Optical orbital angular momentum analogy to the Stern-Gerlach experiment.

Symmetry breaking has been shown to reveal interesting phenomena in physical systems. A notable example is the fundamental work of Otto Stern and Walther Gerlach [Stern and Zerlach, Z. Physik9, 349 (1922)10.1007/BF01326983] nearly 100 years ago demonstrating a spin angular momentum (SAM) deflection that differed from classical theory. Here we use non-separable states of SAM and orbital angular momentum (OAM), known as vector vortex modes, to demonstrate how a classical optics analogy can be used to reveal this non-separability, reminiscent of the work carried out by Stern and Gerlach. We show that by implementing a polarization insensitive device to measure the OAM, the SAM states can be deflected to spatially resolved positions.

Inflammation mediated by gut microbiome alterations promotes lung cancer development and an immunosuppressed tumor microenvironment.

Accumulating evidence indicates that the gut microbiome influences cancer progression and therapy. We recently showed that progressive changes in gut microbial diversity and composition are closely associated with tobacco-associated lung adenocarcinoma (LUAD) in a human-relevant mouse model. Furthermore, we demonstrated that the loss of the antimicrobial protein Lcn2 in these mice, exacerbates pro-tumor inflammatory phenotypes while further reducing microbial diversity. Yet, how gut microbiome alterations impinge on LUAD development remains poorly understood. Here, we investigated the role of gut microbiome changes in LUAD development using fecal microbiota transfer and delineated a pathway by which gut microbiome alterations incurred by loss of Lcn2 fostered the proliferation of pro-inflammatory bacteria of the genus Alistipes, triggering gut inflammation. This inflammation propagated systemically, exerting immunosuppression within the tumor microenvironment, augmenting tumor growth through an IL-6-dependent mechanism and dampening response to immunotherapy. Corroborating our preclinical findings, we found that patients with LUAD with a higher relative abundance of Alistipes species in the gut showed diminished response to neoadjuvant immunotherapy. These insights reveal the role of microbiome-induced inflammation in LUAD and present new potential targets for interception and therapy.

Enhancements to quantum communication performance utilizing a prototype photonic lantern and multiplexed single-photon detection.

The optical interfacing between a free-space channel and single-photon detectors (SPDs) can greatly impact the inherent performance of a free-space quantum key distribution receiver. Direct coupling to detectors creates engineering challenges, and a single-mode fiber requires adaptive optics. Using a multimode fiber (MMF) is common; however, larger core diameters limit the achievable bandwidth. We demonstrate a prototype multimode fiber-based photonic lantern that allows us to retain the benefits of the large multimode coupling while transitioning to multiple, less multimodal fibers, reducing bandwidth limitation.

Spectroscopic definition of ferrous active sites in non-heme iron enzymes.

Non-heme iron enzymes play key roles in antibiotic, neurotransmitter, and natural product biosynthesis, DNA repair, hypoxia regulation, and disease states. These enzymes had been refractory to traditional bioinorganic spectroscopic methods. Thus, we developed variable-temperature variable-field magnetic circular dichroism (VTVH MCD) spectroscopy to experimentally define the excited and ground ligand field states of non-heme ferrous enzymes (Solomon et al., 1995). This method provides detailed geometric and electronic structure insight and thus enables a molecular level understanding of catalytic mechanisms. Application of this method across the five classes of non-heme ferrous enzymes has defined that a general mechanistic strategy is utilized where O2 activation is controlled to occur only in the presence of all cosubstrates.

Quality-of-Life Outcomes from NRG/NSABP B-39/RTOG 0413: Whole-breast Irradiation vs Accelerated Partial-breast Irradiation after Breast Conserving Surgery.

