Chimeric antigen receptors that trigger phagocytosis

Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T cells to kill cancer. The success of CAR-T cell therapies highlights the promise of programmed immunity and suggests that applying CAR strategies to other immune cell lineages may be beneficial. Here, we engineered a family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells. CAR-Ps consist of an extracellular antibody fragment, which can be modified to direct CAR-P activity towards specific antigens. By screening a panel of engulfment receptor intracellular domains, we found that the cytosolic domains from Megf10 and FcRɣ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole human cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing murine macrophages reduce cancer cell number in co-culture by over 40%

CoolMPS: evaluation of antibody labeling based massively parallel non-coding RNA sequencing

Results of massive parallel sequencing-by-synthesis vary depending on the sequencing approach. CoolMPS™ is a new sequencing chemistry that incorporates bases by labeled antibodies. To evaluate the performance, we sequenced 240 human non-coding RNA samples (dementia patients and controls) with and without CoolMPS. The Q30 value as indicator of the per base sequencing quality increased from 91.8 to 94%. The higher quality was reached across the whole read length. Likewise, the percentage of reads mapping to the human genome increased from 84.9 to 86.2%. For both technologies, we computed similar distributions between different RNA classes (miRNA, piRNA, tRNA, snoRNA and yRNA) and within the classes. While standard sequencing-by-synthesis allowed to recover more annotated miRNAs, CoolMPS yielded more novel miRNAs. The correlation between the two methods was 0.97. Evaluating the diagnostic performance, we observed lower minimal P-values for CoolMPS (adjusted P-value of 0.0006 versus 0.0004) and larger effect sizes (Cohen's d of 0.878 versus 0.9). Validating 19 miRNAs resulted in a correlation of 0.852 between CoolMPS and reverse transcriptase-quantitative polymerase chain reaction. Comparison to data generated with Illumina technology confirmed a known shift in the overall RNA composition. With CoolMPS we evaluated a novel sequencing-by-synthesis technology showing high performance for the analysis of non-coding RNAs

The function-dominance correlation drives the direction and strength of biodiversity-ecosystem functioning relationships

Community composition is a primary determinant of how biodiversity change influences ecosystem functioning and, therefore, the relationship between biodiversity and ecosystem functioning (BEF). We examine the consequences of community composition across six structurally realistic plant community models. We find that a positive correlation between species' functioning in monoculture versus their dominance in mixture with regard to a specific function (the "function-dominance correlation") generates a positive relationship between realised diversity and ecosystem functioning across species richness treatments. However, because realised diversity declines when few species dominate, a positive function-dominance correlation generates a negative relationship between realised diversity and ecosystem functioning within species richness treatments. Removing seed inflow strengthens the link between the function-dominance correlation and BEF relationships across species richness treatments but weakens it within them. These results suggest that changes in species' identities in a local species pool may more strongly affect ecosystem functioning than changes in species richness

cGMP-Elevating Compounds and Ischemic Conditioning Provide Cardioprotection Against Ischemia and Reperfusion Injury via Cardiomyocyte-Specific BK Channels.

BACKGROUND: The nitric oxide-sensitive guanylyl cyclase/cGMP-dependent protein kinase type I signaling pathway can afford protection against the ischemia/reperfusion injury that occurs during myocardial infarction. Reportedly, voltage and Ca2+-activated K+ channels of the BK type are stimulated by cGMP/cGMP-dependent protein kinase type I, and recent ex vivo studies implicated that increased BK activity favors the survival of the myocardium at ischemia/reperfusion. It remains unclear, however, whether the molecular events downstream of cGMP involve BK channels present in cardiomyocytes or in other cardiac cell types. METHODS: Gene-targeted mice with a cardiomyocyte- or smooth muscle cell-specific deletion of the BK (CMBK or SMBK knockouts) were subjected to the open-chest model of myocardial infarction. Infarct sizes of the conditional mutants were compared with litter-matched controls, global BK knockout, and wild-type mice. Cardiac damage was assessed after mechanical conditioning or pharmacological stimulation of the cGMP pathway and by using direct modulators of BK. Long-term outcome was studied with respect to heart functions and cardiac fibrosis in a chronic myocardial infarction model. RESULTS: Global BK knockouts and CMBK knockouts, in contrast with SMBK knockouts, exhibited significantly larger infarct sizes compared with their respective controls. Ablation of CMBK resulted in higher serum levels of cardiac troponin I and elevated amounts of reactive oxygen species, lower phosphorylated extracellular receptor kinase and phosphorylated AKT levels and an increase in myocardial apoptosis. Moreover, CMBK was required to allow beneficial effects of both nitric oxide-sensitive guanylyl cyclase activation and inhibition of the cGMP-degrading phosphodiesterase-5, ischemic preconditioning, and postconditioning regimens. To this end, after 4 weeks of reperfusion, fibrotic tissue increased and myocardial strain echocardiography was significantly compromised in CMBK-deficient mice. CONCLUSIONS: Lack of CMBK channels renders the heart more susceptible to ischemia/reperfusion injury, whereas the pathological events elicited by ischemia/reperfusion do not involve BK in vascular smooth muscle cells. BK seems to permit the protective effects triggered by cinaciguat, riociguat, and different phosphodiesterase-5 inhibitors and beneficial actions of ischemic preconditioning and ischemic postconditioning by a mechanism stemming primarily from cardiomyocytes. This study establishes mitochondrial CMBK channels as a promising target for limiting acute cardiac damage and adverse long-term events that occur after myocardial infarction

Twenty questions about design behavior for sustainability, report of the International Expert Panel on behavioral science for design

How behavioral scientists, engineers, and architects can work together to advance how we all understand and practice design—in order to enhance sustainability in the built environment, and beyond.https://www.nature.com/documents/design_behavior_for_sustainability.pdfPublished versio

Inflammaging is driven by upregulation of innate immune receptors and systemic interferon signaling and is ameliorated by dietary restriction

Aging is characterized by a chronic low-grade inflammation known as inflammaging in multiple tissues, representing a risk factor for age-related diseases. Dietary restriction (DR) is the best-known non-invasive method to ameliorate aging in many organisms. However, the molecular mechanism and the signaling pathways that drive inflammaging across different tissues and how they are modulated by DR are not yet understood. Here we identify a multi-tissue gene network regulating inflammaging. This network is characterized by chromatin opening and upregulation in the transcription of innate immune system receptors and by activation of interferon signaling through interferon regulatory factors, inflammatory cytokines, and Stat1-mediated transcription. DR ameliorates aging-induced alterations of chromatin accessibility and RNA transcription of the inflammaging gene network while failing to rescue those alterations on the rest of the genome. Our results present a comprehensive understanding of the molecular network regulating inflammation in aging and DR and provide anti-inflammaging therapeutic targets

Measurement of the t(t)over-bar production cross section in the dilepton channel in pp collisions at √s=8 TeV

The top-antitop quark (t (t) over bar) production cross section is measured in proton-proton collisions at root s = 8 TeV with the CMS experiment at the LHC, using a data sample corresponding to an integrated luminosity of 5.3 fb(-1). The measurement is performed by analysing events with a pair of electrons or muons, or one electron and one muon, and at least two jets, one of which is identified as originating from hadronisation of a bottom quark. The measured cross section is 239 +/- 2 (stat.) +/- 11 (syst.) +/- 6 (lum.) pb, for an assumed top-quark mass of 172.5 GeV, in agreement with the prediction of the standard model