The IgM receptor FcµR limits tonic BCR signaling by regulating expression of the IgM BCR.

The FcµR receptor for the crystallizable fragment (Fc) of immunoglobulin M (IgM) can function as a cell-surface receptor for secreted IgM on a variety of cell types. We found here that FcµR was also expressed in the trans-Golgi network of developing B cells, where it constrained transport of the IgM-isotype BCR (IgM-BCR) but not of the IgD-isotype BCR (IgD-BCR). In the absence of FcµR, the surface expression of IgM-BCR was increased, which resulted in enhanced tonic BCR signaling. B-cell-specific deficiency in FcµR enhanced the spontaneous differentiation of B-1 cells, which resulted in increased serum concentrations of natural IgM and dysregulated homeostasis of B-2 cells; this caused the spontaneous formation of germinal centers, increased titers of serum autoantibodies and excessive accumulation of B cells. Thus, FcµR serves as a critical regulator of B cell biology by constraining the transport and cell-surface expression of IgM-BCR.

A Little Fiber Goes a Long Way.

In this issue of Immunity, Trompette et al. (2018) show that dietary fiber and short chain fatty acids reduce influenza A virus-associated immunopathology by enhancing CD8+ T cell effector function and by promoting the differentiation of alternatively activated macrophages.

Intestinal Interleukin-17 Receptor Signaling Mediates Reciprocal Control of the Gut Microbiota and Autoimmune Inflammation.

Interleukin-17 (IL-17) and IL-17 receptor (IL-17R) signaling are essential for regulating mucosal host defense against many invading pathogens. Commensal bacteria, especially segmented filamentous bacteria (SFB), are a crucial factor that drives T helper 17 (Th17) cell development in the gastrointestinal tract. In this study, we demonstrate that Th17 cells controlled SFB burden. Disruption of IL-17R signaling in the enteric epithelium resulted in SFB dysbiosis due to reduced expression of α-defensins, Pigr, and Nox1. When subjected to experimental autoimmune encephalomyelitis, IL-17R-signaling-deficient mice demonstrated earlier disease onset and worsened severity that was associated with increased intestinal Csf2 expression and elevated systemic GM-CSF cytokine concentrations. Conditional deletion of IL-17R in the enteric epithelium demonstrated that there was a reciprocal relationship between the gut microbiota and enteric IL-17R signaling that controlled dysbiosis, constrained Th17 cell development, and regulated the susceptibility to autoimmune inflammation.

Uncovering prostate cancer aggressiveness signal in T2-weighted MRI through a three-reference tissues normalization technique.

Quantitative T2-weighted MRI (T2W) interpretation is impeded by the variability of acquisition-related features, such as field strength, coil type, signal amplification, and pulse sequence parameters. The main purpose of this work is to develop an automated method for prostate T2W intensity normalization. The procedure includes the following: (i) a deep learning-based network utilizing MASK R-CNN for automatic segmentation of three reference tissues: gluteus maximus muscle, femur, and bladder; (ii) fitting a spline function between average intensities in these structures and reference values; and (iii) using the function to transform all T2W intensities. The T2W distributions in the prostate cancer regions of interest (ROIs) and normal appearing prostate tissue (NAT) were compared before and after normalization using Student's t-test. The ROIs' T2W associations with the Gleason Score (GS), Decipher genomic score, and a three-tier prostate cancer risk were evaluated with Spearman's correlation coefficient (rS ). T2W differences in indolent and aggressive prostate cancer lesions were also assessed. The MASK R-CNN was trained with manual contours from 32 patients. The normalization procedure was applied to an independent MRI dataset from 83 patients. T2W differences between ROIs and NAT significantly increased after normalization. T2W intensities in 231 biopsy ROIs were significantly negatively correlated with GS (rS = -0.21, p = 0.001), Decipher (rS = -0.193, p = 0.003), and three-tier risk (rS = -0.235, p < 0.001). The average T2W intensities in the aggressive ROIs were significantly lower than in the indolent ROIs after normalization. In conclusion, the automated triple-reference tissue normalization method significantly improved the discrimination between prostate cancer and normal prostate tissue. In addition, the normalized T2W intensities of cancer exhibited a significant association with tumor aggressiveness. By improving the quantitative utilization of the T2W in the assessment of prostate cancer on MRI, the new normalization method represents an important advance over clinical protocols that do not include sequences for the measurement of T2 relaxation times.