PURPOSE: NRG Oncology (NRG)/NSABP B-39/RTOG 0413 compared whole-breast irradiation (WBI) to accelerated partial-breast irradiation (APBI). APBI was not equivalent to WBI in local tumor control. Secondary outcome was Quality-of-life (QOL). METHODS: The QOL sub-study used validated self-report questionnaires including the Breast Cancer Treatment Outcome Scale (BCTOS) and SF-36 vitality scale. Assessments occurred: before randomization, at treatment completion (chemotherapy or radiotherapy), 4-weeks later, at 6-, 12-, 24-, and 36-months. Primary aims: cosmesis change equivalency (baseline to 3 years; a priori margin of equivalence 0.4 standard deviations) and fatigue change superiority (baseline to end-of-treatment (EOT)) for APBI vs WBI, by patient groups treated with or without chemotherapy when appropriate. RESULTS: From 3/21/05-5/25/09, 975 patients enrolled in this sub-study; 950 had follow-up data. APBI had 3-year cosmesis equivalent to WBI (95%CI,-0.0001-0.16; equivalence margin -0.22-0.22) in all patients. The APBI group without chemotherapy had less EOT fatigue (p = .011; mean score APBI 63 vs WBI 59); APBI group receiving chemotherapy had worse EOT fatigue (p = .011; APBI 43 vs WBI 49). The APBI group reported less pain (BCTOS) at EOT (WBI 2.29 vs APBI 1.97), but worse pain at 3-years (WBI 1.62 vs APBI 1.71). APBI patients reported greater convenience of care than with WBI and reported less symptom severity at EOT and 4-weeks later. CONCLUSION: Cosmetic outcomes were similar for APBI and WBI groups, with small statistically significant differences in other outcomes that varied over time. Differences in fatigue and other symptoms appeared to resolve by ≥ 6 months. APBI may be preferred by some patients, for whom extended treatment is burdensome.

Differentiating clinical characteristics of perianal inflammatory bowel disease from perianal hidradenitis suppurativa.

BACKGROUND: Perianal draining tunnels in hidradenitis suppurativa (HS) and perianal fistulizing inflammatory bowel disease (IBD) present diagnostic and management dilemmas. METHODS: We conducted a retrospective chart review of patients with perianal disease evaluated at Mayo Clinic from January 1, 1998, through July 31, 2021. Patients' demographic and clinical data were extracted, and 28 clinical features were collected. After experimenting with several machine learning techniques, random forests were used to select the 15 most important clinical features to construct the diagnostic prediction model to distinguish perianal HS from fistulizing perianal IBD. RESULTS: A total of 263 patients were included (98 with HS, 100 with IBD, and 65 with both IBD and HS). Patients with HS had a higher mean body mass index, a higher smoking rate, and more commonly showed cutaneous manifestations of tunnels and comedones, while fistulas, abscesses, induration, anal tags, ulcers, and anal fissures were more common in patients with IBD. In addition to having lesions in the perianal area, patients with IBD often had lesions in the buttocks and perineum, while those with HS had additional lesions in the axillae and groin. Among the statistically significant features, the 15 most important were identified by random forest: fistula, tunnel, digestive symptom, knife-cut ulcer, perineum, body mass index, age, axilla, abscess, tags, smoking, groin, genital cutaneous edema, erythema, and bilateral/unilateral. CONCLUSIONS: The results of this study may help differentiate perianal lesions, especially perineal HS and fistulizing perineal IBD, and provide promise for a better therapeutic outcome.

The anabolic response to a ground beef patty and soy-based meat alternative: a randomized controlled trial.

BACKGROUND: Soy-based meat alternatives (SBMA) are becoming increasingly popular, but it is unclear if they have the same anabolic effect on skeletal muscle as animal meat. OBJECTIVES: We aimed to compare the stimulation of skeletal muscle protein synthesis by consumption of 1 or two 4 oz patties of SBMA with 4 oz (80% protein/20% fat) beef. METHODS: The study design was a randomized controlled trial. Participants were aged 18-40 y of age and in good general health with a body mass index (kg/m2) between 20 and 32. Stable isotope tracer methods were used (L-[ring-2H5] phenylalanine, [U-13C9-15N]- tyrosine, and L-[ring-2H4] tyrosine) to quantify the response of muscle protein fractional synthetic rate (FSR) to consumption of a single beef (4 oz), single SBMA (4 oz), or two 4 oz SBMA patties (8 oz). Whole-body rates of protein synthesis, breakdown, and net balance, as well as plasma essential amino acid concentrations, were also measured. RESULTS: The increase above basal in muscle protein FSR following consumption of the 4 oz beef patty (0.020 ± 0.016%/h) was significantly greater than the increase following consumption of 4 oz SBMA (P = 0.021; 0.003 ± 0.010%/h) but not 8 oz SBMA (P = 0.454; 0.013 ± 0.016%/h). The maximal essential amino acid concentration was significantly correlated (P = 0.046; r = 0.411) with the change in muscle FSR from the basal to the postprandial period. In addition, the change in muscle FSR from the basal to postprandial period was significantly correlated (P = 0.046; r = 0.412) with the corresponding change in whole-body protein synthesis. CONCLUSIONS: Consumption of a 4 oz beef patty stimulates muscle and whole-body protein synthesis >4 oz SBMA patty and similarly to 8 oz of SBMA. This trial was registered at clinicaltrials.gov as NCT05197140.

