Efficient Monetary Allocations and the Illiquidity of Bonds.

We construct a monetary economy with heterogeneity in discounting and consumption risk. Agents can insure against this risk with both money and nominal government bonds, but all trades must be monetized. We demonstrate that a deflationary policy a la Friedman cannot sustain the efficient allocation. The reason is that no-arbitrage imposes a stringent bound on the return money can pay. The efficient allocation can be sustained when bonds have positive yields and – under certain conditions – only if they are illiquid. Illiquidity – meaning bonds cannot be transformed into consumption as efficiently as cash – is necessary to eliminate arbitrage opportunities.Money ; Heterogeneity ; Friedman Rule ; Illiquid Assets

Financial Sophistication and the Distribution of the Welfare Cost of Inflation

The welfare cost of anticipated inflation is quantified in a calibrated model of the U.S. economy that exhibits tractable equilibrium dispersion in wealth and earnings. Inflation does not generate large losses in societal welfare, yet its impact varies noticeably across segments of society depending also on the financial sophistication of the economy. If money is the only asset, then inflation hurts mostly the wealthier and more productive agents, while those poorer and less productive may even benefit from inflation. The converse holds in a more sophisticated financial environment where agents can insure against consumption risk with assets other than money.money, heterogeneity, friedman rule, trade frictions, calibration

Monetary Equilibrium and the Cost of Banking Activity

We investigate the effects of banks’ operating costs on allocations and welfare in a low interest rate environment. We introduce an explicit production function for banks in a microfounded model where banks employ labor resources, hired on a competitive market, to run their operations. In equilibrium, this generates a spread between interest rates on loans and deposits, which naturally reflects the underlying monetary policy and the efficiency of financial intermediation. In a deflation or low inflation environment, equilibrium deposits yield zero returns. Hence, banks end up soaking up labor resources to offer deposits that do not outperform idle balances, thus reducing aggregate efficiency

Profiling the Course of Resolving vs. Persistent Inflammation in Human Monocytes: The Role of IL-1 Family Molecules

Monocytes and macrophages have a central role in all phases of an inflammatory reaction. To understanding the regulation of monocyte activation during a physiological or pathological inflammation, we propose two in vitro models that recapitulate the different phases of the reaction (recruitment, initiation, development, and resolution vs. persistence of inflammation), based on human primary blood monocytes exposed to sequential modifications of microenvironmental conditions. These models exclusively describe the functional development of blood-derived monocytes that first enter an inflammatory site. All reaction phases were profiled by RNA-Seq, and the two models were validated by studying the modulation of IL-1 family members. Genes were differentially modulated, and distinct clusters were identified during the various phases of inflammation. Pathway analysis revealed that both models were enriched in pathways involved in innate immune activation. We observe that monocytes acquire an M1-like profile during early inflammation, and switch to a deactivated M2-like profile during both the resolving and persistent phases. However, during persistent inflammation they partially maintain an M1 profile, although they lose the ability to produce inflammatory cytokines compared to M1 cells. The production of IL-1 family molecules by ELISA reflected the transcriptomic profiles in the distinct phases of the two inflammatory reactions. Based on the results, we hypothesize that persistence of inflammatory stimuli cannot maintain the M1 activated phenotype of incoming monocytes for long, suggesting that the persistent presence of M1 cells and effects in a chronically inflamed tissue is mainly due to activation of newly incoming cells. Moreover, being IL-1 family molecules mainly expressed and secreted by monocytes during the early stages of the inflammatory response (within 4-14 h), and the rate of their production decreasing during the late phase of both resolving and persistent inflammation, we suppose that IL-1 factors are key regulators of the acute defensive innate inflammatory reaction that precedes establishment of longer-term adaptive immunity, and are mainly related to the presence of recently recruited blood monocytes. The well-described role of IL-1 family cytokines and receptors in chronic inflammation is therefore most likely dependent on the continuous influx of blood monocytes into a chronically inflamed site

Induction of Innate Memory in Human Monocytes Exposed to Mixtures of Bacterial Agents and Nanoparticles

Innate memory; Macrophages; MonocytesMemoria innata; Macrófagos; MonocitosMemòria innata; Macròfags; MonòcitsWe assessed whether concomitant exposure of human monocytes to bacterial agents and different engineered nanoparticles can affect the induction of protective innate memory, an immune mechanism that affords better resistance to diverse threatening challenges. Monocytes were exposed in vitro to nanoparticles of different chemical nature, shape and size either alone or admixed with LPS, and cell activation was assessed in terms of production of inflammatory (TNFα, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra). After return to baseline conditions, cells were re-challenged with LPS and their secondary “memory” response measured. Results show that nanoparticles alone are essentially unable to generate memory, while LPS induced a tolerance memory response (less inflammatory cytokines, equal or increased anti-inflammatory cytokines). LPS-induced tolerance was not significantly affected by the presence of nanoparticles during the memory generation phase, although with substantial donor-to-donor variability. This suggests that, despite the overall lack of significant effects on LPS-induced innate memory, nanoparticles may have donor-specific effects. Thus, future nanosafety assessment and nanotherapeutic strategies will need a personalized approach in order to ensure both the safety and efficacy of nano medical compounds for individual patients.This work was supported by the EU Commission H2020 projects PANDORA (GA671881) and ENDONANO (GA 812661) (PI, DB), the Italian MIUR InterOmics Flagship projects MEMORAT and MAME (DB, PI), and the Presidential International Fellowship Program (PIFI) of the Chinese Academy of Science (2020VBA0028) (DB). Part of this work was carried out in the context of the JRC Visiting Scientist agreement no. 05/JRC.F.2/2019 (Directorate F—Health, Consumers and Reference Materials, Consumer Products Safety, Nanobiotechnology Lab)

Citron kinase controls abscission through RhoA and Anillin.

