Metabolic-epigenetic regulation of macrophage polarization.

Tumor-associated macrophages polarized to an M2 phenotype (M2-TAMs) promote neo-angiogenesis, tumor-stromal matrix remodeling, and immuno-evasion, which, collectively, contribute to immunotherapeutic resistance and reduced cancer patient survival. Highly glycolytic “Warburg” cancer cells produce lactate that independently drives naïve M0→immunosuppressive M2 (M0→M2) macrophage polarization, but the mechanisms have not been fully elucidated. The atypical cytokine macrophage migration inhibitory factor (MIF) is a fundamental underlying requirement for immunosuppressive M2 macrophage polarization. Still, it is unknown whether a molecular link exists between lactate-supported and MIF-dependent M2 macrophage polarization. Using a combination of gene expression assays, chromatin immunoprecipitation, and metabolomic analyses, we identified that M2 macrophages incorporate exogenous lactate into the TCA cycle, with subsequent mitochondrial export as citrate and cleavage by ATP-citrate lyase (ACLY) to generate nucleo-cytosolic acetyl-CoA for histone acetylation. For the first time, our studies identify lactate as a bona fide mitochondrial metabolite in M2 macrophages that supports metabolic reprogramming and macrophage-mediated immunosuppression. These results enhance the understanding of the metabolic interplay between lactate-producing “Warburg-like” tumors and immunosuppressive macrophage phenotypes and may help identify molecular targets for the development of TAM-directed immunotherapies. Separately, we also identified that MIF is a critical determinant of metabolic reprogramming during M2 macrophage polarization by sustaining mitochondrial metabolism to support a metabolic-epigenetic link through α-ketoglutarate-dependent histone demethylation. Additionally, our data suggest that a CSN5/NRF2 pathway exists as an intermediary mechanistic link of MIF-dependent metabolic reprogramming during M2 macrophage polarization. These results suggest that small molecule MIF inhibition may be an efficacious immunotherapeutic strategy by targeting metabolic reprogramming during M2-TAM-mediated tumor progression. Altogether, the work described in this dissertation expands our knowledge of the metabolic-epigenetic regulations of M2 macrophage polarization by identifying the contribution of mitochondrial lactate metabolism in ACLY-dependent histone acetylation and by determining the contribution of MIF in metabolic reprogramming-dependent histone demethylation

Fermi-Edge Superfluorescence from a Quantum-Degenerate Electron-Hole Gas

We report on the observation of spontaneous bursts of coherent radiation from a quantum-degenerate gas of nonequilibrium electron-hole pairs in semiconductor quantum wells. Unlike typical spontaneous emission from semiconductors, which occurs at the band edge, the observed emission occurs at the quasi-Fermi edge of the carrier distribution. As the carriers are consumed by recombination, the quasi-Fermi energy goes down toward the band edge, and we observe a continuously red-shifting streak. We interpret this emission as cooperative spontaneous recombination of electron-hole pairs, or superfluorescence, which is enhanced by Coulomb interactions near the Fermi edge. This novel many-body enhancement allows the magnitude of the spontaneously developed macroscopic polarization to exceed the maximum value for ordinary superfluorescence, making electron-hole superfluorescence even more "super" than atomic superfluorescence.Comment: 10 pages, 5 figure

Do Mitigated Wetlands Support Similar Small Mammal Communities as Natural Wetlands?

Wetlands provide many ecosystem services and play an important ecological role in wildlife communities. Although wetland mitigation is a standard tool to combat losses to natural wetlands, it is essential to understand if mitigated wetlands are truly replacing natural wetlands in their full capacity. Because one important role of wetlands is to provide habitat for wildlife communities, it is important to determine if these created or restored wetlands can foster a wildlife community that is similar to natural wetlands. One understudied taxa in the realm of wetland mitigation research is small mammals. Our objectives are to examine community composition, occupancy, abundance, species diversity, species richness, and species evenness of small mammals at mitigated and natural wetlands to determine if there exists a difference between the two types of wetlands. To conduct this research, we are using Sherman traps for a capture-mark-recapture study on small mammals at mitigated and natural wetlands that are paired by similarities in ecoregion, elevation, geology, and wetland classification. In 2020, ten wetland sites were sampled with a total of 3,875 trap nights and 249 captures. Preliminary data analyses show Peromyscus spp. to be more abundant in natural wetlands than mitigated wetlands, and species richness between the two wetland types not to be statistically different. Results will determine if mitigated wetlands are successful in terms of providing habitat for small mammal communities, and in turn will contribute to whether current wetland mitigation is truly fulfilling its intended purpose. These findings could inform future management decisions

Premade Nanoparticle Films for the Synthesis of Vertically Aligned Carbon Nanotubes

Carbon nanotubes (CNTs) offer unique properties that have the potential to address multiple issues in industry and material sciences. Although many synthesis methods have been developed, it remains difficult to control CNT characteristics. Here, with the goal of achieving such control, we report a bottom-up process for CNT synthesis in which monolayers of premade aluminum oxide (Al2O3) and iron oxide (Fe3O4) nanoparticles were anchored on a flat silicon oxide (SiO2) substrate. The nanoparticle dispersion and monolayer assembly of the oleic-acid-stabilized Al2O3 nanoparticles were achieved using 11-phosphonoundecanoic acid as a bifunctional linker, with the phosphonate group binding to the SiO2 substrate and the terminal carboxylate group binding to the nanoparticles. Subsequently, an Fe3O4 monolayer was formed over the Al2O3 layer using the same approach. The assembled Al2O3 and Fe3O4 nanoparticle monolayers acted as a catalyst support and catalyst, respectively, for the growth of vertically aligned CNTs. The CNTs were successfully synthesized using a conventional atmospheric pressure-chemical vapor deposition method with acetylene as the carbon precursor. Thus, these nanoparticle films provide a facile and inexpensive approach for producing homogenous CNTs

