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Objectives: Faculty development is essential for academic emergency physicians to maintain clinical skills and succeed in administrative and leadership roles and for career advancement and satisfaction. Faculty developers in emergency medicine (EM) may struggle to find shared resources to guide faculty development efforts in a way that builds on existing knowledge. We aimed to review the EM-specific faculty development literature since 2000 and come to a consensus about the most useful for EM faculty developers., Methods: A database search was conducted on the topic of faculty development in EM from 2000 to 2020. After identifying relevant articles, we performed a modified Delphi process in three rounds, using a team of educators with a range of experiences with faculty development and education research, to identify articles that would be most useful to a broad audience of faculty developers., Results: We identified 287 potentially relevant articles on the topic of EM faculty development, 244 from the initial literature search, 42 from manual review of the references of the papers meeting inclusion criteria, and one by our study group's recommendation. Thirty-six papers met final inclusion criteria and underwent full-text review by our team. The Delphi process yielded six articles that were deemed most highly relevant over the three rounds. Each of these articles is described here, along with summaries and implications for faculty developers., Conclusions: We present the most useful EM papers from the past two decades for faculty developers seeking to develop, implement, or revise faculty development interventions., Competing Interests: The authors declare no potential conflict of interest., (© 2023 Society for Academic Emergency Medicine.)

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus in Asia that causes severe disease. Despite its clinical importance, treatment options for SFTSV infection remains limited. The SFTSV glycoprotein Gn plays a major role in mediating virus entry into host cells and is therefore a potential antiviral target. In this study, we employed an in silico structure-based strategy to design novel cyclic antiviral peptides that target the SFTSV glycoprotein Gn. Among the cyclic peptides, HKU-P1 potently neutralizes the SFTSV virion. Combinatorial treatment with HKU-P1 and the broad-spectrum viral RNA-dependent RNA polymerase inhibitor favipiravir exhibited synergistic antiviral effects in vitro. The in silico peptide design platform in this study may facilitate the generation of novel antiviral peptides for other emerging viruses.

Background: The role of subclinical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in perpetuating the COVID-19 pandemic is unknown because population seroprevalence data are absent. We aimed to establish the sensitivity and specificity of our enzyme immunoassay and microneutralisation assay, and the seroprevalence of SARS-CoV-2 in Hong Kong before and after the pandemic, as well as in Hong Kong residents evacuated from Hubei province, China., Methods: We did a multicohort study in a hospital and university in Hong Kong. We evaluated the sensitivity of our enzyme immunoassay and microneutralisation assay with RT-PCR data from patients positive for SARS-CoV-2 and the specificity of our enzyme immunoassay and microneutralisation assay with archived serum samples collected before 2019. We compared the seropositivity of the general population of Hong Kong before and after the pandemic had begun, and determined the seropositivity of Hong Kong residents evacuated from Hubei province, China, in March, 2020., Findings: Between Feb 26 and March 18, 2020, we assessed RT-PCR samples from 45 patients who had recovered from COVID-19 to establish the sensitivity of our enzyme immunoassay and microneutralisation assay. To establish the specificity of these assays, we retrieved archived serum. The sensitivity was 91·1% (41 of 45 [95% CI 78·8-97·5]) for the microneutralisation assay, 57·8% (26 of 45 [42·2-72·3]) for anti-nucleoprotein IgG, 66·7% (30 of 45 [51·1-80·0]) for anti-spike protein receptor binding domain (RBD) IgG, and 73·3% (33 of 45 [58·1-85·4]) for enzyme immunoassay (either positive for anti-nucleoprotein or anti-RBD IgG). The specificity was 100% (152 of 152 [95% CI 97·6-100·0]) for both the enzyme immunoassay and microneutralisation assay. Among the Hong Kong general population, 53 (2·7%) of 1938 were enzyme immunoassay positive, but of those who were positive, all 53 were microneutralisation negative, and no significant increase was seen in the seroprevalence between April 12, 2018, and Feb 13, 2020. Among asymptomatic Hubei returnees, 17 (4%) of 452 were seropositive with the enzyme immunoassay or the microneutralisation assay, with 15 (88%) of 17 seropositive with the microneutralisation assay, and two familial clusters were identified., Interpretation: Our serological data suggest that SARS-CoV-2 is a new emerging virus. The seropositivity rate