Biological Endpoints Research Articles

Computational characterization of the binding mode and mechanism of action of tricyclic small molecules at 5-HT1E and 5-HT1F receptors.

5-hydroxytryptamine (serotonin) 1E and 1F receptors (5-HT1E and 5-HT1F, respectively) are highly expressed human G protein-coupled receptors with high sequence identity among themselves and other 5-HT1 receptor subtypes. Although the physiological role of 5-HT1E and 5-HT1F is not fully understood, they are molecular targets of drugs that are effective to treat migraine, depression, and schizophrenia, albeit not without also producing adverse effects. Notably, no selective or high-affinity drugs have been reported for the 5-HT1E receptor to date. Thus, there is widespread interest in understanding at an atomic level of detail how small molecules bind and activate these receptors for the ultimate purpose of designing improved therapeutics. Through computational studies including docking calculations, metadynamics rescoring, and molecular dynamics simulations of cryo-electron microscopy structures, we predict the binding mode and mechanism of action of tricyclic small molecules that are capable of simultaneously activating the 5-HT1E and 5-HT1F receptors. Our results provide testable hypotheses of ligand-receptor interactions and ligand-induced allosteric modulation that may be used to improve the efficacy of these small molecules towards specific biological endpoints.

Global Research Activities on Micro(nano)plastic Toxicity to Earthworms.

Micro(nano)plastics are emerging contaminants that have been shown to cause various ecotoxicological effects on soil biota. Earthworms, as engineers of the ecosystem, play a fundamental role in soil ecosystem processes and have been used as model species in ecotoxicological studies. Research that evaluates micro(nano)plastic toxicity to earthworms has increased greatly over the last decade; however, only few studies have been conducted to highlight the current knowledge and evolving trends of this topic. This study aims to visualize the research status and knowledge structure of the relevant literature. Bibliometrics and visualization analyses were conducted using co-citations, cooperation networks and cluster analysis. The results showed that micro(nano)plastic toxicity to earthworms is an emerging and increasingly popular topic, with 78 articles published from 2013 to 2022, the majority of which were published in the last two years. The most prolific publications and journals involved in this topic were also identified. In addition, the diversity of cooperative relationships among different countries and institutions confirmed the evolution of this research field, in which China contributed substantially. The high-frequency keywords were then determined using co-occurrence analysis, and were identified as exposure, bioaccumulation, soil, pollution, toxicity, oxidative stress, heavy metal, microplastic, Eisenia foetida and community. Moreover, a total of eight clusters were obtained based on topic knowledge clustering, and these included the following themes: plastic pollution, ingestion, combined effects and the biological endpoints of earthworms and toxic mechanisms. This study provides an overview and knowledge structure of micro(nano)plastic toxicity to earthworms so that future researchers can identify their research topics and potential collaborators.

Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): developing tools to enable early intervention in the psychosis highrisk state.

Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): developing tools to enable early intervention in the psychosis highrisk state.

Relative biological effectiveness of low-energy X-rays (25 kV) in mutant p53 cancer cells

Low-energy X-rays as used in radiation therapy and diagnostics such as mammography are associated with a certain risk of promoting tumour development, especially in patients with mutations in cancer-related genes like TP53. The present study therefore addressed the relative biological effectiveness (RBE) of low-energy X-rays for two human adenocarcinoma cell lines of the breast (MDA-MB-468) and pancreas (BxPC-3) with a mutation in the TP53 gene. Clonogenic survival and cytogenetic changes in terms of micronuclei (MN) formation were determined following irradiation with 25 kV X-rays and 200 kV reference irradiation in the dose range of 1–8 Gy. Except the frequency of MN-containing binucleated cells (BNC) (BNC + MN/BNC) in breast cancer cells yielding an RBE between 0.6 and 0.8, both cell lines displayed dose-dependent variations of RBE values between 1 and 2 for all biological end points (cell survival, (BNC + MN/BNC), MN/BNC, MN/(BNC + MN)) with increased effectiveness of 25 kV irradiation in pancreatic compared to breast cancer cells. The results confirm previous findings indicating increased effectiveness of low-energy X-rays and underline the necessity of careful risk estimation for cancer screening programmes.

