REVIEW | doi:10.20944/preprints201906.0231.v1
Subject: Physical Sciences, Radiation & Radiography Keywords: bystander effect, genomic instability, lethal mutations,radiotherapy, diagnostic radiology
Online: 24 June 2019 (08:34:26 CEST)
Non-targeted effects (NTE) such as bystander effects or genomic instability have been known for many years but their significance for radiotherapy or medical diagnostic radiology are far from clear. Central to the issue are reported differences in response of normal and tumour tissues to signals from directly irradiated cells. This review will discuss possible mechanisms and implications of these different responses and will then discuss possible new therapeutic avenues suggested by the analysis. Finally, the importance of NTE for diagnostic radiology and nuclear medicine which stems from the dominance of NTE in the low dose region of the dose response curve will be presented. Areas such as second cancer induction and microenvironment plasticity will be discussed.
ARTICLE | doi:10.20944/preprints201711.0041.v1
Subject: Life Sciences, Molecular Biology Keywords: Bioinformatics; Ionizing radiation; Microarrays; Radiation-induced bystander effects; Transcriptomics
Online: 6 November 2017 (15:02:00 CET)
Ionizing radiation-induced bystander effects (RIBE) encompass a number of effects with potential for a plethora of damages in adjacent non-irradiated tissue. The cascade of molecular events is initiated in response to the exposure to ionizing radiation (IR), something that may occur during diagnostic or therapeutic medical applications. In order to better investigate these complex response mechanisms, we employed a unified framework integrating statistical microarray analysis, signal normalization and translational bioinformatics functional analysis techniques. This approach was applied to several microarray datasets from Gene Expression Omnibus (GEO) related to RIBE. The analysis produced lists of differentially expressed genes, contrasting bystander and irradiated samples versus sham-irradiated controls. Furthermore, comparative molecular analysis through BioInfoMiner, which integrates advanced statistical enrichment and prioritization methodologies, revealed discrete biological processes, at the cellular level. For example, negative regulation of growth, cellular response to Zn2+- Cd2+, Wnt and NIK/NF-kappaB signalling, which refine the description of the phenotypic landscape of RIBE. Our results provide a more solid understanding of RIBE cell-specific response patterns, especially in the case of high-LET radiations like α-particles and carbon-ions.
ARTICLE | doi:10.20944/preprints202108.0465.v1
Subject: Behavioral Sciences, Social Psychology Keywords: smartphones; phubbing; social intelligence; bystander inaccessibility
Online: 24 August 2021 (13:14:56 CEST)
Smartphone use has changed patterns of online and offline interaction. Phubbing (i.e., looking at one’s phone instead of paying attention to others) is an increasingly recognized phenomenon in offline interaction. We examined whether people who phub are more likely to have lower social intelligence, whether phubbing is considered more annoying than being ignored due to reading a magazine, and if people describe smartphones and magazines differently as sources of social distraction. We collected two survey samples (N = 112, N = 108) for a cartoon-based role-playing experiment (the Bystander Inaccessibility Experiment) in which a smartphone user and a person reading a magazine ignored the respondents’ conversational initiatives. Annoyance in each scenario was measured, and written accounts were collected on why the respondents rated the scenarios the way they did. Other measures used included the Generic Scale of Phubbing, Generic Scale of Being Phubbed, and Tromsø Social Intelligence Scale. The results showed that participants in both samples were more annoyed by phubbing than by being ignored due to reading a magazine. Linear regression analyses showed that phubbing was associated with lower social intelligence, even after adjusting for confounding factors. The annoyingness of phubbing was explained with negative attitudes toward smartphones, which were assumed to be used for useless endeavors, while magazines were more appreciated and seen as more cultivating. The role of bystanders’ epistemic access to the smartphone user’s activities is discussed.
REVIEW | doi:10.20944/preprints201907.0134.v2
Subject: Life Sciences, Immunology Keywords: lymphocytic choriomeningitis virus (LCMV); viral infection; autoimmunity; molecular mimicry; bystander activation; immune tolerance
Online: 3 October 2019 (13:51:08 CEST)
Viral infections are a natural part of our existence. They can affect us in many ways that are the result of the interaction between the viral pathogen and our immune system. Most times the resulting immune response is beneficial for the host. The pathogen gets cleared thus protecting our vital organs with no other consequences. Conversely, the reaction of our immune system against the pathogen can cause organ damage (immunopathology) or lead to autoimmune disease. To date, there are several mechanisms for virus-induced autoimmune disease, including molecular mimicry and bystander activation, in support of the “fertile field” hypothesis, terms defined in our review. On the flip side, viral infections have been associated with protection from autoimmunity through mechanisms that include Treg invigoration and immune deviation, in support of the “hygiene hypothesis”, also defined here. Infection with lymphocytic choriomeningitis virus (LCMV) is one of the prototypes showing that the interaction of our immune system with viruses can either accelerate or prevent autoimmunity. Studies using mouse models of LCMV have helped conceive and establish several concepts that we today know and explain how viruses can lead to autoimmune activation or induce tolerance. Some of the most important mechanisms established during the course LCMV are described in this short review.