in Hubei returnees indicates that RT-PCR-confirmed patients only represent a small proportion of the total number of cases. The low seroprevalence suggests that most of the Hong Kong and Hubei population remain susceptible to COVID-19. Future waves of the outbreak are inevitable without a vaccine or antiviral prophylaxis. The role of age-related cross reactive non-neutralising antibodies in the pathogenesis of COVID-19 warrants further investigation., Funding: Richard and Carol Yu, May Tam Mak Mei Yin, Shaw Foundation (Hong Kong), Michael Tong, Marina Lee, and the Government Consultancy Service (see acknowledgments for full list)., (© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Background: Coronavirus disease 2019 (COVID-19) causes severe community and nosocomial outbreaks. Comprehensive data for serial respiratory viral load and serum antibody responses from patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not yet available. Nasopharyngeal and throat swabs are usually obtained for serial viral load monitoring of respiratory infections but gathering these specimens can cause discomfort for patients and put health-care workers at risk. We aimed to ascertain the serial respiratory viral load of SARS-CoV-2 in posterior oropharyngeal (deep throat) saliva samples from patients with COVID-19, and serum antibody responses., Methods: We did a cohort study at two hospitals in Hong Kong. We included patients with laboratory-confirmed COVID-19. We obtained samples of blood, urine, posterior oropharyngeal saliva, and rectal swabs. Serial viral load was ascertained by reverse transcriptase quantitative PCR (RT-qPCR). Antibody levels against the SARS-CoV-2 internal nucleoprotein (NP) and surface spike protein receptor binding domain (RBD) were measured using EIA. Whole-genome sequencing was done to identify possible mutations arising during infection., Findings: Between Jan 22, 2020, and Feb 12, 2020, 30 patients were screened for inclusion, of whom 23 were included (median age 62 years [range 37-75]). The median viral load in posterior oropharyngeal saliva or other respiratory specimens at presentation was 5·2 log 10 copies per mL (IQR 4·1-7·0). Salivary viral load was highest during the first week after symptom onset and subsequently declined with time (slope -0·15, 95% CI -0·19 to -0·11; R 2 =0·71). In one patient, viral RNA was detected 25 days after symptom onset. Older age was correlated with higher viral load (Spearman's ρ=0·48, 95% CI 0·074-0·75; p=0·020). For 16 patients with serum samples available 14 days or longer after symptom onset, rates of seropositivity were 94% for anti-NP IgG (n=15), 88% for anti-NP IgM (n=14), 100% for anti-RBD IgG (n=16), and 94% for anti-RBD IgM (n=15). Anti-SARS-CoV-2-NP or anti-SARS-CoV-2-RBD IgG levels correlated with virus neutralisation titre (R 2 >0·9). No genome mutations were detected on serial samples., Interpretation: Posterior oropharyngeal saliva samples are a non-invasive specimen more acceptable to patients and health-care workers. Unlike severe acute respiratory syndrome, patients with COVID-19 had the highest viral load near presentation, which could account for the fast-spreading nature of this epidemic. This finding emphasises the importance of stringent infection control and early use of potent antiviral agents, alone or in combination, for high-risk individuals. Serological assay can complement RT-qPCR for diagnosis., Funding: Richard and Carol Yu, May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Michael Tong, Marina Lee, Government Consultancy Service, and Sanming Project of Medicine., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Audience: The aim of this simulation case is to educate senior medical students, resident physicians, and advanced practice providers on the recognition, diagnosis, and management of spinal epidural abscesses. This scenario is most applicable to the emergency medicine setting but can be applied to the outpatient office or urgent care settings., Introduction: Spinal epidural abscess is an infection leading to an epidural collection of purulent material. This uncommon condition is estimated to occur less than 12 times per 100,000 hospital admissions.1,2 However, this infection can lead to devastating neurological sequelae via cord compression, spinal vascular interruption, and inflammatory etiologies;3,4 thus, prompt diagnosis is essential. Unfortunately, spinal epidural abscesses may be difficult to identify clinically due to variable clinical presentations. The goal of this scenario is to increase awareness of this critical diagnosis.Detailed history-taking to identify risk factors will aid in the recognition of spinal epidural abscesses. Many of the risk factors are related to increased infectious risk from hematogenous spread, iatrogenic inoculation, or direct extension.1 Individuals with conditions including intravenous (IV) drug use, alcohol abuse, diabetes, human immunodeficiency virus (HIV), cancer, hepatic disease, renal disease, and other immunocompromising