Putative adverse outcome pathways for silver nanoparticle toxicity on mammalian male reproductive system: a literature review

BackgroundAdverse outcome pathways (AOPs) are conceptual frameworks that organize knowledge about biological interactions and toxicity mechanisms. They present a sequence of events commencing with initial interaction(s) of a stressor, which defines the perturbation in a biological system (molecular initiating event, MIE), and a dependent series of key events (KEs), ending with an adverse outcome (AO). AOPs have recently become the subject of intense studies in a view to better understand the mechanisms of nanomaterial (NM) toxicity. Silver nanoparticles (Ag NPs) are one of the most explored nanostructures and are extensively used in various application. This, in turn, has increased the potential for interactions of Ag NPs with environments, and toxicity to human health. The aim of this study was to construct a putative AOPs (pAOP) related to reproductive toxicity of Ag NPs, in order to lay the groundwork for a better comprehension of mechanisms affecting both undesired toxicity (against human cell) and expected toxicity (against microorganisms).MethodsPubMed and Scopus were systematically searched for peer-reviewed studies examining reproductive toxicity potential of Ag NPs. The quality of selected studies was assessed through ToxRTool. Eventually, forty-eight studies published between 2005 and 2022 were selected to identify the mechanisms of Ag NPs impact on reproductive function in human male. The biological endpoints, measurements, and results were extracted from these studies. Where possible, endpoints were assigned to a potential KE and an AO using expert judgment. Then, KEs were classified at each major level of biological organization.ResultsWe identified the impairment of intracellular SH-containing biomolecules, which are major cellular antioxidants, as a putative MIE, with subsequent KEs defined as ROS accumulation, mitochondrial damage, DNA damage and lipid peroxidation, apoptosis, reduced production of reproductive hormones and reduced quality of sperm. These successive KEs may result in impaired male fertility (AO).ConclusionThis research recapitulates and schematically represents complex literature data gathered from different biological levels and propose a pAOP related to the reproductive toxicity induced by AgNPs. The development of AOPs specific to NMs should be encouraged in order to provide new insights to gain a better understanding of NP toxicity.

Clonogenic assay to measure bystander cytotoxicity of targeted alpha-particle therapy.

Radiation therapy induces targeted effects in the cells that are irradiated and also non-targeted effects (i.e. bystander effects) in non-irradiated cells that are close to or at short distance (<∼1mm) from irradiated cells. Bystander effects are mediated by intercellular communications and may result in cytotoxic and genotoxic modifications. Their occurrence and relative contribution to the irradiation outcome are influenced by several parameters among which the particle linear energy transfer seems to be prominent. Bystander effects were first observed after external radiation therapy, but have been described also following targeted radionuclide therapy. Therefore, we propose a method to investigate their occurrence in experimental conditions where cells are exposed to radiopharmaceuticals. In this approach, clonogenic cell death is the biological endpoint of the bystander effects caused by irradiation with alpha particles (a potent inducer of the bystander response).

Prediction of DNA rejoining kinetics and cell survival after proton irradiation for V79 cells using Geant4-DNA

Purpose:Track structure Monte Carlo (MC) codes have achieved successful outcomes in the quantitative investigation of radiation-induced initial DNA damage. The aim of the present study is to extend a Geant4-DNA radiobiological application by incorporating a feature allowing for the prediction of DNA rejoining kinetics and corresponding cell surviving fraction along time after irradiation, for a Chinese hamster V79 cell line, which is one of the most popular and widely investigated cell lines in radiobiology. Methods:We implemented the Two-Lesion Kinetics (TLK) model, originally proposed by Stewart, which allows for simulations to calculate residual DNA damage and surviving fraction along time via the number of initial DNA damage and its complexity as inputs. Results:By optimizing the model parameters of the TLK model in accordance to the experimental data on V79, we were able to predict both DNA rejoining kinetics at low linear energy transfers (LET) and cell surviving fraction. Conclusion:This is the first study to demonstrate the implementation of both the cell surviving fraction and the DNA rejoining kinetics with the estimated initial DNA damage, in a realistic cell geometrical model simulated by full track structure MC simulations at DNA level and for various LET. These simulation and model make the link between mechanistic physical/chemical damage processes and these two specific biological endpoints.

Acute toxicity, oxidative stress, and apoptosis due to short-term triclosan exposure and multi- and transgenerational effects on in vivo endpoints, antioxidant defense, and DNA damage response in the freshwater water flea Daphnia magna

In this study, we measured the acute toxicity of triclosan (TCS) in neonate and adult Daphnia magna water fleas. The median lethal concentrations were 184.689 and 349.511 μg/L, respectively. Oxidative stress induced by TCS was analyzed based on changes in reactive oxygen species (ROS) content and antioxidant enzymatic activities in D. magna. Based on these endpoints, TCS concentrations of 50 and 100 μg/L induced oxidative stress. However, several apoptosis-mediated proteins showed TCS-induced oxidative-stress damage in response to 25 μg/L, indicating that apoptotic proteins were the most sensitive mediators. We also evaluated the multi- and transgenerational effects of TCS on D. magna over three generations in terms of various in vivo endpoints, DNA damage responses, and biochemical reactions. The transgenerational group exposed to TCS exhibited greater negative impacts on antioxidant responses, DNA fragmentation status, and biological endpoints compared with the multigenerational exposure group, leading to decreased reproductive rates and higher ROS content. The transcriptional expression levels of glutathione S-transferase genes in the transgenerational exposure group were upregulated compared to those in the multigenerational group but were fully recovered in F2 offspring. Our findings provide an in-depth understanding of the adaptive effects of multigenerational exposure to TCS.

Cytogenetic effects of magnevist and methotrexate on mice bone marrow

This study was established to investigate the cytogenetic effects of magnevist on mice bone marrow before and after methotrexate (MTX) 2.5 mg/kg. The negative control group was treated with 0.2 ml distilled water. Magnevist was given alone to the mice intraperitoneally with 0.6 mg/kg for 24 hrs and 48 hrs. Similarly, MTX was only intravenously injected with 2.5 mg/kg for 24 hrs and 48 hrs, which were considered as positive controls. Moreover, different combinations of magnevist/ MTX were given in terms of different time points of treatment. Results showed high induction (p&lt;0.05) of chromosomal aberrations (CAs) and micronuclei (MN) and reduction in mitotic index (MI) of following treatments: magnevist, MTX and magnevist/MTX combination, compared to corresponding control groups. Interestingly, the combination magnevist and MTX treatment demonstrated higher induction in all biological end points than other groups. We concluded that the high combination effects may belong to increase in the aggressiveness of MTX that enhanced by magnevist and vice versa.

Low vulnerability of the Mediterranean antipatharian Antipathella subpinnata (Ellis & Solander, 1786) to ocean warming

Antipatharians (black corals) are major components of mesophotic ecosystems in the Mediterranean Sea. The arborescent species Antipathella subpinnata has received particular attention as it is the most abundant and forms dense forests harbouring high levels of biodiversity. This species is currently categorized as “Near Threatened” in the IUCN Red List, due to increasing fishing pressure and bottom-trawling activities. Yet, the effects of ocean warming have never been investigated for this species, nor for any other antipatharians from temperate regions. Our study aimed at evaluating the effects of increasing seawater temperatures on A. subpinnata, by combining predictive distribution modelling with a physiological tolerance experiment. During the latter, we exposed A. subpinnata for 15 days to different temperature conditions spanning the current seasonal range to forecasted temperatures for 2100, while measuring biological endpoints such as oxygen consumption rates and different signs of stress (tissue necrosis, total antioxidant capacity). Unexpectedly, no stress was found at organism nor cellular level (wide thermal breadth) suggesting low susceptibility of this species to mid-term temperature increase. If the response to the 15-days heat stress is representative of the response to longer-term warming, ocean warming is unlikely to affect A. subpinnata. The species distribution model predicted the presence of A. subpinnata at depths that correspond to temperatures colder than its maximum thermal tolerance (as determined by the physiology experiment). This suggests that the presence of A. subpinnata at shallower depths is not limited by physiological constraints but by other ecological factors including interspecific competition.

