Maintenance therapy for CTCL: importance for prevention of disease progression.

There are no established maintenance protocols for cutaneous lymphomas. We aim to determine patient treatments and outcomes during the COVID-19 pandemic in order to uncover the most effective maintenance protocols for cutaneous lymphomas and impact of treatment interruption. Data was collected retrospectively from nine international institutions, including 149 patients. Younger patients had earlier stages of disease and were most frequently treated with skin-directed therapies including topical steroids, mechlorethamine gel, and phototherapy. Treatment interruption varied by treatment type and stage, with patients on topical therapies and earlier stages of disease being least likely to experience interruption. Treatment interruption was significantly associated with progression of disease and worse outcomes, with twice as many patients progressing who had interruption compared to those without interruption. This study may demonstrate the significance of continuous maintenance therapies, even in younger patients with early stages of disease.

Genomic SNPs resolve the phylogeny of an ancient amphibian island radiation from the Seychelles.

Unusually for oceanic islands, the granitic Seychelles host multiple lineages of endemic amphibians. This includes an ancient (likely ca. 60 million years) radiation of eight caecilian species, most of which occur on multiple islands.These caecilians have a complicated taxonomic history and their phylogenetic inter-species relationships have been difficult to resolve. Double-digest RAD sequencing (ddRADseq) has been applied extensively to phylogeography and increasingly to phylogenetics but its utility for resolving ancient divergences is less well established. To address this, we applied ddRADseq to generate a genome-wide SNP panel for phylogenomic analyses of the Seychelles caecilians, whose phylogeny has so far not been satisfactorily resolved with traditional DNA markers. Based on 129,154 SNPs, we resolved deep and shallow splits, with strong support. Our findings demonstrate the capability of genome-wide SNPs for evolutionary inference at multiple taxonomic levels and support the recently proposed synonymy of Grandisonia Taylor, 1968 with Hypogeophis Peters, 1879. We revealed three clades of Hypogeophis (large-, medium- and short-bodied) and identify a single origin of the diminutive, stocky-bodied and pointy-snouted phenotype.

Flow-Mediated Modulation of the Endothelial Cell Lipidome.

The luminal surface of the endothelium is exposed to dynamic blood flow patterns that are known to affect endothelial cell phenotype. While many studies have documented the phenotypic changes by gene or protein expression, less is known about the role of blood flow pattern on the endothelial cell (EC) lipidome. In this study, shotgun lipidomics was conducted on human aortic ECs (HAECs) exposed to unidirectional laminar flow (UF), disturbed flow (DF), or static conditions for 48 hrs. A total of 520 individual lipid species from 17 lipid subclasses were detected. Total lipid abundance was significantly increased for HAECs exposed to DF compared to UF conditions. Despite the increase in the total lipid abundance, HAECs maintained equivalent composition of each lipid subclass (% of total lipid) under both DF and UF. However, by lipid composition (% of total subclass), 28 lipid species were significantly altered between DF and UF. Complimentary RNA sequencing of HAECs exposed to UF or DF revealed changes in transcripts involved in lipid metabolism. Shotgun lipidomics was also performed on HAECs exposed to pro-inflammatory agonists lipopolysaccharide (LPS) or Pam3CSK4 (Pam3) for 48 hrs. Exposure to LPS or Pam3 reshaped the EC lipidome in both unique and overlapping ways. In conclusion, exposure to flow alters the EC lipidome and ECs undergo stimulus-specific lipid reprogramming in response to pro-inflammatory agonist exposure. Ultimately, this work provides a resource to profile the transcriptional and lipidomic changes that occur in response to applied flow that can be accessed by the vascular biology community to further dissect and extend our understanding of endothelial lipid biology.

Identification and Evaluation of Olive Phenolics in the Context of Amine Oxidase Enzyme Inhibition and Depression: In Silico Modelling and In Vitro Validation.