conditions are at increased risk of developing epidural abscesses.1 Primary infectious sources include dental abscesses, endocarditis, vertebral osteomyelitis, and soft tissue infections. Spinal procedures including spinal surgeries, paraspinal injections, and placement of epidural catheters or stimulators can also predispose to infection.2,4Classic symptoms for spinal epidural abscesses include fever, back pain and neurological changes.1,5 Back pain is the most frequent presenting symptom, occurring about 70%-90% of the time.1 However, fever is the least frequent presenting symptom4 and neurological findings only occur in about one-third of cases.2 Neurological symptoms include motor weakness, sensory changes, urinary retention, overflow urinary incontinence, bowel dysfunction, hyperreflexia, radicular pain, spinal shock or cauda equina syndrome.1,4Laboratory findings may include systemic leukocytosis and elevated inflammatory markers. Whereas leukocytosis is estimated to be present in two-thirds of cases,2 Davis, et al. showed that with the concurrent presence of a risk factor, an elevated erythrocyte sedimentation rate (ESR) had 100% sensitivity and 67% specificity for spinal epidural abscesses.5Magnetic resonance imaging (MRI) with gadolinium contrast is the preferred imaging modality for diagnosing spinal epidural abscesses. Computed tomography (CT) with myelography can be considered if MRI is contraindicated.1 Given that abscesses may be multifocal, further spinal imaging beyond a single spinal segment should be considered during evaluation. Lumbar puncture is not recommended due to risk of iatrogenic infectious spread.Treatment of epidural abscesses includes obtaining blood cultures and prompt antibiotic administration with early surgical evaluation to determine if operative intervention is warranted. Staphylococcus aureus is the most common microbial cause, contributing to about two-thirds of cases.3,4 Other microbial causes include coagulase-negative Staphylococcus (ie, Staphylococcus epidermidis ), Streptococcus , gram-negative bacilli (ie, Pseudomonas aeruginosa and E. coli ), and less commonly, anaerobic bacteria, fungi, mycobacteria and parasites.1,2 Empiric antibiotic treatments generally include vancomycin and a third- or fourth- generation cephalosporin.2,4This simulation session will highlight the importance of recognizing and aggressively treating this uncommon but potentially devastating condition., Educational Objectives: After this simulation case, learners will be able to diagnose and manage patients with spinal epidural abscesses. Specifically, learners will be able to:Obtain a detailed history, including past infectious, surgical, procedural and social history to evaluate for epidural abscess risk factors. Describe clinical signs and symptoms of spinal epidural abscesses and understand that initial clinical presentations can be variable.Perform a focused neurological exam including evaluation of motor, sensory, reflexes, and rectal tone.Order appropriate laboratory testing and imaging modalities for spinal epidural abscess diagnosis, including a post-void bladder residual volume.Select appropriate antibiotics for empiric treatment of spinal epidural abscess depending on patient presentation.Disposition the patient to appropriate inpatient care., Educational Methods: The authors conducted this simulation case with a standardized patient. We encourage inclusion of a standardized patient versus a mannequin to provide appropriate motor and sensory exams. For those without a standardized patient program, the authors suggest utilizing a faculty member as the patient. Regardless of individual used, it is strongly recommended that facilitators rehearse the case with the individual in the patient role ahead of time in order to ensure that their performance reflects an accurate neurologic exam. A debriefing session and small-group discussion followed the simulation to review the clinical presentation, diagnosis, management, and treatment of spinal epidural abscesses. This case can also be adapted as an oral boards case., Research Methods: Residents were provided a survey at the completion of the debriefing session to rate different aspects of the simulation, as well as to provide qualitative feedback on the scenario. This survey is specific to our institution's simulation center., Results: While qualitative feedback from the residents was positive, it was viewed as a straightforward case. Our initial presenting symptom was difficulty ambulating with a fever at home, if asked. The residents appreciated performing a neurologic exam on a standardized patient versus attempting this on a mannequin.Our simulation center's feedback form is based on the Center of Medical Simulation's Debriefing Assessment for Simulation in Healthcare (DASH) Student Version Short Form with the inclusion of required qualitative feedback if an element was scored less than a 6 or 7. This session received all 7 scores (extremely effective/outstanding) other than one 5 score for the