Influence of water matrix components and peroxide sources on the transformation products and toxicity of tebuthiuron under UVC-based advanced oxidation processes

Coupling of UV-C irradiation to different peroxides (H2O2, S2O82− and HSO5−) has great potential to degrade persistent organic compounds due to the formation of HO• or SO4•– species. However, an in-depth comparison between the performance of different UV-C/peroxide processes as a function of (i) target compound degradation, (ii) generated transformation products and (iii) lethal/sub lethal toxicity effects has not yet been performed. To this end a comparison study was carried out to evaluate the effectiveness of different UV-C/peroxide processes using the herbicide tebuthiuron (100 or 500 μg L−1) as a model pollutant. TBH degradation experiments were performed at lab-scale in real municipal wastewater treatment plant effluent and distilled water. Faster degradation occurred by increasing peroxide concentration from 735 to 2206 μmol L−1 in the municipal wastewater treatment plant effluent, mainly for S2O82−. Experiments performed in the presence of peroxide trapping agents – HO• and SO4•– (methoxibenzene) or HO• (2-propanol) – revealed that oxidation in the UV-C/S2O82− system occurs mainly through SO4•–. Lower toxicity for the MWWTP effluent was obtained after oxidative treatments using hydrogen peroxide or monopersulfate as oxidants which react mainly through HO• radicals. Two mechanistic pathways were proposed for tebuthiuron degradation: (i) hydrogen abstraction by HO• (H2O2 and HSO5−) and (ii) electron transfer by SO4•– (S2O82−). In addition, one unprecedented transformation product was identified. In conclusion, results emphasize the relevance of comparing the degradation of toxic compounds in the presence of different peroxide sources and matrices and simultaneouly evaluating responses chemical and biological endpoints.

Development of an inexpensive 3D clinostat and comparison with other microgravity simulators using Mycobacterium marinum

2D and 3D Clinostats are used to simulate microgravity on Earth. These machines continuously alter the sample’s orientation, so the acceleration vector changes faster than the biological endpoint being monitored. Two commercially available microgravity simulators are the Rotary Cell Culture System (Synthecon Inc.), which is a 2D clinostat, and the RPM 2.0 (Yuri), which is a 3D clinostat that can operate as a random positioning machine or in constant frame velocity mode. We have developed an inexpensive 3D clinostat that can be 3D printed and assembled easily. To determine the optimal combination of inner (I) and outer (O) frame velocities to simulate microgravity, two factors were considered: the time-averaged magnitude and the distribution of the acceleration vector. A computer model was developed to predict the acceleration vector for combinations of frame velocities between 0.125 revolutions per minute (rpm) and 4 rpm, and a combination of I = 1.5 rpm and O = 3.875 rpm was predicted to produce the best microgravity simulation. Two other frame velocity combinations were also used in further tests: I = 0.75 rpm and O = 3.625 rpm, and I = 2 rpm and O = 1.125 rpm. By operating the RPM 2.0 in constant velocity mode at these three velocity combinations, the RPM 2.0 algorithm data confirmed that these operating conditions simulated microgravity. Mycobacterium marinum was selected for biological comparison experiments as this bacterium can grow as a biofilm or a planktonic culture. Biofilm experiments revealed that the RPM 2.0 and the 3D clinostat with I = 1.5 rpm and O = 3.825 rpm produced similar structures in attached biofilm, and similar changes in transcriptome for the bacteria in suspension compared to the normal gravity transcriptome. Operating the 3D clinostat at I = 2 rpm and O = 1.125 rpm, and the Synthecon 2D clinostat in simulated microgravity orientation at 25 rpm resulted in the same decreased planktonic growth and increased rifampicin survival compared to normal gravity. This study validates the inexpensive 3D clinostat and demonstrates the importance of testing the operating conditions of lab-developed clinostats with biological experiments.