Impact of Disease Burden of Patients with Psoriasis on Biologic Therapy Switching: Real-World Evidence from the CorEvitas Psoriasis Registry.

INTRODUCTION: Due to variable psoriasis symptoms, disease progression, and individual responses to therapy, patients may start, stop, or switch biologic therapies. Real-world data on the associated disease burden of patients with psoriasis who do and do not switch biologics are incomplete. METHODS: This study compared disease burden among patients from the CorEvitas Psoriasis Registry (July 2017-December 2021) who switched biologics and those who did not within 4-12 months following initiation. Disease-related patient-reported outcomes (PROs) were recorded, including skin pain, itching, activity impairment, and effects on health-related quality of life (HRQoL). Disease severity was measured by body surface area (BSA) and Psoriasis Area and Severity Index (PASI). Unadjusted and adjusted regression models were used to compare study outcome measures between the two groups. RESULTS: This study included 2145 patients, with 159 classified as switchers and 1986 as non-switchers. The most common reason for switching therapy was failure to maintain initial response (51.7%; n = 78). Moderate-to-severe disease (BSA ≥ 3) was found among 83.0% (n = 132) of switchers versus 26.1% (n = 516) of non-switchers. PASI > 5 was reported among 49.7% (n = 79) of switchers versus 8.6% (n = 171) of non-switchers. Differences in skin pain, itching, and effects on HRQoL between switchers and non-switchers were larger in magnitude for bio-experienced patients. CONCLUSIONS: Patients who switched biologic therapy experienced a greater disease burden of psoriasis across PROs than non-switchers. Patient-centered factors may be important drivers of biologic switching. Our findings suggest the association between switching and disease burden may be stronger among patients with prior biologic therapy experience.

Patients with psoriasis often need treatment over a long period of time. Common treatments include biologic medications, which help to reduce inflammation. Different patients may experience different psoriasis symptoms, and these symptoms can lead to changes in biologic over time. It is important that we understand how psoriasis severity and patients' day-to-day well-being affect switching of psoriasis biologic medications.In this study, we used information from a database of patients with psoriasis. The database includes information on patients' psoriasis-related medication history, including whether they change their medication. We looked at data from patients who switched and patients who did not switch their biologic medication, and examined differences in their skin pain, itching, tiredness, difficulty participating in normal activities, and effects on day-to-day well-being. Patterns between these two groups were also studied on the basis of whether patients had used biologic medications before or whether they had a related condition, called psoriatic arthritis, in addition to psoriasis.Overall, we found that patients who changed their biologic medication had experienced more difficult psoriasis symptoms than those who had not changed their medication, such as itching and skin pain. These symptoms had a greater impact on switching biologic medication in patients who had used a biologic medication before than for those who were using their first biologic medication.

PET Imaging Using 89Zr Labeled StarPEG Nanocarriers Reveals Heterogeneous Enhanced Permeability and Retention (EPR) in Prostate Cancer.

