Functionally distinct resident macrophage subsets differentially shape responses to infection in the bladder

International audienceResident macrophages are abundant in the bladder, playing key roles in immunity to uropathogens. Yet, whether they are heterogeneous, where they come from, and how they respond to infection remain largely unknown. We identified two macrophage subsets in mouse bladders, MacM in muscle and MacL in the lamina propria, each with distinct protein expression and transcriptomes. Using a urinary tract infection model, we validated our transcriptomic analyses, finding that MacM macrophages phagocytosed more bacteria and polarized to an anti-inflammatory profile, whereas MacL macrophages died rapidly during infection. During resolution, monocyte-derived cells contributed to tissue-resident macrophage pools and both subsets acquired transcriptional profiles distinct from naïve macrophages. Macrophage depletion resulted in the induction of a type 1-biased immune response to a second urinary tract infection, improving bacterial clearance. Our study uncovers the biology of resident macrophages and their responses to an exceedingly common infection in a largely overlooked organ, the bladder

An assessment of drinking water contamination with Helicobacter pylori in Lima, Peru

BackgroundHelicobacter pylori is a gut bacterium that is the primary cause of gastric cancer. H. pylori infection has been consistently associated with lack of access to sanitation and clean drinking water. In this study, we conducted time‐series sampling of drinking water in Lima, Peru, to examine trends of H. pylori contamination and other water characteristics.Materials and methodsDrinking water samples were collected from a single faucet in Lima’s Lince district 5 days per week from June 2015 to May 2016, and pH, temperature, free available chlorine, and conductivity were measured. Quantities of H. pylori in all water samples were measured using quantitative polymerase chain reaction. Relationships between the presence/absence and quantity of H. pylori and water characteristics in the 2015‐2016 period were examined using regression methods accounting for the time‐series design.ResultsForty‐nine of 241 (20.3%) of drinking water samples were contaminated with H. pylori. Statistical analyses identified no associations between sampling date and the likelihood of contamination with H. pylori. Statistically significant relationships were found between lower temperatures and a lower likelihood of the presence of H. pylori (P < .05), as well as between higher pH and higher quantities of H. pylori (P < .05).ConclusionsThis study has provided evidence of the presence of H. pylori DNA in the drinking water of a single drinking water faucet in the Lince district of Lima. However, no seasonal trends were observed. Further studies are needed to determine the presence of H. pylori in other drinking water sources in other districts in Lima, as well as to determine the viability of H. pylori in these water sources. Such studies would potentially allow for better understanding and estimates of the risk of infection due to exposure to H. pylori in drinking water.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142894/1/hel12462.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142894/2/hel12462_am.pd

Aurora: A Software Radio for Electromagnetic Vector Sensors in Space

The AERO (Auroral Emission Radio Observer) and VISTA (Vector Interferometry Space Technology using AERO) missions will advance auroral radio science and radio interferometry technology. AERO is intended to qualify and validate electromagnetic vector sensor technology in space while also answering key scientific questions about the nature and sources of auroral radio emissions. These questions cannot be addressed from the ground due to shielding by the ionosphere. VISTA, together with AERO, will provide the first demonstration of interferometric imaging, beamforming, and nulling using electromagnetic vector sensors at low frequencies (100 kHz – 15 MHz) using Space based sensors. A key component of the AERO-VISTA joint mission is the Aurora software radio system which forms the primary mission payload when combined with an electromagnetic vector sensor antenna (VSA). This radio combines the analog, digital, and signal processing necessary to detect and digitize the signals associated with the radio aurora. We provide a detailed discussion of the radio design, implementation, and performance results from early testing of our engineering model units

Sensitive Period for a Multimodal Response in Human Visual Motion Area

The middle temporal complex (MT/MST) is a brain region specialized for the perception of motion in the visual modality [ [1], [2], [3] and [4]]. However, this specialization is modified by visual experience: after long-standing blindness, MT/MST responds to sound [5]. Recent evidence also suggests that the auditory response of MT/MST is selective for motion [ [6] and [7]]. The developmental time course of this plasticity is not known. To test for a sensitive period in MT/MST development, we used fMRI to compare MT/MST function in congenitally blind, late-blind, and sighted adults. MT/MST responded to sound in congenitally blind adults, but not in late-blind or sighted adults, and not in an individual who lost his vision between ages of 2 and 3 years. All blind adults had reduced functional connectivity between MT/MST and other visual regions. Functional connectivity was increased between MT/MST and lateral prefrontal areas in congenitally blind relative to sighted and late-blind adults. These data suggest that early blindness affects the function of feedback projections from prefrontal cortex to MT/MST. We conclude that there is a sensitive period for visual specialization in MT/MST. During typical development, early visual experience either maintains or creates a vision-dominated response. Once established, this response profile is not altered by long-standing blindness.David and Lucille Packard FoundationNational Center for Research Resources: Harvard-Thorndike General Clinical Research Center at Beth Israel Deaconess Medical Center (NCRR MO1 RR01032)Harvard Clinical and Translational Science Center (UL1 RR025758)National Institutes of Health (U.S.) (grant K24 RR018875)National Institutes of Health (U.S.) (grant RO1-EY12091

Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation

Background: Ischemia reperfusion injury (I/RI) is a common complication of cardiovascular diseases. Resolution of detrimental I/RI-generated prothrombotic and proinflammatory responses is essential to restore homeostasis. Platelets play a crucial part in the integration of thrombosis and inflammation. Their role as participants in the resolution of thromboinflammation is underappreciated; therefore we used pharmacological and genetic approaches, coupled with murine and clinical samples, to uncover key concepts underlying this role. Methods: Middle cerebral artery occlusion with reperfusion was performed in wild-type or annexin A1 (AnxA1) knockout (AnxA1-/-) mice. Fluorescence intravital microscopy was used to visualize cellular trafficking and to monitor light/dye-induced thrombosis. The mice were treated with vehicle, AnxA1 (3.3 mg/kg), WRW4 (1.8 mg/kg), or all 3, and the effect of AnxA1 was determined in vivo and in vitro. Results: Intravital microscopy revealed heightened platelet adherence and aggregate formation post I/RI, which were further exacerbated in AnxA1-/- mice. AnxA1 administration regulated platelet function directly (eg, via reducing thromboxane B2 and modulating phosphatidylserine expression) to promote cerebral protection post-I/RI and act as an effective preventative strategy for stroke by reducing platelet activation, aggregate formation, and cerebral thrombosis, a prerequisite for ischemic stroke. To translate these findings into a clinical setting, we show that AnxA1 plasma levels are reduced in human and murine stroke and that AnxA1 is able to act on human platelets, suppressing classic thrombin-induced inside-out signaling events (eg, Akt activation, intracellular calcium release, and Ras-associated protein 1 [Rap1] expression) to decrease IIbβ3 activation without altering its surface expression. AnxA1 also selectively modifies cell surface determinants (eg, phosphatidylserine) to promote platelet phagocytosis by neutrophils, thereby driving active resolution. (n=5-13 mice/group or 7-10 humans/group.) Conclusions: AnxA1 affords protection by altering the platelet phenotype in cerebral I/RI from propathogenic to regulatory and reducing the propensity for platelets to aggregate and cause thrombosis by affecting integrin (IIbβ3) activation, a previously unknown phenomenon. Thus, our data reveal a novel multifaceted role for AnxA1 to act both as a therapeutic and a prophylactic drug via its ability to promote endogenous proresolving, antithromboinflammatory circuits in cerebral I/RI. Collectively, these results further advance our knowledge and understanding in the field of platelet and resolution biology.Fil: Senchenkova, Elena Y.. State University of Louisiana; Estados UnidosFil: Ansari, Junaid. State University of Louisiana; Estados UnidosFil: Becker, Felix. University Hospital Muenster; AlemaniaFil: Vital, Shantel A.. State University of Louisiana; Estados UnidosFil: Al-Yafeai, Zaki. State University of Louisiana; Estados UnidosFil: Sparkenbaugh, Erica M.. University North Carolina Chapel Hill; Estados UnidosFil: Pawlinski, Rafal. University North Carolina Chapel Hill; Estados UnidosFil: Stokes, Karen Y.. State University of Louisiana; Estados UnidosFil: Carroll, Jennifer L.. State University of Louisiana; Estados UnidosFil: Dragoi, Ana-Maria. State University of Louisiana; Estados UnidosFil: Qin, Cheng Xue. Baker Heart And Diabetes Institute; AustraliaFil: Ritchie, Rebecca H.. Baker Heart And Diabetes Institute; AustraliaFil: Sun, Hai. University Hospital Muenster; AlemaniaFil: Cuellar-Saenz, Hugo H.. State University of Louisiana; Estados UnidosFil: Rubinstein Guichon, Mara Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. Columbia University; Estados UnidosFil: Han, Yiping W.. Columbia University; Estados UnidosFil: Orr, A. Wayne. University Hospital Muenster; AlemaniaFil: Perretti, Mauro. Queen Mary University Of London; Reino UnidoFil: Granger, D. Neil. State University of Louisiana; Estados UnidosFil: Gavins, Felicity N.E.. State University of Louisiana; Estados Unido

Current Issues in Tender Offer Regulation: Lessons From the British

The recent submission to Congress of several proposed amendments to the Williams Act has again made tender offer regulation a controversial subject. Professor DeMott believes that the debate about regulatory reform can benefit from a comparative study of Britih and American tender offer rcgulation. She finds the British system instructive in three important respects. First, the British system specifically indentifies different kinds of transactions that resemble tender offers and regulates those transactions according to the hazards they create for investors. Unlike the American system, which imposes a single set of highly complex regulations only if a transaction qualifies as a tender offer under nebulous judicial definitions, the British system recognizes that certain acquisitions of a small percentage of a corporation\u27s shares, while appropriately subject to some regulation, need not trigger application of the full panoply of rules. The author also notes that the bright line rules uscd by the British to define regulated transactions facilitate financial and legal planning and promote an orderly market for corporate control. Second, by enforcing a more rigorous view of fair and equal treatment of target shareholders than does the American system, the British system may discourage takeover attempts and bidding contests that benefit shareholders. For instance, the British require that a purchaser of thirty percent of target stock offer to buy out remaining shareholders at tihe highest price it paid for the stock. In the author\u27s view, such a protective rule may be too costly: it may also be unnecessary in the United States, where minority shareholders may enjoy appraisal rights and may bring deritative suits against management more easily than their British counterparts. Third, by requiring that target management provide shareholders with an independent appraisal of each tender offer and obtain the sharcholders\u27 approval before engaging in defensive maneuvers that might defeat the offer, the British system provides a moderate solution to the problem of managerial conflicts of interest caused by hostile takeover efforts. Recognizing that some defensive role for target management may be appropriate. Professor Delfott argues that the British approach may be preferable to current proposals that defensive tactics be prohibited

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe