Repeated exposure to subinfectious doses of sars-cov-2 may promote t cell immunity and protection against severe covid-19

Europe is experiencing a third wave of COVID-19 due to the spread of highly transmissible SARS-CoV-2 variants. A number of positive and negative factors constantly shape the rates of COVID-19 infections, hospitalization, and mortality. Among these factors, the rise in increasingly transmissible variants on one side and the effect of vaccinations on the other side create a picture deeply different from that of the first pandemic wave. Starting from the observation that in several European countries the number of COVID-19 infections in the second and third pandemic wave increased without a proportional rise in disease severity and mortality, we hypothesize the existence of an additional factor influencing SARS-CoV-2 dynamics. This factor consists of an immune defence against severe COVID-19, provided by SARS-CoV-2-specific T cells progressively developing upon natural exposure to low virus doses present in populated environments. As suggested by recent studies, low-dose viral particles entering the respiratory and intestinal tracts may be able to induce T cell memory in the absence of inflammation, potentially resulting in different degrees of immunization. In this scenario, non-pharmaceutical interventions would play a double role, one in the short term by reducing the detrimental spreading of SARS-CoV-2 particles, and one in the long term by allowing the development of a widespread (although heterogeneous and uncontrollable) form of immune protection

Light-induced surface sliding of the nematic director in liquid crystals

We report the effect of light-induced sliding of the nematic director over an isotropic boundary surface in an azo-dye doped liquid-crystal cell. We show that illumination of the cell with polarized laser light induces transient dynamic sliding followed by permanent reorientation of the director. The two effects are in competition and tend to orient the director along mutually orthogonal directions. The sliding can be controlled and even completely quenched by the amount of induced anchoring energy. A physical model is proposed which accounts for the experimental results. [S0031-9007(99) PACS numbers: 42.70. Df, 61.30.Cz Light-induced anchoring and reorientation effects in liquid crystals (LC) have been the subject of intense research interests in recent years Optical reorientation was originally concerned with light fields acting on the bulk of a liquid crystal cell, the aligning surface determining only the boundary conditions in the reorientation process. Gibbons et al. These results stimulated an interest to investigate the possibility of getting free surface sliding of the nematic director under the control of the incident light. In the paper of Marusii et al. [8], the authors interpreted the observed molecular reorientation close to the isotropic control surface as an effect of director sliding. However, the impossibility of changing the anchoring energy in their experiment did not allow one to establish definitively the actual nature of the phenomenon. In this paper we report the first clear demonstration of the effect of molecular director sliding over an isotropic surface endowed with very weak anchoring energy. We show that illumination with polarized laser light of an azo-dye doped LC cell induces both a transient dynamic sliding and a permanent reorientation of the molecular director. These two effects are regulated by different physical mechanisms and occur on different time scales. The key points of our experimental observations are (i) on a macroscopic scale, i.e., in the frame of the continuum theory, free director sliding over an isotropic boundary surface is possible, and (ii) this effect can be controlled and even completely quenched by the amount of anchoring energy induced on the surface. The scheme of the experimental setup is shown in The exciting polarized beam from He-Cd laser ͑l 0.442 mm; P 1 mW͒ was focused on the cell from the size of the control surface by the lens L 1 . The director reorientation over this surface was detected by checking the polarization state of a He-Ne laser probe beam ͑l 0.638 mm; P 0.1 mW͒ crossing the cell from the side of the reference surface. The electric field E p of the probe beam was set parallel to the initial director orientation n 0 , and the signal transmitted through an analyzer crossed to it was detected. In this geometry, any rotation of the molecular director (up to 90 ± ) over the control surface led to an increase of the transmitted signal. In fact, in our experimental conditions the Mauguin regime was 0031-9007͞99͞82(9)͞1855(4)$15.0

Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors

Although stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signaling in human erythroid cells is still poorly defined. To provide new insights into cKIT-mediated erythroid expansion in development and disease, we performed phosphoproteomic profiling of primary erythroid progenitors from adult blood (AB), cord blood (CB), and Polycythemia Vera (PV) at steady-state and upon SCF stimulation. While AB and CB, respectively, activated transient or sustained canonical cKIT-signaling, PV showed a non-canonical signaling including increased mTOR and ERK1 and decreased DEPTOR. Accordingly, screening of FDA-approved compounds showed increased PV sensitivity to JAK, cKIT, and MEK inhibitors. Moreover, differently from AB and CB, in PV the mature 145kDa-cKIT constitutively associated with the tetraspanin CD63 and was not endocytosed upon SCF stimulation, contributing to unrestrained cKIT signaling. These results identify a clinically exploitable variegation of cKIT signaling/metabolism that may contribute to the great erythroid output occurring during development and in PV

Understanding the Distributions of Benthic Foraminifera in the Adriatic Sea with Gradient Forest and Structural Equation Models