The Mediterranean diet well known for its beneficial health effects, including mood enhancement, is characterised by the relatively high consumption of extra virgin olive oil (EVOO), which is rich in bioactive phenolic compounds. Over 200 phenolic compounds have been associated with Olea europaea, and of these, only a relatively small fraction have been characterised. Utilising the OliveNetTM library, phenolic compounds were investigated as potential inhibitors of the epigenetic modifier lysine-specific demethylase 1 (LSD1). Furthermore, the compounds were screened for inhibition of the structurally similar monoamine oxidases (MAOs) which are directly implicated in the pathophysiology of depression. Molecular docking highlighted that olive phenolics interact with the active site of LSD1 and MAOs. Protein-peptide docking was also performed to evaluate the interaction of the histone H3 peptide with LSD1, in the presence of ligands bound to the substrate-binding cavity. To validate the in silico studies, the inhibitory activity of phenolic compounds was compared to the clinically approved inhibitor tranylcypromine. Our findings indicate that olive phenolics inhibit LSD1 and the MAOs in vitro. Using a cell culture model system with corticosteroid-stimulated human BJ fibroblast cells, the results demonstrate the attenuation of dexamethasone- and hydrocortisone-induced MAO activity by phenolic compounds. The findings were further corroborated using human embryonic stem cell (hESC)-derived neurons stimulated with all-trans retinoic acid. Overall, the results indicate the inhibition of flavin adenine dinucleotide (FAD)-dependent amine oxidases by olive phenolics. More generally, our findings further support at least a partial mechanism accounting for the antidepressant effects associated with EVOO and the Mediterranean diet.

Plasma-based post-processing of colloidal nanocrystals for applications in heterogeneous catalysis.

This review summarizes the work on the use of plasmas to post-process nanostructures, in particular colloidal nanocrystals, as promising candidates for applications of heterogeneous catalysis. Using plasma to clean or modify the surface of nanostructures is a more precisely controlled method compared to other conventional methods, which is preferable when strict requirements for nanostructure morphology or chemical composition are necessary. The ability of plasma post-processing to create mesoporous materials with high surface areas and controlled microstructure, surfaces, and interfaces has transformational potential in catalysis and other applications that leverage surface/interface processes.

Efficacy and safety of a mineral and vitamin treatment on symptoms of antenatal depression: 12-week fully blinded randomised placebo-controlled trial (NUTRIMUM).

BACKGROUND: Broad-spectrum micronutrients (minerals and vitamins) have shown benefit for treatment of depressive symptoms. AIMS: To determine whether additional micronutrients reduce symptoms of antenatal depression. METHOD: Eighty-eight medication-free pregnant women at 12-24 weeks gestation, who scored ≥13 on the Edinburgh Postnatal Depression Scale (EPDS), were randomised 1:1 to micronutrients or active placebo (containing iodine and riboflavin), for 12 weeks. Micronutrient doses were generally between recommended dietary allowance and tolerable upper level. Primary outcomes (EPDS and Clinical Global Impression - Improvement Scale (CGI-I)) were analysed with constrained longitudinal data analysis. RESULTS: Seventeen (19%) women dropped out, with no group differences, and four (4.5%) gave birth before trial completion. Both groups improved on the EPDS, with no group differences (P = 0.1018); 77.3% taking micronutrients and 72.7% taking placebos were considered recovered. However, the micronutrient group demonstrated significantly greater improvement, based on CGI-I clinician ratings, over time (P = 0.0196). The micronutrient group had significantly greater improvement on sleep and global assessment of functioning, and were more likely to identify themselves as 'much' to 'very much' improved (68.8%) compared with placebo (38.5%) (odds ratio 3.52, P = 0.011; number needed to treat: 3). There were no significant group differences on treatment-emergent adverse events, including suicidal ideation. Homocysteine decreased significantly more in the micronutrient group. Presence of personality difficulties, history of psychiatric medication use and higher social support tended to increase micronutrient response compared with placebo. CONCLUSIONS: This study highlights the benefits of active monitoring on antenatal depression, with added efficacy for overall functioning when taking micronutrients, with no evidence of harm. Trial replication with larger samples and clinically diagnosed depression are needed.

Use of a free proximal ulnar autograft for ipsilateral radial lengthening in a dog with a short radius and subsequent elbow incongruity.