Long-term outcomes of the global tuberculosis and COVID-19 co-infection cohort.

BACKGROUND: Longitudinal cohort data of patients with tuberculosis (TB) and coronavirus disease 2019 (COVID-19) are lacking. In our global study, we describe long-term outcomes of patients affected by TB and COVID-19. METHODS: We collected data from 174 centres in 31 countries on all patients affected by COVID-19 and TB between 1 March 2020 and 30 September 2022. Patients were followed-up until cure, death or end of cohort time. All patients had TB and COVID-19; for analysis purposes, deaths were attributed to TB, COVID-19 or both. Survival analysis was performed using Cox proportional risk-regression models, and the log-rank test was used to compare survival and mortality attributed to TB, COVID-19 or both. RESULTS: Overall, 788 patients with COVID-19 and TB (active or sequelae) were recruited from 31 countries, and 10.8% (n=85) died during the observation period. Survival was significantly lower among patients whose death was attributed to TB and COVID-19 versus those dying because of either TB or COVID-19 alone (p<0.001). Significant adjusted risk factors for TB mortality were higher age (hazard ratio (HR) 1.05, 95% CI 1.03-1.07), HIV infection (HR 2.29, 95% CI 1.02-5.16) and invasive ventilation (HR 4.28, 95% CI 2.34-7.83). For COVID-19 mortality, the adjusted risks were higher age (HR 1.03, 95% CI 1.02-1.04), male sex (HR 2.21, 95% CI 1.24-3.91), oxygen requirement (HR 7.93, 95% CI 3.44-18.26) and invasive ventilation (HR 2.19, 95% CI 1.36-3.53). CONCLUSIONS: In our global cohort, death was the outcome in >10% of patients with TB and COVID-19. A range of demographic and clinical predictors are associated with adverse outcomes.

Human intelectin-2 (ITLN2) is selectively expressed by secretory Paneth cells.

Intelectins (intestinal lectins) are highly conserved across chordate evolution and have been implicated in various human diseases, including Crohn's disease (CD). The human genome encodes two intelectin genes, intelectin-1 (ITLN1) and intelectin-2 (ITLN2). Other than its high sequence similarity with ITLN1, little is known about ITLN2. To address this void in knowledge, we report that ITLN2 exhibits discrete, yet notable differences from ITLN1 in primary structure, including a unique amino terminus, as well as changes in amino acid residues associated with the glycan-binding activity of ITLN1. We identified that ITLN2 is a highly abundant Paneth cell-specific product, which localizes to secretory granules, and is expressed as a multimeric protein in the small intestine. In surgical specimens of ileal CD, ITLN2 mRNA levels were reduced approximately five-fold compared to control specimens. The ileal expression of ITLN2 was unaffected by previously reported disease-associated variants in ITLN2 and CD-associated variants in neighboring ITLN1 as well as NOD2 and ATG16L1. ITLN2 mRNA expression was undetectable in control colon tissue; however, in both ulcerative colitis (UC) and colonic CD, metaplastic Paneth cells were found to express ITLN2. Together, the data reported establish the groundwork for understanding ITLN2 function(s) in the intestine, including its possible role in CD.

Nrf2 through Aryl Hydrocarbon Receptor Regulates IL-22 Response in CD4+ T Cells.

