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Intestinal immune responses to microbes are controlled by the cytokine IL-10 to avoid immune pathology. Here, we use single-cell RNA sequencing of colon lamina propria leukocytes (LPLs) along with RNA-seq and ATAC-seq of purified CD4+T cells to show that the transcription factors Blimp-1 (encoded by Prdm1) and c-Maf co-dominantly regulate Il10while negatively regulating proinflammatory cytokines in effector T cells. Double-deficient Prdm1fl/flMaffl/flCd4Cremice infected with Helicobacter hepaticusdeveloped severe colitis with an increase in TH1/NK/ILC1 effector genes in LPLs, while Prdm1fl/flCd4Creand Maffl/flCd4Cremice exhibited moderate pathology and a less-marked type 1 effector response. LPLs from infected Maffl/flCd4Cremice had increased type 17 responses with increased Il17aand Il22expression and an increase in granulocytes and myeloid cell numbers, resulting in increased T cell–myeloid–neutrophil interactions. Genes over-expressed in human inflammatory bowel disease showed differential expression in LPLs from infected mice in the absence of Prdm1or Maf, revealing potential mechanisms of human disease.

To describe coronavirus disease 2019 (COVID-19)–related pediatric hospitalizations during a period of B.1.617.2 (Δ) variant predominance and to determine age-specific factors associated with severe illness.We abstracted data from medical charts to conduct a cross-sectional study of patients aged <21 years hospitalized at 6 United States children’s hospitals from July to August 2021 for COVID-19 or with an incidental positive severe acute respiratory syndrome coronavirus 2 test. Among patients with COVID-19, we assessed factors associated with severe illness by calculating age-stratified prevalence ratios (PR). We defined severe illness as receiving high-flow nasal cannula, positive airway pressure, or invasive mechanical ventilation.Of 947 hospitalized patients, 759 (80.1%) had COVID-19, of whom 287 (37.8%) had severe illness. Factors associated with severe illness included coinfection with respiratory syncytial virus (RSV) (PR 3.64) and bacteria (PR 1.88) in infants; RSV coinfection in patients aged 1 to 4 years (PR 1.96); and obesity in patients aged 5 to 11 (PR 2.20) and 12 to 17 years (PR 2.48). Having ≥2 underlying medical conditions was associated with severe illness in patients aged <1 (PR 1.82), 5 to 11 (PR 3.72), and 12 to 17 years (PR 3.19).Among patients hospitalized for COVID-19, factors associated with severe illness included RSV coinfection in those aged <5 years, obesity in those aged 5 to 17 years, and other underlying conditions for all age groups <18 years. These findings can inform pediatric practice, risk communication, and prevention strategies, including vaccination against COVID-19.

Objectives: The objective was to evaluate the effects of elagolix on dyspareunia in women with endometriosis-associated pain.Methods: Data were pooled from two similar, randomized, double-blind, placebo-controlled, 6-month phase 3 studies (Elaris Endometriosis-I and Elaris Endometriosis-II) of elagolix at two doses (150 mg QD and 200 mg BID) in women with endometriosis-associated pain. In this post hoc analysis, dyspareunia responders were defined as having a clinically meaningful decrease from baseline in the dyspareunia score and decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary. Sexual relationship was assessed using the 30-item Endometriosis Health Profile questionnaire sexual relationship module.Results: A total of 1384 women reported ⩾1 day of sexual activity at baseline (35 days prior to and including day 1 of treatment). Of these 1384 women, 1297 (94%) reported ⩾1 day of any dyspareunia (mild, moderate, or severe), of which 51% reported ⩾1 day of severe dyspareunia. Among sexually active women who reported any dyspareunia at baseline, both elagolix doses led to improvements in dyspareunia. Women in the 200-mg BID group showed more months at which the dyspareunia response rates were statistically significantly greater than placebo, particularly in a subgroup of women with severe dyspareunia at baseline. Compared to placebo, both elagolix doses led to statistically significantly greater improvements in the mean 30-item Endometriosis Health Profile sexual relationship module score.Conclusion: Up to 6 months of elagolix treatment improved dyspareunia in women with endometriosis-associated pain in a dose-dependent manner, with 200-mg BID dose showing the most significant improvements in dyspareunia and quality of sexual relationships compared with placebo.

The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4+T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4+T cells in disease models involving the TH1 subset of helper T cells (malaria), TH2 cells (allergy) and TH17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in TH1 and TH2 responses, TH17 cell–mediated pathology was reduced in this context, with an accompanying decrease in TH17 cells and increase in Foxp3+regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor RORγt (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner. The transcription factor c-Maf controls IL-10 production in T cells. O’Garra and colleagues use systems and in vivo functional analysis of T cell subsets to reveal distinct context-specific roles for c-Maf.

The production of sorbitol and gluconic acid by isolated glucose-fructose oxidoreductase (GFOR) fromZymomonas mobilishas been studied in a convective, 100-mL loop reactor with tangential ultrafiltration. Using a dilution rate of 0.04/h and 5 kU/L GFOR, substrate conversion (3Msugar) in a single stage was >85%, and productivities of 126 g sorbitol/(L-d) were obtained. At a constant recycle rate (3/min) and a membrane area of 50 cm2, the dilution rates (and thus productivities) were however limited by a more than 30-fold reduction of the permeate flow in the presence of high sugar and protein concentrations (5 g/L). Protein was added, together with 10 mMdithiothreitol, to improve the stability of GFOR during substrate turnover and crossflow filtration, thus leading to a stable operation of the enzyme reactor for at least 5 d.

In the version of this article initially published, the Supplementary Data file was an incorrect version. The correct version is now provided. The error has been corrected in the HTML and PDF version of the article.