OBJECTIVE: To report the technique and outcome of proximal ulnar autograft transplantation to achieve ipsilateral radial lengthening in a dog with premature closure of both proximal and distal radial physes. STUDY DESIGN: Case report. ANIMALS: An 8-month-old female spayed Border Collie. METHODS: The dog was presented for a grade III/IV left thoracic limb lameness localized to the elbow. Orthogonal radiographs of both forelimbs revealed a 7% length deficit of the left radius and elbow subluxation indices indicative of left elbow incongruity due to suspect premature closure of both radial physes. Radial lengthening consisted of a proximal ulnar ostectomy, a radial osteotomy, and transplantation of the ulnar autograft into the radial osteotomy site secured with an eight-hole dynamic compression plate. Orthopedic examinations were conducted at 2 weeks, 4 weeks, and 3 years postoperatively. Radiographic examinations were completed preoperatively, immediately postoperatively, and at 4 weeks and 3 years postoperatively. RESULTS: Lameness improved with a grade II/IV lameness at 4 weeks postoperatively and complete resolution at 3 years postoperatively. Radiographic examination at 4 weeks showed persistent radial lengthening of 1 cm, and a decreased humeroradial index (HRI), humeroulnar index (HUI), and radioulnar index (RUI) compared with preoperative values. At the 3 year examination, the HRI and HUI had increased indicating progression of elbow incongruity. The patient remained clinically unaffected. CONCLUSION: In dogs with radial shortening and elbow incongruity, use of an ipsilateral proximal ulnar autograft with rigid internal fixation can be an effective treatment for radial lengthening to improve elbow congruity and resolve lameness.

Is core knowledge a natural subdivision of infant cognition?

We examine Spelke's core knowledge taxonomy and test its boundaries. We ask whether Spelke's core knowledge is a distinct type of cognition in the sense that the cognitive processes it includes and excludes are biologically and mechanically coherent.

Mechanosensitive membrane domains regulate calcium entry in arterial endothelial cells to protect against inflammation.

Endothelial cells (ECs) in the descending aorta are exposed to high laminar shear stress, and this supports an antiinflammatory phenotype. High laminar shear stress also induces flow-aligned cell elongation and front-rear polarity, but whether these are required for the antiinflammatory phenotype is unclear. Here, we showed that caveolin-1-rich microdomains polarize to the downstream end of ECs that are exposed to continuous high laminar flow. These microdomains were characterized by high membrane rigidity, filamentous actin (F-actin), and raft-associated lipids. Transient receptor potential vanilloid (TRPV4) ion channels were ubiquitously expressed on the plasma membrane but mediated localized Ca2+ entry only at these microdomains where they physically interacted with clustered caveolin-1. These focal Ca2+ bursts activated endothelial nitric oxide synthase within the confines of these domains. Importantly, we found that signaling at these domains required both cell body elongation and sustained flow. Finally, TRPV4 signaling at these domains was necessary and sufficient to suppress inflammatory gene expression and exogenous activation of TRPV4 channels ameliorated the inflammatory response to stimuli both in vitro and in vivo. Our work revealed a polarized mechanosensitive signaling hub in arterial ECs that dampened inflammatory gene expression and promoted cell resilience.

Fruit and Vegetable Intake Patterns, Kidney Failure, and Mortality in Adults with and without Chronic Kidney Disease in the United States.

BACKGROUND: Fruits and vegetables (F&Vs) are vital components of healthy diets but may be restricted in chronic kidney disease (CKD) to avoid high-potassium intake. We previously generated F&V patterns for patients in the National Health and Nutrition Examination Survey (NHANES) and demonstrated an increased prevalence of the overall low-intake pattern in patients with CKD. OBJECTIVE: To evaluate the association of F&V patterns (overall low intake, high unprocessed, moderate processed, and high ultraprocessed) with the risk of kidney failure and its composite with death. METHODS: Adults in NHANES III with valid dietary data and longitudinal follow-up for kidney failure and death were included. F&V patterns were identified using 24-h dietary recalls and latent class analysis, yielding 4 patterns. Cox models were used to evaluate the prospective association between each pattern and hazard of kidney failure or a composite of kidney failure or death over ≤20 y. Models were adjusted for demographics and select comorbidities and weighted for the complex survey design. Secondary analyses evaluated serum carotenoids as objective biomarkers of F&V intake. RESULTS: Among 16,726 eligible participants in NHANES III, F&V consumption consistent with the high-ultraprocessed pattern associated with the highest risk of kidney failure after demographic and comorbidity adjustment, but attenuated with adjustment for kidney function. The high unprocessed pattern associated with the lowest adjusted risk of death or kidney failure combined [hazard ratio (HR): 0.73; 95% confidence interval (CI): 0.65, 0.81 relative to overall low intake]. Higher-serum carotenoids were associated with a lower adjusted risk of death or kidney failure combined (HR: 0.57; 95% CI: 0.49, 0.65 for quartile 4 compared with quartile 1). Results were similar in patients with CKD at baseline. CONCLUSIONS: Higher intake of unprocessed F&Vs was associated with better outcomes in the general population and patients with CKD. Results emphasize the need to safely improve F&V intake in CKD.

