Cytotoxic Programming of CD4+ T Cells Is Regulated by Opposing Actions of the Related Transcription Factors Eos and Aiolos.

In contrast to the "helper" activities of most CD4+ T effector subsets, CD4+ cytotoxic T lymphocytes (CD4-CTLs) perform functions normally associated with CD8+ T and NK cells. Specifically, CD4-CTLs secrete cytotoxic molecules and directly target and kill compromised cells in an MHC class II-restricted fashion. The functions of these cells have been described in diverse immunological contexts, including their ability to provide protection during antiviral and antitumor responses, as well as being implicated in autoimmunity. Despite their significance to human health, the complete mechanisms that govern their programming remain unclear. In this article, we identify the Ikaros zinc finger transcription factor Eos (Ikzf4) as a positive regulator of CD4-CTL differentiation during murine immune responses against influenza virus infection. We find that the frequency of Eos+ cells is elevated in lung CD4-CTL populations and that the cytotoxic gene program is compromised in Eos-deficient CD4+ T cells. Consequently, we observe a reduced frequency and number of lung-residing, influenza virus-responsive CD4-CTLs in the absence of Eos. Mechanistically, we determine that this is due, at least in part, to reduced expression of IL-2 and IL-15 cytokine receptor subunits on the surface of Eos-deficient CD4+ T cells, both of which support the CD4-CTL program. Finally, we find that Aiolos, a related Ikaros family member and known CD4-CTL antagonist, represses Eos expression by antagonizing STAT5-dependent activation of the Ikzf4 promoter. Collectively, our findings reveal a mechanism wherein Eos and Aiolos act in opposition to regulate cytotoxic programming of CD4+ T cells.

Low-cost PM2.5 sensors can help identify driving factors of poor air quality and benefit communities.

Air quality is critical for public health. Residents rely chiefly on government agencies such as the Environmental Protection Agency (EPA) in the United States to establish standards for the measurement of harmful contaminants including ozone, sulfur dioxide, carbon monoxide, volatile organic chemicals (VOCs), and fine particulate matter at or below 2.5 µm. According to the California Air Resources Board [1], "short-term PM2.5 exposure (up to 24-h duration) has been associated with premature mortality, increased hospital admissions for heart or lung causes, acute and chronic bronchitis, asthma attacks, emergency room visits, respiratory symptoms, and restricted activity days". While public agency resources may provide guidance, it is often inadequate relative to the widespread need for effective local measurement and management of air quality risks. To that end, this paper explores the use of low-cost PM2.5 sensors for measuring air quality through micro-scale (local) analytical comparisons with reference grade monitors and identification of potential causal factors of elevated sensor readings. We find that a) there is high correlation between the PM2.5 measurements of low-cost sensors and reference grade monitors, assessed through calibration models, b) low-cost sensors are more prevalent and provide more frequent measurements, and c) low-cost sensor data enables exploratory and explanatory analytics to identify potential causes of elevated PM2.5 readings. This understanding should encourage community scientists to place more low-cost sensors in their neighborhoods, which can empower communities to demand policy changes that are necessary to reduce particle pollution, and provide a basis for subsequent research.

Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity.

During intracellular infection, T follicular helper (TFH) and T helper 1 (TH1) cells promote humoral and cell-mediated responses, respectively. Another subset, CD4-cytotoxic T lymphocytes (CD4-CTLs), eliminate infected cells via functions typically associated with CD8+ T cells. The mechanisms underlying differentiation of these populations are incompletely understood. Here, we identify the transcription factor Aiolos as a reciprocal regulator of TFH and CD4-CTL programming. We find that Aiolos deficiency results in downregulation of key TFH transcription factors, and consequently reduced TFH differentiation and antibody production, during influenza virus infection. Conversely, CD4-CTL programming is elevated, including enhanced Eomes and cytolytic molecule expression. We further demonstrate that Aiolos deficiency allows for enhanced IL-2 sensitivity and increased STAT5 association with CD4-CTL gene targets, including Eomes, effector molecules, and IL2Ra. Thus, our collective findings identify Aiolos as a pivotal regulator of CD4-CTL and TFH programming and highlight its potential as a target for manipulating CD4+ T cell responses.