The enhanced permeability and retention (EPR) effect controls passive nanodrug uptake in tumors, and may provide a high tumor payload with prolonged retention for cancer treatment. However, EPR-mediated tumor uptake and distribution vary by cancer phenotype. Thus, we hypothesized that a companion PET-imaging surrogate may benefit EPR-mediated therapeutic drug delivery. We developed two 89Zr-radiolabeled nanocarriers based on 4-armed-starPEG40kDa with or without talazoparib (TLZ), a potent PARPi, as surrogates for the PEG-TLZ4 therapeutic scaffold. For PET imaging, PEG-DFB4 and PEG-DFB1-TLZ3 were radiolabeled with 89Zr by replacing one or all four TLZ on PEG-TLZ4 with deferoxamine B (DFB). The radiolabeled nanodrugs [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 were tested in vivo in prostate cancer subcutaneous xenografts (22Rv1, LTL-545, and LTL-610) and 22Rv1 metastatic models. Their EPR-mediated tumoral uptake and penetration was compared to CT26, a known EPR-high MicroPET/CT images, organ biodistribution, and calculated kinetic parameters showed high uptake in CT26 and LTL-545, moderate to low uptake in LTL-610 and 22Rv1. MicroPET/CT and high-resolution autoradiographic images showed nanocarrier penetration into highly permeable CT26, but heterogeneous peripheral accumulation was observed in LTL-545, LTL-610, and 22Rv1 subcutaneous xenografts and metastatic tumors. CD31 staining of tumor sections showed homogenous vascular development in CT26 tumors and heterogeneity in other xenografts. Both [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 showed similar accumulation and distribution in subcutaneous and metastatic tumor models. Both nanocarriers can measure tumor model passive uptake heterogeneity. Although heterogeneous, prostate cancer xenografts had low EPR. These starPEG nanocarriers could be used as PET imaging surrogates to predict drug delivery and efficacy.

Localized cystic disease of the kidney: study of 14 cases and review of the literature.

Localized cystic disease of the kidney (LCDK) is rare without hereditary background and does not progress. It can mimic neoplastic process, leading to unnecessary surgical intervention. We present 14 patients [male-to-female 9:5; mean age 50.3 years (range: 3-79)] with LCDK in a multinational cohort. Flank pain (n=5) and incidental lesions (n=4) were common. All cases were unilateral (9 right, 5 left), and contralateral kidneys were mostly normal (n=11). No family history was present, and none had extrarenal solid organ cysts. Radical and partial nephrectomies were performed in 9 and 5 cases, respectively. All lesions were multilocular, ranging from 1.8 - 20cm. 2 cases had diffuse renal involvement. Cystic septa contained nonneoplastic elements including renal tubules and glomeruli without primitive epithelial cellular elements, blastema, or immature stromal cells. In addition, we also comprehensively reviewed 75 previously reported cases. Conclusions. LCDK should be considered in the differential of cystic kidney lesions.

MYC is Sufficient to Generate Mid-Life High-Grade Serous Ovarian and Uterine Serous Carcinomas in a p53-R270H Mouse Model.

Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment are understood. MYC, an oncogene, is amongst the most amplified genes in high-grade serous ovarian cancer (HGSOC), but it has not previously been utilized to drive HGSOC GEMMs. We coupled Myc and dominant-negative mutant p53-R270H with a fallopian tube epithelium (FTE)-specific promoter Ovgp1 to generate a new GEMM of HGSOC. Female mice developed lethal cancer at an average of 14.5 months. Histopathologic examination of mice revealed HGSOC characteristics, including nuclear p53 and nuclear MYC in clusters of cells within the FTE and ovarian surface epithelium. Unexpectedly, nuclear p53 and MYC clustered cell expression was also identified in the uterine luminal epithelium, possibly from intraepithelial metastasis from the FTE. Extracted tumor cells exhibited strong loss of heterozygosity at the p53 locus, leaving the mutant allele. Copy-number alterations in these cancer cells were prevalent, disrupting a large fraction of genes. Transcriptome profiles most closely matched human HGSOC and serous endometrial cancer. Taken together, these results demonstrate that the Myc and Trp53-R270H transgenes were able to recapitulate many phenotypic hallmarks of HGSOC through the utilization of strictly human-mimetic genetic hallmarks of HGSOC. This new mouse model enables further exploration of ovarian cancer pathogenesis, particularly in the 50% of HGSOC which lack homology-directed repair mutations. Histologic and transcriptomic findings are consistent with the hypothesis that uterine serous cancer may originate from the FTE. SIGNIFICANCE: Mouse models using transgenes which generate spontaneous cancers are essential tools to examine the etiology of human diseases. Here, the first Myc-driven spontaneous model is described as a valid HGSOC model. Surprisingly, aspects of uterine serous carcinoma were also observed in this model.

Solvent Minimized Synthesis of Amides by Reactive Extrusion.