Utilization of the EpiMed Coronabank Chemical Collection to identify potential SARS-CoV-2 antivirals: in silico studies targeting the nsp14 ExoN domain and PLpro naphthalene binding site.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 29 proteins including four structural, 16 nonstructural (nsps), and nine accessory proteins (https://epimedlab.org/sars-cov-2-proteome/). Many of these proteins contain potential targetable sites for the development of antivirals. Despite the widespread use of vaccinations, the emergence of variants necessitates the investigation of new therapeutics and antivirals. Here, the EpiMed Coronabank Chemical Collection (https://epimedlab.org/crl/) was utilized to investigate potential antivirals against the nsp14 exoribonuclease (ExoN) domain. Molecular docking was performed to evaluate the binding characteristics of our chemical library against the nsp14 ExoN site. Based on the initial screen, trisjuglone, ararobinol, corilagin, and naphthofluorescein were identified as potential lead compounds. Molecular dynamics (MD) simulations were subsequently performed, with the results highlighting the stability of the lead compounds in the nsp14 ExoN site. Protein-RNA docking revealed the potential for the lead compounds to disrupt the interaction with RNA when bound to the ExoN site. Moreover, hypericin, cyanidin-3-O-glucoside, and rutin were previously identified as lead compounds targeting the papain-like protease (PLpro) naphthalene binding site. Through performing MD simulations, the stability and interactions of lead compounds with PLpro were further examined. Overall, given the critical role of the exonuclease activity of nsp14 in ensuring viral fidelity and the multifunctional role of PLpro in viral pathobiology and replication, these nsps represent important targets for antiviral drug development. Our databases can be utilized for in silico studies, such as the ones performed here, and this approach can be applied to other potentially druggable SARS-CoV-2 protein targets.

Correction: Gastric coagulation and postprandial amino acid absorption of milk is affected by mineral composition: a randomized crossover trial.

Correction for 'Gastric coagulation and postprandial amino acid absorption of milk is affected by mineral composition: a randomized crossover trial' by Elise J. M. van Eijnatten et al., Food Funct., 2024, 15, 3098-3107, https://doi.org/10.1039/D3FO04063A.

Wireless monitoring of respiration with EEG reveals relationships between respiration, behaviour and brain activity in freely moving mice.

Active sampling in the olfactory domain is an important aspect of mouse behaviour, and there is increasing evidence that respiration-entrained neural activity outside of the olfactory system sets an important global brain rhythm. It is therefore important to accurately measure breathing during natural behaviours. We develop a new approach to do this in freely moving animals, by implanting a telemetry-based pressure sensor into the right jugular vein, which allows for wireless monitoring of thoracic pressure. After verifying this technique against standard head-fixed respiration measurements, we combined it with EEG and EMG recording and used evolving partial coherence analysis to investigate the relationship between respiration and brain activity across a range of experiments in which the mice could move freely. During voluntary exploration of odours and objects, we found that the association between respiration and cortical delta and theta rhythms decreased, while the association between respiration and cortical alpha rhythm increased. During sleep, however, the presentation of an odour was able to cause a transient increase in sniffing without changing dominant sleep rhythms (delta and theta) in the cortex. Our data align with the emerging idea that the respiration rhythm could act as a synchronising scaffold for specific brain rhythms during wakefulness and exploration, but suggest that respiratory changes are less able to impact brain activity during sleep. Combining wireless respiration monitoring with different types of brain recording across a variety of behaviours will further increase our understanding of the important links between active sampling, passive respiration, and neural activity.

Feasibility and Perioperative Outcomes of Minimally Invasive Higher Order Myomectomy.