IL-17A and IL-22 derived from Th17 cells play a significant role in mucosal immunity and inflammation. TGF-ß and IL-6 promote Th17 differentiation; however, these cytokines have multiple targets. The identification and screening of additional molecules that regulate IL-17A and IL-22 responses in certain inflammatory conditions is of great clinical significance. In this study, we show that CDDO-Im, a specific Nrf2 activator, promotes IL-17A and IL-22 responses in murine Th17 cells. In contrast, CDDO-Im inhibits IL-17A response in multiple sclerosis patient-derived PBMCs. However, Nrf2 specifically regulates IL-22 response in vivo. Nrf2 acts through the regulation of antioxidant response element (ARE) binding motifs in target genes to induce or repress transcription. Promoter analysis revealed that Il17a, Rorc, and Ahr genes have several ARE motifs. We showed that Nrf2 bound to ARE repressor (ARE-R2) of Rorc and inhibited Rorc-dependent IL-17A transactivation. The luciferase reporter assay data showed that CDDO-Im regulated Ahr promoter activity. Chromatin immunoprecipitation quantitative PCR data showed that Nrf2 bound to ARE of AhR. Finally, we confirmed that the CDDO-Im-mediated induction of IL-22 production in CD4+ T cells was abrogated in CD4-specific Ahr knockout mice (AhrCD4 ). CH-223191, a specific AhR antagonist, inhibits CDDO-Im-induced IL-22 production in CD4+ T cells, which further confirmed the AhR-dependent regulation. Collectively, our data showed that Nrf2 via AhR pathways regulated IL-22 response in CD4+ T cells.

T-cell derived acetylcholine aids host defenses during enteric bacterial infection with Citrobacter rodentium.

The regulation of mucosal immune function is critical to host protection from enteric pathogens but is incompletely understood. The nervous system and the neurotransmitter acetylcholine play an integral part in host defense against enteric bacterial pathogens. Here we report that acetylcholine producing-T-cells, as a non-neuronal source of ACh, were recruited to the colon during infection with the mouse pathogen Citrobacter rodentium. These ChAT+ T-cells did not exclusively belong to one Th subset and were able to produce IFNγ, IL-17A and IL-22. To interrogate the possible protective effect of acetylcholine released from these cells during enteric infection, T-cells were rendered deficient in their ability to produce acetylcholine through a conditional gene knockout approach. Significantly increased C. rodentium burden was observed in the colon from conditional KO (cKO) compared to WT mice at 10 days post-infection. This increased bacterial burden in cKO mice was associated with increased expression of the cytokines IL-1ß, IL-6, and TNFα, but without significant changes in T-cell and ILC associated IL-17A, IL-22, and IFNγ, or epithelial expression of antimicrobial peptides, compared to WT mice. Despite the increased expression of pro-inflammatory cytokines during C. rodentium infection, inducible nitric oxide synthase (Nos2) expression was significantly reduced in intestinal epithelial cells of ChAT T-cell cKO mice 10 days post-infection. Additionally, a cholinergic agonist enhanced IFNγ-induced Nos2 expression in intestinal epithelial cell in vitro. These findings demonstrated that acetylcholine, produced by specialized T-cells that are recruited during C. rodentium infection, are a key mediator in host-microbe interactions and mucosal defenses.

Interleukin-22 (IL-22) Binding Protein Constrains IL-22 Activity, Host Defense, and Oxidative Phosphorylation Genes during Pneumococcal Pneumonia.

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide, and interleukin-22 (IL-22) helps contain pneumococcal burden in lungs and extrapulmonary tissues. Administration of IL-22 increases hepatic complement 3 and complement deposition on bacteria and improves phagocytosis by neutrophils. The effects of IL-22 can be tempered by a secreted natural antagonist, known as IL-22 binding protein (IL-22BP), encoded by Il22ra2 To date, the degree to which IL-22BP controls IL-22 in pulmonary infection is not well defined. Here, we show that Il22ra2 inhibits IL-22 during S. pneumoniae lung infection and that Il22ra2 deficiency favors downregulation of oxidative phosphorylation (OXPHOS) genes in an IL-22-dependent manner. Il22ra2-/- mice are more resistant to S. pneumoniae infection, have increased IL-22 in lung tissues, and sustain longer survival upon infection than control mice. Transcriptome sequencing (RNA-seq) analysis of infected Il22ra2-/- mouse lungs revealed downregulation of genes involved in OXPHOS. Downregulation of this metabolic process is necessary for increased glycolysis, a crucial step for transitioning to a proinflammatory phenotype, in particular macrophages and dendritic cells (DCs). Accordingly, we saw that macrophages from Il22ra2-/- mice displayed reduced OXPHOS gene expression upon infection with S. pneumoniae, changes that were IL-22 dependent. Furthermore, we showed that macrophages express IL-22 receptor subunit alpha-1 (IL-22Ra1) during pneumococcal infection and that Il22ra2-/- macrophages rely more on the glycolytic pathway than wild-type (WT) controls. Together, these data indicate that IL-22BP deficiency enhances IL-22 signaling in the lung, thus contributing to resistance to pneumococcal pneumonia by downregulating OXPHOS genes and increasing glycolysis in macrophages.

