutorial.

This tutorial offers an introduction to terrestrial and close-range hyperspectral imaging and some of its uses in human color vision research. The main types of hyperspectral cameras are described together with procedures for image acquisition, postprocessing, and calibration for either radiance or reflectance data. Image transformations are defined for colorimetric representations, color rendering, and cone receptor and postreceptor coding. Several example applications are also presented. These include calculating the color properties of scenes, such as gamut volume and metamerism, and analyzing the utility of color in observer tasks, such as identifying surfaces under illuminant changes. The effects of noise and uncertainty are considered in both image acquisition and color vision applications.

A Late G1 Lipid Checkpoint That Is Dysregulated in Clear Cell Renal Carcinoma Cells.

Lipids are important nutrients that proliferating cells require to maintain energy homeostasis as well as to build plasma membranes for newly synthesized cells. Previously, we identified nutrient-sensing checkpoints that exist in the latter part of the G1 phase of the cell cycle that are dependent upon essential amino acids, Gln, and finally, a checkpoint mediated by mammalian target of rapamycin (mTOR), which integrates signals from both nutrients and growth factors. In this study, we have identified and temporally mapped a lipid-mediated G1 checkpoint. This checkpoint is located after the Gln checkpoint and before the mTOR-mediated cell cycle checkpoint. Intriguingly, clear cell renal cell carcinoma cells (ccRCC) have a dysregulated lipid-mediated checkpoint due in part to defective phosphatase and tensin homologue (PTEN). When deprived of lipids, instead of arresting in G1, these cells continue to cycle and utilize lipid droplets as a source of lipids. Lipid droplets have been known to maintain endoplasmic reticulum homeostasis and prevent cytotoxic endoplasmic reticulum stress in ccRCC. Dysregulation of the lipid-mediated checkpoint forces these cells to utilize lipid droplets, which could potentially lead to therapeutic opportunities that exploit this property of ccRCC.