STUDY OBJECTIVE: To investigate perioperative outcomes of minimally invasive higher order myomectomy as defined by removal of 10 or more fibroids. DESIGN: A retrospective cohort study between January 2018 and December 2022. SETTING: A tertiary academic medical center. PATIENTS: Women who underwent minimally invasive myomectomy via laparoscopic or robotic approach. INTERVENTIONS: Surgical intervention in the form of minimally invasive myomectomy. MEASUREMENTS AND MAIN RESULTS: A total of 735 women met inclusion criteria of whom 578 had fewer than 10 fibroids removed, and 157 patients had 10 or more removed (average number of fibroids removed 3.8 vs 14.7, p <.001; specimen's weight 317.4 g vs 371.0 g, p = .07). Body mass index was similar in both groups (p = .66) and patients with higher order myomectomy were more likely to have a history of myomectomy (12.0% vs 26.8%, p <.001). The average estimated blood loss (EBL) was 246 mL vs 470 mL in each group (p <.001). There were no significant differences in packed red blood cell transfusion (1.0% vs 0.6%, p = .65), conversion to laparotomy (0.5% vs 0.6%, p = .86), or complications including visceral injury, wound complication, venous thromboembolism, ileus, or readmission (5.9% vs 4.5%, p = .49). The hospital length of stay was similar in both groups (0.5 days vs 0.5 days, p = .63). On linear regression analysis, after adjusting for specimen's weight, operative time, and history of myomectomy, EBL remained significantly higher in patients with 10 or more fibroids removed (p = .02). CONCLUSION: EBL is increased in higher order myomectomy; however, blood transfusions, conversion to laparotomy, complication rates, and length of hospital stay did not differ compared with patients with fewer than 10 fibroids removed, highlighting the feasibility of minimally invasive higher order myomectomy.

Written Language Practice, Self-Efficacy, and Beliefs: A Survey of Speech-Language Pathologists Working With School-Aged Clients.

PURPOSE: This study examined the clinical practice, self-efficacy, and beliefs about assessing and treating written language among speech-language pathologists (SLPs) working with school-aged clients (aged 5-21 years) in school and nonschool settings in the United States. METHOD: A survey was completed by a nationwide sample of 344 SLPs working with school-aged clients in the United States. Statistical analyses were conducted to determine differences between (a) SLPs' self-efficacy in assessing and treating spoken versus written language and (b) school-based and non-school-based SLPs' clinical practice, self-efficacy, and beliefs about their roles with written language. RESULTS: All respondents reported significantly lower rates of self-efficacy in assessing and treating written language compared to spoken language, and their self-efficacy had a significant, positive relationship with the amount of clinical time devoted to written language. School-based SLPs devoted a significantly lower percentage of clinical time to written language, had significantly lower self-efficacy in addressing written language, and had lower rates of agreement on statements about their roles and responsibilities with written language compared to non-school-based SLPs. These differences were not found with spoken language. The most prevalent written language needs on respondents' workloads were reported as written expression (69.3%) and reading comprehension (66%). CONCLUSIONS: School-based and non-school-based SLPs report different levels of clinical time devoted to written language, self-efficacy in addressing written language, and beliefs about their roles in addressing written language. There is a need to investigate the reasons for these differences and the potential impact of preservice and in-service training in ameliorating them. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25511047.

Paediatric onset lymphomatoid papulosis: results of a multicentre retrospective cohort study, on behalf of the EORTC Cutaneous Lymphoma Tumours Group (CLTG).

BACKGROUND: Lymphomatoid Papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population is scarce. OBJECTIVES: To characterize epidemiological, clinical, histopathological, and prognostic features of paediatric LyP. METHODS: This was a retrospective, multicentre international cohort study including 87 cases of children and adolescents with LyP diagnosed between 1998 and 2022. Patients aged ≤ 18 years old at disease onset were included. Diagnosis was made in each centre based on clinical-pathological correlation. RESULTS: Eighty-seven patients from 12 centres were included. The mean age at onset was 7.0 years (range 3 months-18 years) with a male to female ratio of 2:1. The mean time between onset of first cutaneous lesions and diagnosis was 1.3 years (range 0-14 years). Initial misdiagnosis concerned 26.4% of patients. Initially, LyP was most often misdiagnosed as Pityriasis lichenoides et varioliformis acuta (PLEVA), insect bites, or mollusca contagiosa. Erythematous papules or papulonodules were the most frequent clinical presentation. Pruritus was specifically mentioned for 20.7% of patients. The main histological subtype was type A in 55.1% of the cases. If analysed, monoclonal TCR rearrangement was found in 76.5% of the skin biopsies. The overall survival rate was 100% with follow up at 5 years available for 33 patients and at 15 years for 8 patients. A development of associated haematological malignancy (HM) occurred in 9.6% of the cases (7/73), including four mycosis fungoides (MF) cases, one primary cutaneous anaplastic large cell lymphoma (pc-ALCL), one systemic ALCL and one case of acute myeloid leukaemia. If we compare incidence rates of cancer with the world 0-19 years old population from 2001-2010, we estimate a significantly higher risk of associated malignancy in general, occurring before the age of 19 years old with incidence rate ratio of 87.49 (CI 86.01-88.99). CONCLUSIONS: We report epidemiological data from a large international cohort of children and adolescents with LyP. Overall the prognosis of the disease is good, with excellent survival rates for all patients. Due to increased risk of associated HM, a long-term follow-up should be recommended for LyP patients.