Evaluation of cytotoxicity and genotoxicity of a novel oxovanadium complex with orotate

The development of new drugs based on metal complexes requires a detailed analysis of their biological endpoints. In this study, we report the genotoxic profile and influence on cell proliferation and death of the oxovanadium(IV) complex with orotic acid ([VO(C5H4N2O4)2], VO(oro)). Human hepatocellular carcinoma cells (HepG2) were the most sensitive tumor cells to VO(oro), which interfered with the integrity of cell membranes and proliferative capacity in a dose-dependent manner, inducing cell death by apoptosis. Regarding genotoxicity, VO(oro) did not induce considerable levels of DNA damage in HepG2 cells (comet test) and gene mutations (Ames test). However, it caused a statistically significant increase in the frequency of micronuclei at the highest concentration tested (12.5 µmol.L–1), indicating aneuploidy and clastogenicity. The data presented here provide information on various biological aspects of the VO(oro) complex, which may allow the elucidation of its mechanism of action as a possible therapeutic agent.

Extended Rule of Five and Prediction of Biological Activity of peptidic HIV-1-PR Inhibitors

In this research work, we have applied “Lipinski’s RO5” for pharmacokinetics (PK) study and to predict the activity of peptidic HIV-1 protease inhibitors. Peptidic HIV-1-PRIs have been taken from literature with their observed biological activities (OBAs) in term of IC50. The logarithms of the inverse of IC50 have been used as biological end point o(log1/C) in the study. For calculation of physicochemical parameters, the molecular modeling and geometry optimization of all the derivatives have been carried out with CAChe Pro software using semiempirical PM3 method. Prediction of the biological activity of the inhibitors has shown that the best QSAR model is constructed from pharmacokinetic properties, molecular weight and hydrogen bond acceptor. This also proved that these properties play important role to describe the PKs of the drugs. On the basis of the derived models one can build up a theoretical basis to access the biological activity of the compounds of the same series.

Predicting environmental concentrations and the potential risk of Plant Protection Products (PPP) on non-target soil organisms accounting for regional and landscape ecological variability in european soils.

Plant Protection Products (PPP) raise concerns as their application may cause effects on some soil organisms considered non-target species which could be highly sensitive to some pesticides. The European Food and Safety Authority (EFSA), in collaboration with the Joint Research Centre (JRC) of the European Commission, has developed guidance and a software tool, Persistence in Soil Analytical Model (PERSAM), for conducting soil exposure assessments. EFSA PPR Panel has published recommendations for the risk assessment of non-target soil organisms. We have used PERSAM for calculating PPPs predicted environmental concentrations (PECs); and used the estimated PEC for assessing potential risks using Toxicity Exposure Ratios (TER) for selected soil organisms and good agricultural practices. Soil characteristics and environmental variables change along a latitudinal axis through the European continent, influencing the availability of PPP, their toxicity upon soil biota, and hence, impacting on the risk characterization. Although PERSAM includes as input geographical information, the information is aggregated and not further detailed in the model outputs. Therefore, there is a need to develop landscape based environmental risk assessment methods addressing regional variability. The objective was to integrate spatially explicit exposure (PECs) and effect data (biological endpoints i.e. LC50, NOEC, etc.) to estimate the risk quotient (TER) of four PPP active substances (esfenvalerate, cyclaniliprole, picoxystrobin, fenamidone) on non-target species accounting European landscape and agricultural variability. The study was focused on the effects produced by the above-mentioned pesticides on two soil organisms: E. fetida earthworms and Folsomia sp. collembolans. After running PERSAM assuming a worst case application of PPPs, PECs in total soil and pore water were obtained for different depths in northern, central and southern European soils. With this data, soil variability and climatic differences among soils divided in three large Euroregions along a latitudinal transect (Northern, Central, Southern Europe) were analysed. Summarising, a trend to accumulate higher PECs and TERs in total soil was observed in the north decreasing towards the south. Higher PECs and TERs could be expected in pore water in southern soils, decreasing towards the north. The risk disparity between pollutant concentrations at different soils compartments should be taken into account for regulatory purposes, as well as the potential landscape variabilities among different Euroregions.