element assessing if the instructor set the stage for an engaging learning experience. The learner's feedback for this 5 score was "kinda went right into the case which was ok." Our form also includes an area for general feedback about the case at the end. Comments included "Great sim. Expert case writing," "Fun case and learned a lot," and "Great case! Appreciated feedback on consulting and the difficult consultant situation.", Discussion: This is a cost-effective method for reviewing epidural abscess. We chose a chief complaint and history that was slightly atypical from "classic" presentations, but not so esoteric that the residents felt cheated at the end of the scenario. When using a standardized patient in a scenario that may involve a sensitive physical exam, we review with learners and the standardized patient what expectations are during the pre-brief session. For example, residents may say, "we would like to check to see if rectal tone is intact," and then the standardized patient would verbalize back the expected physical exam findings., Topics: Medical simulation, spinal epidural abscess, spinal cord compression, infectious disease., (© 2020 Lou, et al.)

The evolutionally conserved forkhead box O (Foxo) family of transcription factors is pivotal in the control of nutrient sensing and stress responses. Recent studies have revealed that the Foxo proteins have been rewired to regulate highly specialized T cell activities. Here, we review the latest advances in the understanding of how Foxo transcription factors control T cell biology, including T cell trafficking, naive T cell homeostasis, effector and memory responses, as well as the differentiation and function of regulatory T cells. We also discuss the emerging evidence on Foxo-mediated regulation in antitumor immunity. Future work will further explore how the Foxo-dependent programs in T cells can be exploited for cancer immunotherapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Peripheral T cells are maintained in the absence of vigorous stimuli, and respond to antigenic stimulation by initiating cell cycle progression and functional differentiation. Here we show that depletion of the Ets family transcription factor GA-binding protein (GABP) in T cells impairs T-cell homeostasis. In addition, GABP is critically required for antigen-stimulated T-cell responses in vitro and in vivo. Transcriptome and genome-wide GABP-binding site analyses identify GABP direct targets encoding proteins involved in cellular redox balance and DNA replication, including the Mcm replicative helicases. These findings show that GABP has a nonredundant role in the control of T-cell homeostasis and immunity.

Malignancy can be suppressed by the immune system in a process termed immunosurveillance. However, to what extent immunosurveillance occurs in spontaneous cancers and the composition of participating cell types remains obscure. Here, we show that cell transformation triggers a tissue-resident lymphocyte response in oncogene-induced murine cancer models. Non-circulating cytotoxic lymphocytes, derived from innate, T cell receptor (TCR)αβ, and TCRγδ lineages, expand in early tumors. Characterized by high expression of NK1.1, CD49a, and CD103, these cells share a gene-expression signature distinct from those of conventional NK cells, T cells, and invariant NKT cells. Generation of these lymphocytes is dependent on the cytokine IL-15, but not the transcription factor Nfil3 that is required for the differentiation of tumor-infiltrating NK cells, and IL-15 deficiency, but not Nfil3 deficiency, results in accelerated tumor growth. These findings reveal a tumor-elicited immunosurveillance mechanism that engages unconventional type-1-like innate lymphoid cells and type 1 innate-like T cells., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance; yet, excessive Treg cell activities suppress anti-tumour immune responses. Compared to the resting Treg (rTreg) cell phenotype in secondary lymphoid organs, Treg cells in non-lymphoid tissues exhibit an activated Treg (aTreg) cell phenotype. However, the function of aTreg cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg cell suppression of lymphoproliferative diseases, has an unexpected function in inhibiting aTreg-cell-mediated immune tolerance in mice. We find that aTreg cells turned over at a slower rate than rTreg cells, but were not locally maintained in tissues. aTreg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. Treg-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg cell homing to non-lymphoid organs, causing CD8(+) T-cell-mediated autoimmune diseases. Compared to Treg cells from healthy tissues, tumour-infiltrating Treg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated Treg cells, activate effector CD8(+) T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTreg cells that have a crucial function in suppressing CD8(+) T-cell responses; and the Foxo signalling pathway in Treg cells can be titrated to break tumour immune tolerance preferentially.