ARTICLE | doi:10.20944/preprints202108.0361.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Neisseria gonorrhoeae; E. coli; K. pneumoniae; Acinetobacter; P. aeruginosa; fluoroquinolones; antimicrobial resistance; stewardship; antibiotic consumption; bystander selection
Online: 17 August 2021 (10:32:27 CEST)
It is unclear how important it is to reduce fluoroquinolone consumption in the general population to prevent the spread of fluoroquinolone resistance in Neisseria gonorrhoeae (bystander selection). Methods We assessed bystander selection by using Spearman’s correlation to assess if the country-level prevalence of fluoroquinolone resistance in N. gonorrhoeae was correlated with the prevalence of fluoroquinolone resistance in four other gram-negative species - Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Results Fluoroquinolone resistance in N. gonorrhoeae was positively associated with homologous resistance in all 4 species - A. baumanii. (ρ=0.61, P=0.0003, E. coli (ρ=0.67, P<0.0001), K. pneumoniae (ρ=0.52, P=0.0004) and P. aeruginosa (ρ=0.40, P=0.0206). Positive associations were also found between the national prevalence of fluoroquinolone resistance and fluoroquinolone consumption in the general population in the preceding year for 4 of the 5 species. Conclusions Gonococcal fluoroquinolone resistance can be productively viewed as being part of a syndemic of fluoroquinolone resistance. Strengthening antimicrobial stewardship programs may help retard the spread of fluoroquinolone resistance in N. gonorrhoeae.
ARTICLE | doi:10.20944/preprints202207.0182.v1
Subject: Life Sciences, Biophysics Keywords: ADAM; Adaptive response; ALK1; ALK5; Bystander effects; Hyper-radiosensitive response; Low-dose radiation; Low dose rate; MMP; TGF-β3
Online: 12 July 2022 (09:25:07 CEST)
Hyper-radiosensitivity (HRS) is the increased sensitivity to low doses of ionizing radiation observed in most cell lines. We previously demonstrated that HRS is permanently abolished in cells irradiated at a low dose rate (LDR), in a mechanism dependent on transforming growth factor β3 (TGF-β3). In this study, we aimed to elucidate the activation and receptor binding of TGF-β3 in this mechanism. T-47D cells were pre-treated with inhibitors of potential receptors and activators of TGF-β3, along with addition of small extracellular vesicles (sEVs) from LDR primed cells, before their radiosensitivity was assessed by the clonogenic assay. The protein content of sEVs from LDR primed cells was analyzed with mass spectrometry. Our results show that sEVs contain TGF-β3 regardless of priming status, but only sEVs from LDR primed cells remove HRS in reporter cells. Inhibition of the matrix metalloproteinase (MMP) family prevents removal of HRS, suggesting an MMP-dependent activation of TGF-β3 in the LDR primed cells. We demonstrate a functional interaction between TGF-β3 and activin receptor like kinase 1 (ALK1), by showing that TGF-β3 removes HRS through ALK1 binding, independent of ALK5 and TGF-βRII. These results are an important contribution to a more comprehensive understanding of the mechanism behind TGF-β3 mediated removal of HRS.
REVIEW | doi:10.20944/preprints201912.0135.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: vascular homing peptide; cell penetrating peptide; angiogenesis; vascular heterogeneity; fibrosis; targeted delivery; decorin; transforming growth factor-β (tgf-β), bystander effect, cendr peptide; tissue regeneration; regenerative medicine
Online: 10 December 2019 (15:02:39 CET)
Growth factors, chemokines and cytokines guide tissue regeneration after injuries. However, their applications as recombinant proteins are almost non-existent due to the difficulty of maintaining their bioactivity in the protease-rich milieu of injured tissues in humans. Safety concerns have ruled out their systemic administration. The vascular system provides a natural platform for circumvent the limitations of the local delivery of protein-based therapeutics. Tissue selectivity in drug accumulation can be obtained as organ-specific molecular signatures exist in the blood vessels in each tissue, essentially forming a postal code system (“vascular zip codes”) within the vasculature. These target-specific “vascular zip codes” can be exploited in regenerative medicine as the angiogenic vasculature forming in the regenerating tissues has a unique molecular signature. The identification of vascular homing peptides capable of finding these unique “vascular zip codes” after their systemic administration provides an opportunity for the target-specific delivery of therapeutics to tissue injuries. Therapeutic proteins can be “packaged” together with homing peptides by expressing them as multi-functional recombinant proteins. These multi-functional recombinant proteins provide an example how molecular engineering gives a compound an ability to home to regenerating tissue and enhance its therapeutic potential. Regenerative medicine has been dominated by the locally applied therapeutic approaches despite these therapies are not moving to clinical medicine with success. There might be a time to change the paradigm towards systemically administered, target organ-specific therapeutic molecules in future drug discovery and development for regenerative medicine