Plant–soil negative feedback (NF) is recognized as an important factor affecting plant communities. The objectives of this work were to assess the effects of litter phytotoxicity and autotoxicity on ...root proliferation, and to test the hypothesis that DNA is a driver of litter autotoxicity and plant–soil NF. The inhibitory effect of decomposed litter was studied in different bioassays. Litter biochemical changes were evaluated with nuclear magnetic resonance (NMR) spectroscopy. DNA accumulation in litter and soil was measured and DNA toxicity was assessed in laboratory experiments. Undecomposed litter caused nonspecific inhibition of root growth, while autotoxicity was produced by aged litter. The addition of activated carbon (AC) removed phytotoxicity, but was ineffective against autotoxicity. Phytotoxicity was related to known labile allelopathic compounds. Restricted¹³C NMR signals related to nucleic acids were the only ones negatively correlated with root growth on conspecific substrates. DNA accumulation was observed in both litter decomposition and soil history experiments. Extracted total DNA showed evident species‐specific toxicity. Results indicate a general occurrence of litter autotoxicity related to the exposure to fragmented self‐DNA. The evidence also suggests the involvement of accumulated extracellular DNA in plant–soil NF. Further studies are needed to further investigate this unexpected function of extracellular DNA at the ecosystem level and related cellular and molecular mechanisms.
In breast cancer (BC) care, radiotherapy is considered an efficient treatment, prescribed both for controlling localized tumors or as a therapeutic option in case of inoperable, incompletely resected ...or recurrent tumors. However, approximately 90% of BC-related deaths are due to the metastatic tumor progression. Then, it is strongly desirable to improve tumor radiosensitivity using molecules with synergistic action. The main aim of this study is to develop curcumin-loaded solid nanoparticles (Cur-SLN) in order to increase curcumin bioavailability and to evaluate their radiosensitizing ability in comparison to free curcumin (free-Cur), by using an in vitro approach on BC cell lines. In addition, transcriptomic and metabolomic profiles, induced by Cur-SLN treatments, highlighted networks involved in this radiosensitization ability. The non tumorigenic MCF10A and the tumorigenic MCF7 and MDA-MB-231 BC cell lines were used. Curcumin-loaded solid nanoparticles were prepared using ethanolic precipitation and the loading capacity was evaluated by UV spectrophotometer analysis. Cell survival after treatments was evaluated by clonogenic assay. Dose-response curves were generated testing three concentrations of free-Cur and Cur-SLN in combination with increasing doses of IR (2-9 Gy). IC
value and Dose Modifying Factor (DMF) was measured to quantify the sensitivity to curcumin and to combined treatments. A multi-"omic" approach was used to explain the Cur-SLN radiosensitizer effect by microarray and metobolomic analysis. We have shown the efficacy of the Cur-SLN formulation as radiosensitizer on three BC cell lines. The DMFs values, calculated at the isoeffect of SF = 50%, showed that the Luminal A MCF7 resulted sensitive to the combined treatments using increasing concentration of vehicled curcumin Cur-SLN (DMF: 1,78 with 10 µM Cur-SLN.) Instead, triple negative MDA-MB-231 cells were more sensitive to free-Cur, although these cells also receive a radiosensitization effect by combination with Cur-SLN (DMF: 1.38 with 10 µM Cur-SLN). The Cur-SLN radiosensitizing function, evaluated by transcriptomic and metabolomic approach, revealed anti-oxidant and anti-tumor effects. Curcumin loaded- SLN can be suggested in future preclinical and clinical studies to test its concomitant use during radiotherapy treatments with the double implications of being a radiosensitizing molecule against cancer cells, with a protective role against IR side effects.
Purpose
The purpose of this paper is to understand the impact of digital technologies adoption on the forms of organization of large architecture and engineering (A/E) firms. Network theory has ...attracted scholarly and managerial attention, particularly from the perspective of the changes of project organization. However, little research focuses on network theory as a lens for understanding and managing the new forms of firms’ organization. Additionally, conventional organizational analyses are hampered by the lack of methods for understanding the changes in roles and relationships due to the adoption of digital technologies and examining their impact on organizational structures.
Design/methodology/approach
To address this gap, this research adopted a mixed-method case-study approach. This approach combined interviews, regular check-ins, and document analysis with data mining and social network analysis (SNA) to capture the changes of intra-organizational roles and relationships and for understanding their impact on the firm’s organizational structure. Using the data gathered, the authors created a dendrogram that shows the formal organizational structure, a sociogram that displays the informal organizational structure and a network map that visualizes the interplay between the two structures.