Mothers' Perspectives on a Mother/Infant Dyad Postpartum Primary Care Program Following Gestational Diabetes Mellitus: A Qualitative Pilot Study.

PURPOSE: The purpose of this study is to characterize mothers' experiences within a mother/infant dyad postpartum primary care program (Dyad) following gestational diabetes mellitus (GDM) to inform improvements in the delivery of care. METHODS: A qualitative pilot study of women (n = 10) enrolled in a mother/infant Dyad program was conducted in a primary care practice at a large, urban academic medical center. Respondents were asked a series of open-ended questions about their experience with GDM, the Dyad program, and health behaviors. Interviews were audio-recorded, transcribed verbatim, and analyzed using ground theory with NVivo 12 Plus software. RESULTS: Three key themes emerged: (1) Dyad program experience, (2) implementation of health behavior changes, and (3) acknowledgment of future GDM and type 2 diabetes mellitus (T2DM) health risks. Respondents felt that the program conveniently served mother and infant health care needs in a single appointment. Respondents also valued support from primary care providers when implementing health behavior changes. The Dyad program provided an opportunity for respondents to understand their current and future risk for developing GDM and T2DM. CONCLUSIONS: Postpartum women enrolled in the Dyad program received highly personalized primary care services. The results of our study will help integrate patient-centered strategies into models for GDM care to maintain patient engagement in postpartum clinical services.

Mediastinal Fibrosarcoma in a Dog-Case Report.

This represents the first published case report of mediastinal fibrosarcoma in a dog. An 8-year-old male neutered mixed breed dog was presented for evaluation of lethargy and increased panting. Thoracic focused assessment with sonography for trauma revealed moderate pleural effusion. Thoracic radiograph findings were suggestive of a cranial mediastinal mass. Computed tomography revealed a mass within the right ventral aspect of the cranial mediastinum. On surgical exploration, a cranial mediastinal mass with an adhesion to the right cranial lung lobe was identified and removed en-bloc using a vessel sealant device and requiring a partial lung lobectomy. Histopathology results described the cranial mediastinal mass as fibrosarcoma with reactive mesothelial cells identified within the sternal lymph node. The patient was treated with systemic chemotherapy following surgical removal. To date, the dog has survived 223 days following diagnosis with recurrence noted 161 days following diagnosis and radiation therapy was initiated. Primary cranial mediastinal fibrosarcoma while a seemingly rare cause of thoracic pathology in dogs, should be considered in the differential diagnosis for a cranial mediastinal mass.

Mother-Infant Dyad program in primary care: evidence-based postpartum care following gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM), a common complication of pregnancy, is associated with a 10-fold increased risk of type 2 diabetes mellitus (T2DM) compared to the general population. Evidence-based guidelines recommend that patients with GDM receive postpartum care for T2DM risk reduction including an oral glucose tolerance test (OGTT) 4-12 weeks after delivery, yet half of patients with GDM did not return for their postpartum visits by 12 weeks postpartum. Additionally, only 10% utilize primary care within 12 months of delivery and one-third of GDM patients receive timely postpartum OGTT. OBJECTIVE: To determine if the Mother-Infant Dyad postpartum primary care program provides a framework to link well-child visits with postpartum primary care visits to increase postpartum clinical interactions promoting longitudinal care, such as postpartum visit attendance and T2DM screening. STUDY DESIGN: All patients with a diagnosis of GDM that received care at a postpartum mother-infant dyad program at a Midwestern academic medical center internal medicine and pediatrics primary care clinic were enrolled. Clinic level data was obtained by baseline and 6-month post-enrollment surveys and chart review. A comparison population was identified from Medicaid claims data using propensity score matching to enable a comparison of program participants' outcomes to a population comprised of similar individuals diagnosed with GDM that received care at sites not participating in the Dyad program. Our primary outcome was completion of T2DM screening in the 4-12 week postpartum period. The secondary outcomes were postpartum visit attendance with a prenatal provider, and prediabetes diagnoses. RESULTS: A total of 75 mother-infant dyads were seen by the clinic. Of the enrolled women, 43% were Non-Hispanic White and 30% were Non-Hispanic Black; mean age was 30.75 years. The matched comparison group (n = 62) had a mean age of 30.75 years, were 43% Non-Hispanic White and 30% Non-Hispanic Black. Women who participated in the program were more likely to receive T2DM screenings than women who did not participate (87 vs. 79%, p<.001) and complete postpartum visits (95 vs. 58%, respectively; p<.001). Additionally, a higher rate of new prediabetes diagnoses was observed (12 vs. 6%, p < .001). CONCLUSION: The Mother-Infant Dyad postpartum primary care program improved T2DM screenings and postpartum visit attendance. In addition, a greater proportion of Dyad program participants experienced new prediabetes diagnoses that those in the comparison group. Our findings suggest that the dyad care model, in which women with GDM engage in postpartum primary care concurrent with well-child visits, can improve longitudinal postpartum care after a GDM diagnosis.