Calcium Intake and Metabolism in Infants and Young Children: A Systematic Review of Balance Studies for Supporting the Development of Calcium Requirements

ABSTRACTDetermining calcium requirements for infants and children is vital due to high calcium needs for growth. Balance studies enable comprehensive measurement of calcium metabolism and can support nutrient requirement development. This systematic review summarizes evidence from mass balance and isotopic studies in children aged 0–4 y to address key questions on calcium loss and absorption/retention identified by an expert group developing calcium requirements. Literature searches were implemented in multiple electronic databases to June 2020. Balance studies assessing calcium intake, loss, absorption, or retention in healthy children were eligible. A newly developed risk-of-bias assessment tool was used for balance studies, and a modified Grades of Recommendation, Assessment, Development, and Evaluation approach determined strength of evidence. Altogether, 23 studies (15 mass balance; 8 isotope) with 485 total participants were included. Only 3 studies were of children >6 mo. Mass balance studies suggested infant feed components may influence calcium balance. The random-effects model meta-regression on 42 mass balance study arms showed an average net calcium retention of 40.4% among infants aged 0–6 mo (β = 0.404 [95% CI: 0.302, 0.506]). Isotope studies suggested calcium intake of 240 to 400 mg/d may promote optimal calcium absorption with minimal loss, and intake from human milk may lead to greater absorption and retention efficacy than formula or solid foods. Most studies had low risk of bias. Strength of evidence was low due to variability in infant feedings, limited endogenous and dermal calcium loss measures, and few studies isolating calcium effects. To improve certainty of the body of evidence, more balance studies isolating effects of calcium intake in this age group are needed. Future work on calcium needs should incorporate both balance measures and biological endpoints of importance (e.g. bone mineral density or content) to determine adequate calcium intake for growth in infants and children.

Challenges in Glioblastoma Radiomics and the Path to Clinical Implementation

Simple SummaryGlioblastoma (GBM) is a cancer with poor prognosis, its 5-year survival expectation is approximately 5%. Advances in oncologic treatment techniques have not led to significant improvements in survival outcomes for GBM patients. Part of the reason for the treatment failures in GBM patients is that treatments fail to account for heterogeneities both within and between different tumors. Radiomics is a rapidly emerging research field that examines the relationship between medical imaging features and patient clinical outcomes and biological characteristics of tumours. This review outlines the applications of radiomics for GBM patient management and the barriers facing the implementation of radiomics into clinical practice. In completing this review, we hope to inform clinicians and researchers on how radiomics may be used to improve patient clinical outcomes.Radiomics is a field of medical imaging analysis that focuses on the extraction of many quantitative imaging features related to shape, intensity and texture. These features are incorporated into models designed to predict important clinical or biological endpoints for patients. Attention for radiomics research has recently grown dramatically due to the increased use of imaging and the availability of large, publicly available imaging datasets. Glioblastoma multiforme (GBM) patients stand to benefit from this emerging research field as radiomics has the potential to assess the biological heterogeneity of the tumour, which contributes significantly to the inefficacy of current standard of care therapy. Radiomics models still require further development before they are implemented clinically in GBM patient management. Challenges relating to the standardisation of the radiomics process and the validation of radiomic models impede the progress of research towards clinical implementation. In this manuscript, we review the current state of radiomics in GBM, and we highlight the barriers to clinical implementation and discuss future validation studies needed to advance radiomics models towards clinical application.

Bone Marrow Relative Biological Effectiveness for a 212Pb-labeled Anti-HER2/neu Antibody

We have determined the in vivo relative biological effectiveness (RBE) of an alpha-particle-emitting radiopharmaceutical therapeutic agent (212Pb-labeled anti-HER2/neu antibody) for the bone marrow, a potentially dose-limiting normal tissue. The RBE was measured in mice using femur marrow cellularity as the biological endpoint. External beam radiation therapy (EBRT), delivered by a small-animal radiation research platform was used as the reference radiation. Alpha-particle emissions were delivered by 212Bi after the decay of its parent nuclide 212Pb, which was conjugated onto an anti-HER2/neu antibody. The alpha-particle absorbed dose to the marrow after an intravenous administration (tail vein) of 122.1 to 921.3 kBq 212Pb-TCMC-7.16.4 was calculated. The mice were sacrificed at 0 to 7 days after treatment and the radioactivity from the femur bone marrow was measured. Changes in marrow cellularity were assessed by histopathology. The dose response for EBRT and 212Pb-anti-HER2/neu antibody were linear-quadratic and linear, respectively. On transforming the EBRT dose-response relationship into a linear relationship using the equivalent dose in 2-Gy fractions of external beam radiation formalism, we obtained an RBE (denoted RBE2) of 6.4, which is independent of cellularity and absorbed dose. Because hematologic toxicity is dose limiting in almost all antibody-based RPT, in vivo measurements of RBE are important in helping identify an initial administered activity in phase 1 escalation trials. Applying the RBE2 and assuming typical antibody clearance kinetics (biological half-life of 48 hours), using a modified blood-based dosimetry method, an average administered activity of approximately 185.5 MBq (5.0 mCi) per patient could be administered before hematologic toxicity is anticipated.