The effect of montelukast on exhaled nitric oxide of alveolar and bronchial origin in inhaled corticosteroid-treated asthma

SummaryBackgroundInhaled corticosteroid therapy suppresses nitric oxide levels (NO) of airway origin but not necessarily NO of alveolar or small airway origin. Systemic therapy with an oral anti-leukotriene agent may suppress NO production in distal airways and alveoli not reached by inhaled therapy.MethodsAdult patients with mild asthma were treated for 3 weeks with inhaled fluticasone 250μg twice daily then with inhaled fluticasone plus oral montelukast 10mg daily for 3 additional weeks. We monitored exhaled NO (eNO), spirometry, lung volumes, and asthma symptoms scores at baseline and at the end of each treatment period. In a subset of patients, we continued with montelukast monotherapy and repeated these measurements.ResultsIn the 18 patients studied, pulmonary function parameters and asthma symptom scores were not altered significantly from baseline by any therapy. The total eNO at baseline was 55±35.3ppb, dropping to 28.1±15.3ppb (p=0.005) after 3 weeks of fluticasone and to 23.5±14ppb (p=0.001 vs. baseline) after the addition of montelukast. The trend towards reduced total eNO with the combination therapy vs. monotherapy was not statistically significant. Alveolar eNO dropped from 4.2±2.4 at baseline to 3.0±1.5 (p=0.1) after fluticasone and then to 2.2±0.9 (p=0.08 vs. baseline) after fluticasone plus montelukast, increasing then to 3.8±1.8 after montelukast alone (p=0.6 vs. baseline).ConclusionsLeukotriene receptor antagonists administered systemically might decrease small airway/alveolar sites of inflammation when combined to inhaled corticosteroid therapy

Complement System Part II: Role in Immunity

International audienceThe complement system has been considered for a long time as a simple lytic cascade, aimed to kill bacteria infecting the host organism. Nowadays, this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation, and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis) of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing opsonization and a direct killing by C5b–9 membrane attack complex and by triggering inflammatory responses with the anaphylatoxins C3a and C5a. Opsonization plays also a major role in the mounting of an adaptive immune response, involving antigen presenting cells, T-, and B-lymphocytes. Nevertheless, it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Inadequate complement activation becomes a disease cause, as in atypical hemolytic uremic syndrome, C3 glomerulopathies, and systemic lupus erythematosus. Age-related macular degeneration and cancer will be described as examples showing that complement contributes to a large variety of conditions, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target

A cohort study of bacteremic pneumonia: The importance of antibiotic resistance and appropriate initial therapy?

Bacteremic pneumonia is usually associated with greater mortality. However, risk factors associated with hospital mortality in bacteremic pneumonia are inadequately described. The study was a retrospective cohort study, conducted in Barnes-Jewish Hospital (2008–2015). For purposes of this investigation, antibiotic susceptibility was determined according to ceftriaxone susceptibility, as ceftriaxone represents the antimicrobial agent most frequently recommended for hospitalized patients with community-acquired pneumonia as opposed to nosocomial pneumonia. Two multivariable analyses were planned: the first model included resistance to ceftriaxone as a variable, whereas the second model included the various antibiotic-resistant species (methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacteriaceae). In all, 1031 consecutive patients with bacteremic pneumonia (mortality 37.1%) were included. The most common pathogens associated with infection were S aureus (34.1%; methicillin resistance 54.0%), Enterobacteriaceae (28.0%), P aeruginosa (10.6%), anaerobic bacteria (7.3%), and Streptococcus pneumoniae (5.6%). Compared with ceftriaxone-susceptible pathogens (46.8%), ceftriaxone-resistant pathogens (53.2%) were significantly more likely to receive inappropriate initial antibiotic treatment (IIAT) (27.9% vs 7.1%; P < 0.001) and to die during hospitalization (41.5% vs 32.0%; P = 0.001). The first logistic regression analysis identified IIAT with the greatest odds ratio (OR) for mortality (OR 2.2, 95% confidence interval [CI] 1.5–3.2, P < 0.001). Other independent predictors of mortality included age, mechanical ventilation, immune suppression, prior hospitalization, prior antibiotic administration, septic shock, comorbid conditions, and severity of illness. In the second multivariable analysis that included the antibiotic-resistant species, IIAT was still associated with excess mortality, and P aeruginosa infection was identified as an independent predictor of mortality (OR 1.6, 95% CI 1.1–2.2, P = 0.047), whereas infection with ceftriaxone-resistant Enterobacteriaceae (OR 0.6, 95% CI 0.4–1.0, P = 0.050) was associated with lower mortality. More than one-third of our patients hospitalized with bacteremic pneumonia died. IIAT was identified as the most important risk factor for hospital mortality and the only risk factor amenable to potential intervention. Specific antibiotic-resistant pathogen species were also associated with mortality