MicroRNA (miR)-mediated regulation of protein abundance is a pervasive mechanism of directing cellular processes. The well-studied and abundant miR-182 has previously been implicated in many aspects of T cell function, DNA repair, and cancer. In this study, we show that miR-182 is the most highly induced miR in B cells undergoing class-switch recombination. To elucidate the requirement of miR-182 in lymphocyte function, we extensively characterized mice with a targeted deletion of Mir182. We show that despite its dramatic induction, loss of miR-182 has minimal impact on B cell development, the ability of B cells to undergo class-switch recombination ex vivo and to undergo Ag-driven affinity maturation in vivo. Furthermore, in striking contrast to knockdown studies that demonstrated the requirement of miR-182 in T cell function, miR-182-deficient mice display no defect in T cell development and activation. Finally, we show that T cell-dependent immune response to experimental Listeria monocytogenes infection is intact in miR-182-deficient mice. We conclude that, contrary to previous studies, miR-182 does not play a significant role in all measured aspects of mouse adaptive immunity. This striking absence of a phenotype highlights the lack of correlation between expression pattern and functional requirement, underscores the limitations of using knockdown approaches to assess miR requirements, and suggests that miR networks may compensate for the chronic loss of specific miRs., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Oxidative stress has been suggested to play a causative role in the development of obesity-induced insulin resistance and type 2 diabetes. Given the antioxidant potency of previously reported xanthones isolated from Swertia mussotii. These natural products were further evaluated against other targets in diabetes, aldose reductase and α-glucosidase, in order to identify novel multitarget-directed antidiabetic agents. Among the 14 xanthones screened, 1,3,7,8-tetrahydroxyxanthone (6), 1,3,5,8-tetrahydroxyxanthone (7), and 2,3,6,8-tetrahydroxyxanthone-7C-(β-D-glucoside) (12) were confirmed as good antioxidants and α-glucosidase inhibitors. Xanthone 7 was also confirmed as a potent inhibitor of aldose reductase (ALR2). Xanthone 7 was the most active α-glucosidase and ALR2 inhibitor, with IC50 values of 5.2±0.3 μM and 88.6±1.6 nM, respectively, while compound 12 was shown to be the most active antioxidant. Given the overall profile, xanthone 7 is considered to be the most promising multitarget antidiabetic agent, and may have potential for the treatment of both diabetes and diabetic complications., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel and concise scheme has been developed successfully for the syntheses of N-substituted fagomine derivatives. The transformation of lactone (2) to 1,5-diol (3) was carried on with high yield (93-95%). The cyclization of 4 to 5 is a high stereoselective reaction (de value > 98%). It is disclosed that bulky substituent at N atom of the piperidine decreases the inhibition activity except those substituents having the ability of solvation or forming disulfide bond with M444 at the active site of α-glycosidase, which enhance the interaction with enzyme. Compounds with S-configuration at C-3 show greater activity than those with R-configuration. The structure-activity relationship study is also supported by molecular docking analysis., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Two new xanthones, 1,8-dihydroxy-3-methoxyxanthone 7-O-[α-L-rhamnopyranosyl(1 → 2)-β-D-glucopyranoside] (1) and 1,8- dihydroxy-3-methoxyxanthone 7-O-[α-L-rhamnopyranosyl(1 → 3)-α-L-rhamno-pyranosyl (1 → 2)-β-D-xylopyranoside] (2), together with 26 known xanthones (3-28), were isolated from the aqueous ethanol extract of the traditional Chinese herb Swertia mussotii. Their structures were elucidated via spectroscopic analyses including 2D NMR. The inhibition of α-glucosidase by the isolated xanthones was evaluated by an in vitro high-throughput screening assay. Our results indicated that 1,3,5,8-tetrahydroxyxanthone is the best inhibitor with an IC50 value of 5.33 ± 0.09 µM, while the O-glycosylated xanthones were poor α-glycosidase inhibitors., (Georg Thieme Verlag KG Stuttgart · New York.)