The small GTPase RhoA plays a crucial role in the different stages of cytokinesis, including contractile ring formation, cleavage furrow ingression, and midbody abscission. Citron kinase (CIT-K), a protein required for cytokinesis and conserved from insects to mammals, is currently considered a cytokinesis-specific effector of active RhoA. In agreement with previous observations, we show here that, as in Drosophila cells, CIT-K is specifically required for abscission in mammalian cells. However, in contrast with the current view, we provide evidence that CIT-K is an upstream regulator rather than a downstream effector of RhoA during late cytokinesis. In addition, we show that CIT-K is capable of physically and functionally interacting with the actin-binding protein anillin. Active RhoA and anillin are displaced from the midbody in CIT-K-depleted cells, while only anillin, but not CIT-K, is affected if RhoA is inactivated in late cytokinesis. The overexpression of CIT-K and of anillin leads to abscission delay. However, the delay produced by CIT-K overexpression can be reversed by RhoA inactivation, while the delay produced by anillin overexpression is RhoA-independent. Altogether, these results indicate that CIT-K is a crucial abscission regulator that may promote midbody stability through active RhoA and anillin

Association of Microvesicles With Graft Patency in Patients Undergoing CABG Surgery

Abstract Background Graft patency is one of the major determinants of long-term outcome following coronary artery bypass graft surgery (CABG). Biomarkers, if indicative of the underlying pathophysiological mechanisms, would suggest strategies to limit graft failure. The prognostic value of microvesicles (MVs) for midterm graft patency has never been tested. Objectives The aim of this study was to evaluate whether MV pre-operative signature (number, cellular origin, procoagulant phenotype) could predict midterm graft failure and to investigate potential functional role of MVs in graft occlusion. Methods This was a nested case-control substudy of the CAGE (CoronAry bypass grafting: factors related to late events and Graft patency) study that enrolled 330 patients undergoing elective CABG. Of these, 179 underwent coronary computed tomography angiography 18 months post-surgery showing 24% graft occlusion. Flow cytometry MV analysis was performed in 60 patients (30 per group with occluded [cases] and patent [control subjects] grafts) on plasma samples collected the day before surgery and at follow-up. Results Before surgery, cases had 2- and 4-fold more activated platelet-derived and tissue-factor positive MVs respectively than control subjects. The MV procoagulant capacity was also significantly greater. Altogether this MV signature properly classified graft occlusion (area under the curve 0.897 [95% confidence interval: 0.81 to 0.98]; p Conclusions The pre-operative signature of MVs is independently associated with midterm graft occlusion in CABG patients and a cumulative MV score stratifies patients' risk. Because the MV signature mirrors platelet activation, patients with a high MV score could benefit from a personalized antiplatelet therapy

p140Cap regulates memory and synaptic plasticity through Src-mediated and citron-N-mediated actin reorganization.

Abstract A major challenge in the neuroscience field is the identification of molecules and pathways that control synaptic plasticity and memory. Dendritic spines play a pivotal role in these processes, as the major sites of excitatory synapses in neuronal communication. Previous studies have shown that the scaffold protein p140Cap localizes into dendritic spines and that its knockdown negatively modulates spine shape in culture. However, so far, there is no information on its in vivo relevance. By using a knock-outmousemodel, we here demonstrate that p140Cap is a key element for both learning and synaptic plasticity. Indeed, p140Cap(-/-) mice are impaired in object recognition test, as well as in LTP and in LTD measurements. The in vivo effects of p140Cap loss are presumably attenuated by noncell-autonomous events, since primary neurons obtained from p140Cap(-/-) mice show a strong reduction in number of mushroom spines and abnormal organization of synapse-associated F-actin. These phenotypes are most likely caused by a local reduction of the inhibitory control of RhoA and of cortactin toward the actin-depolymerizing factor cofilin. These events can be controlled by p140Cap through its capability to directly inhibit the activation of Src kinase and by its binding to the scaffold protein Citron-N. Altogether, our results provide new insight into how protein associated with dynamic microtubules may regulate spine actin organization through interaction with postsynaptic density components

A New Thiopurine S-Methyltransferase Haplotype Associated With Intolerance to Azathioprine

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A new test (VITTORIO Test) for functional fitness assessment in rehabilitation after cardiac surgery

Cardiac Rehabilitation (CR) plays a central role in early detection of physical limitations. Traditionally exercise tolerance has been used as an indicator of overall PF. However exercise tolerance has been shown to poorly predict patients’ ability to perform daily-life activities. The goal of the present study is to evaluate a new test, named VITTORIO TEST, for assessing various component of daily activities among patients in CR after cardiac surgery. VITTORIO test consists in 8 items that assess lower and upper extremity strength and flexibility, agility, dynamic balance, aerobic capacity. 500 patients (359 males; 141 females) admitted to CR programs following cardiac surgery (349 coronary artery bypass surgery; 151 valvular surgery) were enrolled in the study. They were evaluated with an initial test (T1) (10.7±6.3 days after cardiac surgery) and a final test (T2) after a inhospital intensive training program (mean length 16.8 ± 6.6 days) consisting in stretching, large muscle group and aerobic activity, resistance exercises. Statistical analysis showed a significant improvement of all items at the end of the rehabilitation program. Old patients (>70 years) and particularly females demonstrate exercise improvement comparable to that of younger subjects especially regards lower extremity strength and aerobic capacity. VITTORIO test is inexpensive, simple and easy to perform by the patient. Through the identification and the measurement of different aspects of physical disability, it allows a personalized rehabilitation exercise program. It could be used as an outcome measure of CR programs