Patient Navigation to Enhance Access to Care for Underserved Patients with a Suspicion or Diagnosis of Cancer.

BACKGROUND: Interventions aimed at improving access to timely cancer care for patients in low- and middle-income countries (LMIC) are urgently needed. We aimed to evaluate a patient navigation (PN) program to reduce referral time to cancer centers for underserved patients with a suspicion or diagnosis of cancer at a public general hospital in Mexico City. MATERIALS AND METHODS: From January 2016 to March 2017, consecutive patients aged >18 years with a suspicion or diagnosis of cancer seen at Ajusco Medio General Hospital in Mexico City who required referral to a specialized center for diagnosis or treatment were enrolled. A patient navigator assisted patients with scheduling, completing paperwork, obtaining results in a timely manner, transportation, and addressing other barriers to care. The primary outcome was the proportion of patients who obtained a specialized consultation at a cancer center within the first 3 months after enrollment. RESULTS: Seventy patients (median age 54, range 19-85) participated in this study. Ninety-six percent (n = 67) identified >1 barrier to cancer care access. The most commonly reported barriers to health care access were financial burden (n = 50) and fear (n = 37). Median time to referral was 7 days (range 0-49), and time to specialist appointment was 27 days (range 1-97). Ninety-one percent of patients successfully obtained appointments at cancer centers in <3 months. CONCLUSION: Implementing PN in LMIC is feasible, and may lead to shortened referral times for specialized cancer care by helping overcome barriers to health care access among underserved patients. IMPLICATIONS FOR PRACTICE: A patient navigation program for patients with suspicion or diagnosis of cancer in a second-level hospital was feasible and acceptable. It reduced patient-reported barriers, and referral time to specialized appointments and treatment initiation were within international recommended limits. Patient navigation may improve access to care for underserved patients in developing countries.

Correction to: Health-Related Information-Seeking Behaviors and Preferences Among Mexican Patients with Cancer.

The original version of this article unfortunately contained a mistake. The name of "Viridiana Perez-Montessoro" is now corrected in the author group of this article. The original article has been corrected.

Health-Related Information-Seeking Behaviors and Preferences Among Mexican Patients with Cancer.

Understanding the preferred sources of health-related information among patients with cancer is essential for designing successful cancer education and prevention strategies. However, little is known about health-related information-seeking practices among patients living in low- and middle-income countries. We studied the preferred sources of health-related information among Mexican patients with cancer and explored which factors influence these choices. The health-related information-seeking practices among patients with cancer treated at a public hospital in Mexico City were evaluated using questions from the Spanish Version of the Health Information National Trends Survey. The characteristics of patients who sought health-related information, and of those who chose the internet as their preferred source of information, were analyzed. Fisher's exact test and logistic regression were used for statistical analyses. One hundred forty-eight patients answered the survey (median age 60 years, 70% female), of which 88 (59%) had sought for health-related information. On multivariate analysis, the only characteristic associated with lower odds of seeking health-related information was increasing age (OR 0.93, 95% CI 0.90-0.97). Sixty-one respondents (69%) listed the internet as their preferred source of health-related information. On multivariate analysis, only being of the female gender (OR 4.9, 95% CI 1.3-18.3) was related with higher odds of preferring other sources of information over the internet. Among Mexican patients with cancer, the Internet is the most widely used information source. Older age was the characteristic most strongly associated with not seeking health-related information, while being female was strongly associated with preferring other sources of information over the Internet.

Phylotype Dynamics of Bacterial P Utilization Genes in Microbialites and Bacterioplankton of a Monomictic Endorheic Lake.

Microbes can modulate ecosystem function since they harbor a vast genetic potential for biogeochemical cycling. The spatial and temporal dynamics of this genetic diversity should be acknowledged to establish a link between ecosystem function and community structure. In this study, we analyzed the genetic diversity of bacterial phosphorus utilization genes in two microbial assemblages, microbialites and bacterioplankton of Lake Alchichica, a semiclosed (i.e., endorheic) system with marked seasonality that varies in nutrient conditions, temperature, dissolved oxygen, and water column stability. We focused on dissolved organic phosphorus (DOP) utilization gene dynamics during contrasting mixing and stratification periods. Bacterial alkaline phosphatases (phoX and phoD) and alkaline beta-propeller phytases (bpp) were surveyed. DOP utilization genes showed different dynamics evidenced by a marked change within an intra-annual period and a differential circadian pattern of expression. Although Lake Alchichica is a semiclosed system, this dynamic turnover of phylotypes (from lake circulation to stratification) points to a different potential of DOP utilization by the microbial communities within periods. DOP utilization gene dynamics was different among genetic markers and among assemblages (microbialite vs. bacterioplankton). As estimated by the system's P mass balance, P inputs and outputs were similar in magnitude (difference was <10 %). A theoretical estimation of water column P monoesters was used to calculate the potential P fraction that can be remineralized on an annual basis. Overall, bacterial groups including Proteobacteria (Alpha and Gamma) and Bacteroidetes seem to be key participants in DOP utilization responses.

Eruptive disseminated pyogenic granulomas following lightning injury.

BACKGROUND: Pyogenic granuloma (PG) is a common benign acquired vascular tumor. It classically presents as a solitary friable nodule on the face or distal extremities. Disseminated eruption is rare and can occur spontaneously or secondary to various triggers, including burn injury. To date, the literature reports only 13 cases of eruptive PGs following burn injury, most from exposure to boiling milk or water. We report the first case of disseminated eruptive PGs following a lightning injury. CASE: A 17-year-old previously healthy boy developed second- and third-degree burns following lightning injury. Two weeks later, he developed widespread dark-purple polypoid exophytic tumors ranging from 1 to 10 cm in diameter extending beyond the limits of the initial burn injury. The lesions were friable and often formed erosions and crusts. The patient was otherwise well and laboratory and microbiological investigations were normal. Excisional biopsy of a lesion was diagnostic of PG and the patient was treated with surgical excision of the lesions, without recurrence. CONCLUSION: The exact pathogenesis of multiple PGs remains unknown. Several pathogenic mechanisms have been suggested, including production of angiogenic factors that stimulate endothelial proliferation and formation of minute arteriovenous fistulas by trauma.

Community metabolism in a deep (stratified) tropical reservoir during a period of high water-level fluctuations.

As long as lakes and reservoirs are an important component of the global carbon cycle, monitoring of their metabolism is required, especially in the tropics. In particular, the response of deep reservoirs to water-level fluctuations (WLF) is an understudied field. Here, we study community metabolism through oxygen dynamics in a deep monomictic reservoir where high WLF (~10 m) have recently occurred. Simultaneous monitoring of environmental variables and zooplankton dynamics was used to assess the effects of WLF on the metabolism of the eutrophic Valle de Bravo (VB) reservoir, where cyanobacteria blooms are frequent. Mean gross primary production (P g) was high (2.2 g C m(-2) day(-1)), but temporal variation of P g was low except for a drastic reduction during circulation attributed to zooplankton grazing. The trophogenic layer showed net autotrophy on an annual basis, but turned to net heterotrophy during mixing, and furthermore when the whole water-column oxygen balance was calculated, considering the aphotic respiration (Raphotic). The high total respiration resulting (3.1 g C m(-2) day(-1)) is considered to be partly due to mixing enhanced by WLF. Net ecosystem production was equivalent to a net export of 3.4 mg CO2 m(-2) day(-1) to the atmosphere. Low water levels are posed to intensify boundary-mixing events driven by the wind during the stratification in VB. Long-term monitoring showed changes in the planktonic community and a strong silicon decrease that matched with low water-level periods. The effects of low water-level on metabolism and planktonic community in VB suggest that water-level manipulation could be a useful management tool to promote phytoplankton groups other than cyanobacteria.

Cerebrospinal Fluid Testing in Leptomeningeal Progression of HER2-Negative Breast Cancer Reveals HER2 Positivity, Leading to HER2-Targeted Therapy: A Case Report.