Dose Response Curve Using Chemically Induced PCC Assay in Peripheral Cells Irradiated In-vitro to 5 MeV Alpha Particles Emitted From Radon Source

Bio-dosimetry is defined as estimation of dose received by individuals based on biological end points induced by ionizing radiation. By using cytogenetic assay, it is possible to quantify the absorbed dose. High linear energy transfer (LET) radiation produces dense ionizations along their path and causes more clustered DNA damage compared to low LET. Radon is a natural radioactive element present in the atmosphere mainly produced during decay of uranium. The main objective of the present study is to construct dose response curve by using Premature Chromosome Condensation (PCC) techniques in blood cells exposed in-vitro to radon exposure. Blood samples were drawn from healthy non-smokers (n=4), aged between 28 to 42 years and exposed to twenty doses of radon ranged between 0 to 5.5 mGy. A total of about 24000 metaphase spreads were counted to find the DNA damages include ring chromosomes (RC), dicentric chromosomes (DC) and acentric fragments (AF). As the dose increases gradual increase was observed in RC, DC and AF with the slope of 0.001, 0.005 and 0.064 respectively. So far, no calibration reference curve was generated for low dose radon using chemically induced PCC assay and hence this study is considered as first of its kind.

Predicting toxicity of endocrine disruptors and blood–brain barrier permeability using chirality-sensitive descriptors and machine learning

Estrogen receptor (ER) mediated endocrine disruption and blood–brain barrier (BBB) permeability are two crucial pharmacological endpoints that must be assessed for any drug candidate. However, experimental testing is expensive and time-consuming, and in recent years, Quantitative Structure-Property Relationships (QSPRs) have emerged as a viable in silico alternative. However, most QSPR models reported on ER toxicity and BBB permeability have been carried out using 2D descriptors, whereas it has been established that ER binding and BBB permeability are stereoselective processes in which the spatial arrangement of atoms in the molecule plays a key role. The current study addresses this problem using a chirality-sensitive 3D-QSPR methodology entitled ‘EigenValue ANalysiS (EVANS). The EVANS approach merges information from 3D molecular structure with 2D physicochemical properties to generate eigenvalues which are used as descriptors in QSPR modelling. For chiral compounds, EVANS computes descriptors by considering distance attributes from a plethora of enantiomeric states, thereby accounting for the contributions of multiple conformers towards a particular biological endpoint. We deploy the EVANS methodology with machine learning algorithms to build predictive QSPR models for estrogen receptor (ER) mediated endocrine disruption and BBB permeability. Regression analyses of ER binding on a dataset of 132 chemical entities returned a robust and predictive model, with the support vector machine model having rtrain2=0.84 and rtest2=0.70. Classification models for BBB permeability on a dataset of 607 chemicals also showed high prediction accuracy, with the artificial neural network model showing the best performance (Accuracy = 0.85, AUC = 0.82, precision = 0.85, F1 score = 0.89). For comparison, conventional 2D-QSPR models were also built for these endpoints, and it was observed that EVANS generates eigenvalues that are superior to descriptors used in standard 2D-QSPR. Overall, our results demonstrate that EVANS is a powerful 3D-QSPR methodology that offers several advantages over existing QSAR/QSPR methods, and can be a useful computational tool in the pharmacological and toxicological evaluation of new and existing drugs.