Herein, we report on the translation of a small scale ball-milled amidation protocol into a large scale continuous reactive extrusion process. Critical components to the successful translation were: a) understanding how the different operating parameters of a twin-screw extruder should be harnessed to control prolonged continuous operation, and b) consideration of the physical form of the input materials. The amidation reaction is applied to 36 amides spanning a variety of physical form combinations (liquid-liquid, solid-liquid and solid-solid). Following this learning process, we have developed an understanding for the translation of each physical form combination and demonstrated a 7-hour reactive extrusion process for the synthesis of an amide on 500 gram scale (1.3 mols of product).

Editors' Note: 2024 Annual Report Regarding JAACAP's Antiracist Journey.

In 2020, we wrote to you about our dedication and vision for JAACAP "to be antiracist at every level."1 Over the last 4 years we have pursued initiatives "to reshape the Journal to pursue this vision."2-4 In this article, we provide an update on these goals and initiatives (Figure 1). These initiatives include both scientific journals in the JAACAP family, JAACAP and JAACAP Open. Through this work we aspire to be a leader among mental health journals in our intentional pursuit of antiracist policies and practices.

The W2024 database of the water isotopologue H 2 16 O .

The rovibrational spectrum of the water molecule is the crown jewel of high-resolution molecular spectroscopy. While its significance in numerous scientific and engineering applications and the challenges behind its interpretation have been well known, the extensive experimental analysis performed for this molecule, from the microwave to the ultraviolet, is admirable. To determine empirical energy levels for H 2 16 O , this study utilizes an improved version of the MARVEL (Measured Active Rotational-Vibrational Energy Levels) scheme, which now takes into account multiplet constraints and first-principles energy-level splittings. This analysis delivers 19027 empirical energy values, with individual uncertainties and confidence intervals, utilizing 309 290 transition wavenumbers collected from 189 (mostly experimental) data sources. Relying on these empirical, as well as some computed, energies and first-principles intensities, an extensive composite line list, named CW2024, has been assembled. The CW2024 dataset is compared to lines in the canonical HITRAN 2020 spectroscopic database, providing guidance for future experimental investigations.

Humoral Immunity and Antibody Responses against Diphtheria, Tetanus, and Pneumococcus after Immune Effector Cell Therapies: A Prospective Study.

Patients undergoing immune effector cell therapy (IECT) are at high risk for infections. We assessed seropositivity against pneumococcus, tetanus, and diphtheria in patients before and after IECT and the patients' response to vaccination. We enrolled patients who underwent IECT from January 2020 to March 2022. Antibody levels for diphtheria, tetanus, and pneumococcus were measured before IECT, at 1 month, and 3-6 months after. Eligible patients were vaccinated after IECT. In non-seroprotected patients, we discontinued testing. Before IECT, most patients had seroprotective antibody levels against tetanus (68/69, 99%) and diphtheria (65/69, 94%), but fewer did against pneumococcus (24/67, 36%). After IECT, all patients had seroprotective antibody levels for tetanus at 1 month (68/68) and 3-6 months (56/56). For diphtheria, 65/65 patients (100%) had seroprotective antibody levels at 1 month, and 48/53 (91%) did at 3-6 months. For pneumococcus, seroprotective antibody levels were identified in 91% (21/23) of patients at 1 month and 79% (15/19) at 3-6 months following IECT. Fifteen patients received a pneumococcal vaccine after IECT, but none achieved seroprotective response. One patient received the tetanus-diphtheria vaccine and had a seroprotective antibody response. Because some patients experience loss of immunity after IECT, studies evaluating vaccination strategies post-IECT are needed.

Green spaces provide substantial but unequal urban cooling globally.

Climate warming disproportionately impacts countries in the Global South by increasing extreme heat exposure. However, geographic disparities in adaptation capacity are unclear. Here, we assess global inequality in green spaces, which urban residents critically rely on to mitigate outdoor heat stress. We use remote sensing data to quantify daytime cooling by urban greenery in the warm seasons across the ~500 largest cities globally. We show a striking contrast, with Global South cities having ~70% of the cooling capacity of cities in the Global North (2.5 ± 1.0 °C vs. 3.6 ± 1.7 °C). A similar gap occurs for the cooling adaptation benefits received by an average resident in these cities (2.2 ± 0.9 °C vs. 3.4 ± 1.7 °C). This cooling adaptation inequality is due to discrepancies in green space quantity and quality between cities in the Global North and South, shaped by socioeconomic and natural factors. Our analyses further suggest a vast potential for enhancing cooling adaptation while reducing global inequality.