Four new xanthones, 3,5,6,8-tetrahydroxyxanthone-1-C-β-D-glucoside (1), 7-hydroxy-3,4,8-trimethoxyxanthone-1-O-(β-D-glucoside) (2), 6-hydroxy-3,5-dimethoxyxanthone-1-O-(β-D-glucoside) (3), 3,4,7,8-tetramethoxyxanthone-1-O-(β-D-glucoside) (4), together with twenty-one known xanthones (5-25) were isolated from the ethanol aqueous extract of Swertia mussotii. Their structures were elucidated via spectroscopic analyses. Oxygen radical absorbance capacity of all the isolated xanthones was systematically evaluated by ORAC(FL) assay. Results disclose that all the tested xanthones display moderate to excellent antioxidant activity, where 1 is the most active compound and 13 is the least one. A preliminary structure-activity relationship is also discussed., (© 2013.)

Regulatory T (Treg) cells differentiate from thymocytes or peripheral T cells in response to host and environmental cues, culminating in induction of the transcription factor forkhead box P3 (Foxp3) and the Treg cell-specific epigenome. An intermediate amount of antigen stimulation is required to induce Foxp3 expression by engaging T cell receptor (TCR)-activated [e.g., nuclear factor (NF)-κB] and TCR-inhibited (e.g., Foxo) transcription factors. Furthermore, Treg cell differentiation is associated with attenuated Akt signaling, resulting in enhanced nuclear retention of Foxo1, which is indispensable for Treg cell function. These findings reveal that Treg cell lineage commitment is not only controlled by genetic and epigenetic imprinting, but also modulated by transcriptional programs responding to extracellular signals., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Natural T helper 17 (nTH17) cells are a population of interleukin 17 (IL-17)-producing cells that acquire effector function in the thymus during development. Here we demonstrate that the serine/threonine kinase Akt has a critical role in regulating nTH17 cell development. Although Akt and the downstream mTORC1-ARNT-HIFα axis were required for generation of inducible TH17 (iTH17) cells, nTH17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for development of nTH17 cells. Moreover, distinct isoforms of Akt controlled the generation of TH17 cell subsets, as deletion of Akt2, but not of Akt1, led to defective generation of iTH17 cells. These findings define mechanisms regulating nTH17 cell development and reveal previously unknown roles of Akt and mTOR in shaping subsets of T cells.

Regulatory T (T(reg)) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses. Foxp3 operates as a late-acting differentiation factor controlling T(reg) cell homeostasis and function, whereas the early T(reg)-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors. However, whether Foxo proteins act beyond the T(reg)-cell-commitment stage to control T(reg) cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of T(reg )cell function. T(reg) cells express high amounts of Foxo1 and display reduced T-cell-receptor-induced Akt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with T(reg)-cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of T(reg) cells. Genome-wide analysis of Foxo1 binding sites reveals ~300 Foxo1-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt-Foxo1 signalling module controls a novel genetic program indispensable for T(reg) cell function.

Reestablishing homeostasis after tissue damage depends on the proper organization of stem cells and their progeny, though the repair mechanisms are unclear. The mammalian intestinal epithelium is well suited to approach this problem, as it is composed of well-delineated units called crypts of Lieberkühn. We found that Wnt5a, a noncanonical Wnt ligand, was required for crypt regeneration after injury in mice. Unlike controls, Wnt5a-deficient mice maintained an expanded population of proliferative epithelial cells in the wound. We used an in vitro system to enrich for intestinal epithelial stem cells to discover that Wnt5a inhibited proliferation of these cells. Surprisingly, the effects of Wnt5a were mediated by activation of transforming growth factor-β (TGF-β) signaling. These findings suggest a Wnt5a-dependent mechanism for forming new crypt units to reestablish homeostasis.

The asymmetric unit of the title compound, C(14)H(2)Cl(4)F(3)NO(2), contains two independent mol-ecules. In each mol-ecule, the phthalimide ring system is nearly planar [maximum atomic deviation = 0.031 (2) or 0.038 (2) Å] and oriented with respect to the benzene ring at 65.04 (7) or 71.76 (10)°. Weak inter-molecular C-H⋯O and C-H⋯F hydrogen bonding is present in the crystal structure.