Findings
From this analysis, the authors identified four main findings: informal roles – as go-to people for advice and information about digital technologies – play within A/E firms facing digital transformation; such go-to people operate through informal networked relationships and beyond their formal roles; most of these relationships do not overlap with the formal reporting relationships; the combination of both these roles and relationships create an informal social network. The authors also show how managers can use SNA to understand the changes in roles and relationships due to the adoption of digital technologies and to diagnose their impact on organizational structures.
Originality/value
This research contributes to the literature of organizational design and change management from a network perspective in the context of the digital transformation of large A/E firms. It provides a systematic data-driven approach to understanding the changes of intra-organizational roles and relationships within A/E firms facing digital transformation and to diagnosing the impact of these changes on firms’ organizational structures.
Self‐inhibition of growth has been observed in different organisms, but an underlying common mechanism has not been proposed so far. Recently, extracellular DNA (exDNA) has been reported as ...species‐specific growth inhibitor in plants and proposed as an explanation of negative plant–soil feedback. In this work the effect of exDNA was tested on different species to assess the occurrence of such inhibition in organisms other than plants. Bioassays were performed on six species of different taxonomic groups, including bacteria, fungi, algae, plants, protozoa and insects. Treatments consisted in the addition to the growth substrate of conspecific and heterologous DNA at different concentration levels. Results showed that treatments with conspecific DNA always produced a concentration dependent growth inhibition, which instead was not observed in the case of heterologous DNA. Reported evidence suggests the generality of the observed phenomenon which opens new perspectives in the context of self‐inhibition processes. Moreover, the existence of a general species‐specific biological effect of exDNA raises interesting questions on its possible involvement in self‐recognition mechanisms. Further investigation at molecular level will be required to unravel the specific functioning of the observed inhibitory effects.
The inhibitory effect of extracellular DNA (exDNA) on the growth of conspecific individuals was demonstrated in different kingdoms. In plants, the inhibition has been observed on root growth and seed ...germination, demonstrating its role in plant-soil negative feedback. Several hypotheses have been proposed to explain the early response to exDNA and the inhibitory effect of conspecific exDNA. We here contribute with a whole-plant transcriptome profiling in the model species
exposed to extracellular self- (conspecific) and nonself- (heterologous) DNA. The results highlight that cells distinguish self- from nonself-DNA. Moreover, confocal microscopy analyses reveal that nonself-DNA enters root tissues and cells, while self-DNA remains outside. Specifically, exposure to self-DNA limits cell permeability, affecting chloroplast functioning and reactive oxygen species (ROS) production, eventually causing cell cycle arrest, consistently with macroscopic observations of root apex necrosis, increased root hair density and leaf chlorosis. In contrast, nonself-DNA enters the cells triggering the activation of a hypersensitive response and evolving into systemic acquired resistance. Complex and different cascades of events emerge from exposure to extracellular self- or nonself-DNA and are discussed in the context of Damage- and Pathogen-Associated Molecular Patterns (DAMP and PAMP, respectively) responses.
DOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 (
) gene. The disease has a wide clinical spectrum encompassing recurrent infections ...(candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory features, including autoimmune (cytopenia and vasculitis) as well as allergic disorders (eczema, asthma, and food allergy). Hypomorphic function and somatic reversion of
has been reported to result in incomplete phenotype without IgE overproduction. Here we describe a case of DOCK8 deficiency in a 8-year-old Caucasian girl. The patient's disease was initially classified as autoimmune thrombocytopenia, which then evolved toward a combined immunodeficiency phenotype with recurrent infections, persistent EBV infection and lymphoproliferation. Two novel variants (one deletion and one premature stop codon) were characterized, resulting in markedly reduced, but not absent, DOCK8 expression. Somatic reversion of the
deletion was identified in T cells. Hypomorphic function and somatic reversion were associated with restricted T cell repertoire, decreased STAT5 phosphorylation and impaired immune synapse functioning in T cells. Although the patient presented with incomplete phenotype (absence of markedly increase IgE and eosinophil count), sclerosing cholangitis was incidentally detected, thus indicating that hypomorphic function and somatic reversion of
may delay disease progression but do not necessarily prevent from severe complications.