Abstract: In the last three decades, benthic foraminiferal ecology has been intensively investigated to improve the potential application of these marine organisms as proxies of the effects of climate change and other global change phenomena. It is still challenging to define the most important factors affecting foraminiferal communities and derived faunistic parameters. In this study, we examined the abiotic-biotic relationships of foraminiferal communities in the central-southern area of the Adriatic Sea using modern machine learning techniques. We combined gradient forest (Gf) and structural equation modeling (SEM) to test hypotheses about determinants of benthic foraminiferal assemblages. These approaches helped determine the relative effect of sizes of different environmental variables responsible for shaping living foraminiferal distributions. Four major faunal turnovers (at 13–28 m, 29–58 m, 59–215 m, and >215 m) were identified along a large bathymetric gradient (13–703 m water depth) that reflected the classical bathymetric distribution of benthic communities. Sand and organic matter (OM) contents were identified as the most relevant factors influencing the distribution of foraminifera either along the entire depth gradient or at selected bathymetric ranges. The SEM supported causal hypotheses that focused the factors that shaped assemblages at each bathymetric range, and the most notable causal relationships were direct effects of depth and indirect effects of the Gf-identified environmental parameters (i.e., sand, pollution load Index–PLI, organic matter–OM and total nitrogen–N) on foraminifera infauna and diversity. These results are relevant to understanding the basic ecology and conservation of foraminiferal communitie

Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors

Although stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signaling in human erythroid cells is still poorly defined. To provide new insights into cKIT-mediated erythroid expansion in development and disease, we performed phosphoproteomic profiling of primary erythroid progenitors from adult blood (AB), cord blood (CB), and Polycythemia Vera (PV) at steady-state and upon SCF stimulation. While AB and CB, respectively, activated transient or sustained canonical cKIT-signaling, PV showed a non-canonical signaling including increased mTOR and ERK1 and decreased DEPTOR. Accordingly, screening of FDA-approved compounds showed increased PV sensitivity to JAK, cKIT, and MEK inhibitors. Moreover, differently from AB and CB, in PV the mature 145kDa-cKIT constitutively associated with the tetraspanin CD63 and was not endocytosed upon SCF stimulation, contributing to unrestrained cKIT signaling. These results identify a clinically exploitable variegation of cKIT signaling/metabolism that may contribute to the great erythroid output occurring during development and in PV

Converting simulated total dry matter to fresh marketable yield for field vegetables at a range of nitrogen supply levels

Simultaneous analysis of economic and environmental performance of horticultural crop production requires qualified assumptions on the effect of management options, and particularly of nitrogen (N) fertilisation, on the net returns of the farm. Dynamic soil-plant-environment simulation models for agro-ecosystems are frequently applied to predict crop yield, generally as dry matter per area, and the environmental impact of production. Economic analysis requires conversion of yields to fresh marketable weight, which is not easy to calculate for vegetables, since different species have different properties and special market requirements. Furthermore, the marketable part of many vegetables is dependent on N availability during growth, which may lead to complete crop failure under sub-optimal N supply in tightly calculated N fertiliser regimes or low-input systems. In this paper we present two methods for converting simulated total dry matter to marketable fresh matter yield for various vegetables and European growth conditions, taking into consideration the effect of N supply: (i) a regression based function for vegetables sold as bulk or bunching ware and (ii) a population approach for piecewise sold row crops. For both methods, to be used in the context of a dynamic simulation model, parameter values were compiled from a literature survey. Implemented in such a model, both algorithms were tested against experimental field data, yielding an Index of Agreement of 0.80 for the regression strategy and 0.90 for the population strategy. Furthermore, the population strategy was capable of reflecting rather well the effect of crop spacing on yield and the effect of N supply on product grading

A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells

Background: An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. Methods: Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. Results: Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. Conclusion: Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

The interaction between cancer cells and microenvironment has a critical role in tumor development and progression. Although microRNAs regulate all the major biological mechanisms, their influence on tumor microenvironment is largely unexplored. Here, we investigate the role of microRNAs in the tumor-supportive capacity of stromal cells. We demonstrated that miR-15 and miR-16 are downregulated in fibroblasts surrounding the prostate tumors of the majority of 23 patients analyzed. Such downregulation of miR-15 and miR-16 in cancer-associated fibroblasts (CAFs) promoted tumor growth and progression through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration. Moreover, reconstitution of miR-15 and miR-16 impaired considerably the tumor-supportive capability of stromal cells in vitro and in vivo. Our data suggest a molecular circuitry in which miR-15 and miR-16 and their correlated targets cooperate to promote tumor expansion and invasiveness through the concurrent activity on stromal and cancer cells, thus providing further support to the development of therapies aimed at reconstituting miR-15 and miR-16 in advanced prostate cancer. © 2011 Macmillan Publishers Limited All rights reserved

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-XL is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-XL inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-XL. In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC

A new bioavailable fenretinide formulation with antiproliferative, antimetabolic, and cytotoxic effects on solid tumors

Fenretinide is a synthetic retinoid characterized by anticancer activity in preclinical models and favorable toxicological profile, but also by a low bioavailability that hindered its clinical efficacy in former clinical trials. We developed a new formulation of fenretinide complexed with 2-hydroxypropyl-beta-cyclodextrin (nanofenretinide) characterized by an increased bioavailability and therapeutic efficacy. Nanofenretinide was active in cell lines derived from multiple solid tumors, in primary spheroid cultures and in xenografts of lung and colorectal cancer, where it inhibited tumor growth independently from the mutational status of tumor cells. A global profiling of pathways activated by nanofenretinide was performed by reverse-phase proteomic arrays and lipid analysis, revealing widespread repression of the mTOR pathway, activation of apoptotic, autophagic and DNA damage signals and massive production of dihydroceramide, a bioactive lipid with pleiotropic effects on several biological processes. In cells that survived nanofenretinide treatment there was a decrease of factors involved in cell cycle progression and an increase in the levels of p16 and phosphorylated p38 MAPK with consequent block in G0 and early G1. The capacity of nanofenretinide to induce cancer cell death and quiescence, together with its elevated bioavailability and broad antitumor activity indicate its potential use in cancer treatment and chemoprevention