Interplay of Donor-Recipient Relationship and Donor Race in Living Liver Donation in the United States.

INTRODUCTION: Living liver donation improves survival of end-stage liver disease (ESLD) patients. Yet, it continues to represent a small proportion of United States (U.S.) liver transplantation with existing racial disparities. We investigated the interplay of donor-recipient relationship and donor race to understand donor subgroups with no significant increase. METHODS: We studied 4407 living liver donors in the U.S. from January 1, 2012, to December 31, 2022 (median age = 36 years, and 59% were biologically related to the recipient). We quantified the change in the number of donors per 3-year increment using negative binomial regression (incidence rate ratio [IRR]), stratified by donor-recipient relationship and race/ethnicity. RESULTS: Among biologically related donors, the observed annual number of White donors increased from 146 to 253, Hispanic donors from 18 to 53, and Black donors decreased from 11 to 10. Among unrelated donors, White donors increased from 65 to 221, Hispanic donors from 4 to 25, and Black donors from 3 to 11. For the IRR of biologically related donors aged <40 and ≥40 years, White donors increased by 18% and 22%; Hispanic donors increased by 25% and 54%; and Black donors did not change. Likewise, the IRR of unrelated donors aged <40 and ≥40 years, White donors increased by 48% and 55%; Hispanic donors increased by 52% and 65%; and Black donors did not change. CONCLUSIONS: While biologically related donors represent the majority of donors, unrelated donors have substantially risen in recent years, primarily driven by White donors. Although the rate of unrelated donations increased among Hispanic donors, the absolute number remains very small (≤25 donors/year). Interventions are needed to increase education among Hispanic and Black communities to grow unrelated living liver donations across race/ethnicity.

Protection against fibrosis by a bacterial consortium in metabolic dysfunction-associated steatohepatitis and the role of amino acid metabolism.

The gut microbiota drives progression to liver fibrosis, the main determinant of mortality in metabolic dysfunction-associated steatohepatitis (MASH). In this study, we aimed to identify bacterial species associated with protection against liver fibrosis in a high-risk population, and test their potential to protect against liver fibrosis in vivo. Based on stool shotgun metagenomic sequencing of 340 subjects from a population cohort disproportionally affected by MASH, we identified bacterial species from the Bacteroidales and Clostridiales orders associated with reduced risk of liver fibrosis. A bacterial consortium was subsequently tested in a mouse model of MASH, which demonstrated protective effects against liver fibrosis. Six of the eight inoculated bacteria were detected in mouse stool and liver. Intrahepatic presence of bacteria was further confirmed by bacterial culture of mouse liver tissue. Changes in liver histological parameters, gut functional profiles, and amino acid profiles were additionally assessed. Comparison between fibrosis-associated human metagenome and bacteria-induced metagenome changes in mice identified microbial functions likely to mediate the protective effect against liver fibrosis. Amino acid profiling confirmed an increase in cysteine synthase activity, associated with reduced fibrosis. Other microbiota-induced changes in amino acids associated with reduced fibrosis included increased gut asparaginase activity and decreased hepatic tryptophan-to-kynurenine conversion. This human-to-mouse study identified bacterial species and their effects on amino acid metabolism as innovative strategies to protect against liver fibrosis in MASH.

Inflammation-induced epigenetic imprinting regulates intestinal stem cells.

It remains unknown whether and how intestinal stem cells (ISCs) adapt to inflammatory exposure and whether the adaptation leaves scars that will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5+ ISCs in well-defined clinically relevant models of acute gastrointestinal graft-versus-host disease (GI GVHD). Utilizing single-cell transcriptomics, as well as organoid, metabolic, epigenomic, and in vivo models, we found that Lgr5+ ISCs undergo metabolic changes that lead to the accumulation of succinate, which reprograms their epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures and also in vivo following serial transplantation. Furthermore, ISCs demonstrated a reduced capacity for in vivo regeneration despite resolution of the initial inflammatory exposure, demonstrating the persistence of the maladaptive impact induced by the inflammatory encounter. Thus, inflammation imprints the epigenome of ISCs in a manner that persists and affects their sensitivity to adapt to future stress or challenges.