Extracellular DNA (exDNA) can be actively released by living cells and different putative functions have been attributed to it. Further, homologous exDNA has been reported to exert species-specific ...inhibitory effects on several organisms. Here, we demonstrate by different experimental evidence, including 1H-NMR metabolomic fingerprint, that the growth rate decline in Saccharomyces cerevisiae fed-batch cultures is determined by the accumulation of exDNA in the medium. Sequencing of such secreted exDNA represents a portion of the entire genome, showing a great similarity with extrachromosomal circular DNA (eccDNA) already reported inside yeast cells. The recovered DNA molecules were mostly single strands and specifically associated to the yeast metabolism displayed during cell growth. Flow cytometric analysis showed that the observed growth inhibition by exDNA corresponded to an arrest in the S phase of the cell cycle. These unprecedented findings open a new scenario on the functional role of exDNA produced by living cells.
DNA is usually known as the molecule that carries the instructions necessary for cell functioning and genetic inheritance. A recent discovery reported a new functional role for extracellular DNA. ...After fragmentation, either by natural or artificial decomposition, small DNA molecules (between ∼50 and ∼2000 bp) exert a species specific inhibitory effect on individuals of the same species. Evidence shows that such effect occurs for a wide range of organisms, suggesting a general biological process. In this paper we explore the possible molecular mechanisms behind those findings and discuss the ecological implications, specifically those related to plant species coexistence.
Introduction.
Discontinuation (D/C) of Imatinib or other TKIs in Chronic Myeloid Leukemia (CML) represents an important issue in the management of this disease. It is generally accepted that relapse ...develops (and treatment must be resumed) when patients (pts) lose Major Molecular Remission (MMR), i.e. when the amount of the BCR-ABL1 transcript, measured in peripheral blood by RT-PCR, exceeds 0.1 %. The Imatinib Suspension And Validation (ISAV) study, which started in 2011, enrolled pts with CML treated with Imatinib who showed no evidence of BCR-ABL1 transcript for at least 18 months before enrollment.
Methods.
A digital PCR (dPCR) for BCR-ABL1 was performed at the time of Imatinib D/C while a second dPCR was performed when non relapsed patients exited the study, 36 months later. dPCR experiments were performed by the QX200 system (BioRad) in the same lab and using the same methodology. The BCR-ABL1 fusion and ABL1 transcripts were quantified using DigiDrop P210 MasterMix and DigiDrop P210 Positive Control (Bioclarma), according to manufacturer's protocol. The target concentration in each sample was expressed as percentage of BCR-ABL1/ABL1.
Results.
A total of 107 pts were enrolled in the ISAV study. Relapses occurred in 54 pts (52%); among the 53 non relapsed pts, 41 (77%) presented at least one positive RT-PCR result following Imatinib D/C, and only 12 (23%) maintained PCR negativity throughout the duration of the study. Among the non-relapsed pts dPCR performed at treatment D/C showed positivity in 20.6% of cases (95% confidence interval C.I. 9-36%), while 91.1% of pts (95%, C.I. 80-97%) evaluated 36 months later showed a positive dPCR value, although no patient resumed treatment. The evaluation of non relapsed pts by dPCR showed that mean values at D/C were 0.00143% +/- 0.0006 (SE); when tested at study exit, the same pts showed average dPCR values of 0.0115 % +/- 0.002.
This difference is statistically highly significant and corresponds to a change of approximately 1 log in the residual tumor burden: from 2x107 to 2x108 cells. There was no correlation between the results of RT-PCR performed during the study and the dPCR status at study exit: pts who tested negative by RT-PCR during the study were uniformly negative in dPCR at D/C but tested positive at study exit in 83.3% of cases; pts who showed at least on positive RT-PCR during the study showed positivity by dPCR in 25% at D/C and in 89.3% at study exit. Finally, half of the pts who tested negative by dPCR at study exit showed dPCR positivity when tested at the time of Imatinib D/C.
Conclusions.
These results show that during a three year period, the D/C of Imatinib led to the increase of approximately 1 log in the tumour burden of non-relapsed pts, although none of them lost MMR and resumed treatment.
These data strongly indicate the need for a long-term monitoring of pts who D/C Imatinib; they also suggest that the functional status of residual CML cells rather than their number could represent the critical factor to predict the tumour load present after 3 years of Imatinib D/C.
Le Coutre:Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau. Elena:Novartis: Consultancy; Pfizer: Consultancy. Assouline:Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Stagno:Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Kim:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Il-Yang co.: Research Funding. Fava:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.
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