The treatment of breast cancer is largely determined by protein expression assays of estrogen receptor, progesterone receptor, and Her2/neu (HER2) status. These prognostic markers may vary due to tumor heterogeneityor the evolution of prognostic markers throughout the course of treatment. This report presents a case of a patient who initially presented with HER2-negative breast cancer and had rapidly progressed on numerous lines of treatment. An analysis of cerebrospinal fluid via next-generation sequencing and biopsy of metastasis to the liver identified HER2-positive cancer, which allowed for the use of trastuzumab deruxtecan, a HER2-targeted therapy. This led to an excellent clinical response with improvement in performance status and quality of life. This case report demonstrates the importance of continuing to follow a patient's cancer pathology to open the doors for other opportunities for treatment. Cancer has the potential to evolve and there is a benefit of obtaining rebiopsies to ensure the correct targeted therapies are provided to the patient.

Extensive in vivo human milk peptidomics reveals specific proteolysis yielding protective antimicrobial peptides.

Milk is traditionally considered an ideal source of the basic elemental nutrients required by infants. More detailed examination is revealing that milk represents a more functional ensemble of components with benefits to both infants and mothers. A comprehensive peptidomics method was developed and used to analyze human milk yielding an extensive array of protein products present in the fluid. Over 300 milk peptides were identified originating from major and many minor protein components of milk. As expected, the majority of peptides derived from ß-casein, however no peptide fragments from the major milk proteins lactoferrin, α-lactalbumin, and secretory immunoglobulin A were identified. Proteolysis in the mammary gland is selective-released peptides were drawn only from specific proteins and typically from only select parts of the parent sequence. A large number of the peptides showed significant sequence overlap with peptides with known antimicrobial or immunomodulatory functions. Antibacterial assays showed the milk peptide mixtures inhibited the growth of Escherichia coli and Staphylococcus aureus . The predigestion of milk proteins and the consequent release of antibacterial peptides may provide a selective advantage through evolution by protecting both the mother's mammary gland and her nursing offspring from infection.

Cervical cancer in the pregnant population.

Cervical cancer is the second most encountered cancer in pregnant patients. The 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer updated the staging of primary cervical carcinoma and disease process, with formal incorporation of imaging as a vital source of information in the management process to improve accuracy. Diagnosis and treatment of the pregnant population is a complex interplay of achieving adequate diagnostic information and optimal treatment while minimizing toxicity and risks to the mother and fetus. While novel imaging techniques and anticancer therapies are rapidly developed, much information on the safety and feasibility of different therapies is not yet available in the pregnant population. Therefore, managing pregnant patients with cervical cancer is complex and requires a multidisciplinary approach.

Using a mobile health app in a weight management program for overweight and obese adolescents and young adults with spina bifida.

CONTEXT: Adolescents and young adults (AYA) with spina bifida (SB) are more susceptible to obesity due to impaired mobility. There is limited access to physical activity for this population. OBJECTIVE: The primary aim of this study was to evaluate the feasibility of a mobile health app in a weight management program for AYA with SB. This was determined by measuring program adherence, active use of the app (defined as ≥3 uses per week), and user rating of the Pt Pal™ mobile app. Secondary outcomes were changes in BMI, quality of life, and health behavior, and the number of active participants over time. METHODS: Patients from the SB Clinic of a large metropolitan hospital between the ages of 11-21 years and overweight were invited to participate. The program consisted of group nutrition sessions and an individualized exercise plan using a mobile app with coaching. Outcome measures were program adherence, changes in BMI, and validated survey responses. Descriptive statistical analysis was performed. RESULTS: Fifteen participants enrolled, and ten participants completed the program. Five of the ten participants attended the nutrition sessions. The number of active app users declined after the first week. Seventy percent of participants decreased their BMI. Most participants reported the program improved their ability to exercise regularly, eat a healthier diet and feel more self-confident. Peds QL™ psychosocial health domains increased postintervention. The YRBS showed increased physical activity and less sedentary time postintervention. CONCLUSIONS: This mobile app-based weight management program with coaching implemented may not be feasible for adoption in the general population of AYA with SB; however, it was well received by some, and further testing is needed to determine how to improve feasibility. This study provides useful information to guide future programs utilizing digital health and coaching.