Racial and Ethnic Disparities in Health-Related Outcomes in Crohn's Disease: Results From the National Health and Wellness Survey.

Background: Crohn's disease (CD) is a chronic inflammatory condition affecting the entire gastrointestinal tract that is associated with significant humanistic, clinical, and economic burdens. Few studies have assessed the association between CD severity and patient-reported outcomes (PROs), healthcare resource utilization (HCRU), and medical costs; even fewer have examined differences in disease outcomes among patients of various racial/ethnic groups. Methods: In this cross-sectional study, sociodemographic data, PROs, and economic outcomes for participants with self-reported CD were collected from the National Health and Wellness Survey (2018-2020). Multivariable analyses were used to assess the association of CD severity and race/ethnicity with health-related quality of life (HRQoL), work productivity and activity impairment (WPAI), HCRU, and medical costs. Results: Analyses included 1077 participants with CD (818 non-Hispanic White, 109 non-Hispanic Black, and 150 Hispanic). Participants with self-reported moderate/severe CD reported significantly worse HRQoL and WPAI, greater HCRU, and higher medical costs than those with self-reported mild CD. Non-Hispanic Black participants reported better HRQoL and fewer healthcare provider visits than non-Hispanic White participants. There were no significant differences in PROs between non-Hispanic White and Hispanic groups. Interactions between race/ethnicity and CD severity emerged for some, but not all groups: Specifically, non-Hispanic Black participants with moderate/severe CD reported greater absenteeism and more gastroenterologist visits than non-Hispanic Black participants with mild CD. Conclusions: Participants with moderate/severe CD reported worse PROs, greater HCRU, and higher medical costs than those with mild CD. Additionally, racial/ethnic differences were found across several HCRU and economic outcomes. Further research is needed to better understand factors contributing to burden among patients with varying CD severity across racial/ethnic groups.

Learning about Literacy: Speech-Language Pathologists' Pre-Service and In-Service Training Experiences in the United States.

To better understand speech-language pathologists' (SLPs') pre-service and in-service training experiences in literacy and the relationship between their literacy training experiences and current practice, self-efficacy, and beliefs regarding their roles in literacy assessment and treatment, a web-based survey of SLPs was conducted (n = 444). Responses revealed that 60% of respondents completed at least one literacy course in their graduate programs: 55% took courses that embedded content in literacy assessment or treatment, and 23% took courses dedicated to literacy. These results varied based on the decade of graduation. Although 73.5% of respondents felt that their graduate programs trained them well or very well to assess and treat spoken language, only 8.5% felt the same about literacy. Most respondents (80%) reported completing in-service literacy training, and 89% reported wanting more literacy training. Completion of in-service training was positively, significantly related to respondents' current literacy-related clinical practice, self-efficacy, and beliefs regarding their roles; however, pre-service literacy training was not significantly related to any of these. Though in-service training appears to play a role in helping SLPs deliver literacy services, more emphasis on increasing the quantity and quality of pre-service and in-service training in the assessment and treatment of literacy is needed.

T cell cholesterol transport is a metabolic checkpoint that links intestinal immune responses to dietary lipid absorption.

The intrinsic pathways that control membrane organization in immune cells and the impact of such pathways on cellular function are not well defined. Here we report that the non-vesicular cholesterol transporter Aster-A links plasma membrane (PM) cholesterol availability in T cells to immune signaling and systemic metabolism. Aster-A is recruited to the PM during T-cell receptor (TCR) activation, where it facilitates the removal of newly generated "accessible" membrane cholesterol. Loss of Aster-A leads to excess PM cholesterol accumulation, resulting in enhanced TCR nano-clustering and signaling, and Th17 cytokine production. Finally, we show that the mucosal Th17 response is restrained by PM cholesterol remodeling. Ablation of Aster-A in T cells leads to enhanced IL-22 production, reduced intestinal fatty acid absorption, and resistance to diet-induced obesity. These findings delineate a multi-tiered regulatory scheme linking immune cell lipid flux to nutrient absorption and systemic physiology.