FGFR and PTEN signaling interact during lens development to regulate cell survival.

Lens epithelial cells express many receptor tyrosine kinases (RTKs) that stimulate PI3K-AKT and RAS-RAF-MEK-ERK intracellular signaling pathways. These pathways ultimately activate the phosphorylation of key cellular transcription factors and other proteins that control proliferation, survival, metabolism, and differentiation in virtually all cells. Among RTKs in the lens, only stimulation of fibroblast growth factor receptors (FGFRs) elicits a lens epithelial cell to fiber cell differentiation response in mammals. Moreover, although the lens expresses three different Fgfr genes, the isolated removal of Fgfr2 at the lens placode stage inhibits both lens cell survival and fiber cell differentiation. Phosphatase and tensin homolog (PTEN), commonly known as a tumor suppressor, inhibits ERK and AKT activation and initiates both apoptotic pathways, and cell cycle arrest. Here, we show that the combined deletion of Fgfr2 and Pten rescues the cell death phenotype associated with Fgfr2 loss alone. Additionally, Pten removal increased AKT and ERK activation, above the levels of controls, in the presence or absence of Fgfr2. However, isolated deletion of Pten failed to stimulate ectopic fiber cell differentiation, and the combined deletion of Pten and Fgfr2 failed to restore differentiation-specific Aquaporin0 and DnaseIIß expression in the lens fiber cells.

Potent, persistent induction and modulation of cellular immune responses in rhesus macaques primed with Ad5hr-simian immunodeficiency virus (SIV) env/rev, gag, and/or nef vaccines and boosted with SIV gp120.

Immunity elicited by multicomponent vaccines delivered by replication-competent Ad5hr-simian immunodeficiency virus (SIV) recombinants was systematically investigated. Rhesus macaques were immunized mucosally at weeks 0 and 12 with Ad5hr-SIV(smH4) env/rev, with or without Ad5hr-SIV(mac239) gag or Ad5hr-SIV(mac239) nef, or with all three recombinants. The total Ad5hr dosage was comparably adjusted among all animals with empty Ad5hr-DeltaE3 vector. The macaques were boosted with SIV gp120 in monophosphoryl A-stable emulsion adjuvant at 24 and 36 weeks. Controls received Ad5hr-DeltaE3 vector or adjuvant only. By ELISPOT analysis, all four SIV gene products elicited potent cellular immune responses that persisted 42 weeks post-initial immunization. Unexpectedly, modulation of this cellular immune response was observed among macaques receiving one, two, or three Ad5hr-SIV recombinants. Env responses were significantly enhanced throughout the immunization period in macaques immunized with Ad5hr-SIV env/rev plus Ad5hr-SIV gag and tended to be higher in macaques that also received Ad5hr-SIV nef. Macaques primed with all three recombinants displayed significant down-modulation in numbers of gamma interferon (IFN-gamma)-secreting cells specific for SIV Nef, and the Env- and Gag-specific responses were also diminished. Modulation of antibody responses was not observed. Down-modulation was seen only during the period of Ad5hr-recombinant priming, not during subunit boosting, although SIV-specific IFN-gamma-secreting cells persisted. The effect was not attributable to Ad5hr replication differences among immunization groups. Vaccine delivery via replication-competent live vectors, which can persistently infect new cells and continuously present low-level antigen, may be advantageous in overcoming competition among complex immunogens for immune recognition. Effects of current multicomponent vaccines on individual immune responses should be evaluated with regard to future vaccine design.