PALAEOCLIMATIC EVOLUTION IN LOUTRA ARIDEAS CAVE (ALMOPIA SPELEOPARK, MACEDONIA, N. GREECE) BY STABLE ISOTOPIC ANALYSIS OF FOSSIL BEAR BONES AND TEETH

Carbon and oxygen stable isotope values (δ13C, δ18O) were obtained from structural carbonate in the bioapatite of bear bones (Ursus ingressus) from Loutra Arideas cave, Almopia Speleopark, Macedonia, N. Greece. Samples of Late Pleistocene bear bones were studied for palaeoclimatic reconstruction of the area. The age range of the fossil layers is from 32ka BP to a maximum of 38ka BP. Generally, the palaeoclimatic proxy is correlated with literature data for climatic variations in the area during Late Pleistocene, whereas dietary behavior was investigated taking into account possible diagenetic processes that may have affected the carbonate matrix of the bones

The effect of nitrogen fertilization on root characteristics of Camelina sativa L. in greenhouse pots

Climate change has made mandatory the introduction of new crops in Greece, such as the cultivation of camelina [Camelina sativa (L.) Crantz]. Nitrogen (N) and the development of root system are two important factors affecting crop growth and yield. Camelina has been studied mainly for its composition and oil. In the present study, root development of camelina crop was thoroughly investigated; mainly in terms of Nitrogen fertilization. Therefore, a camelina greenhouse experiment was established in Western Greece, in the region of Agrinio, in March 2019 in completely randomized design with four treatments, (control 0 ppm N, 30 ppm N, 60, ppm N and 90 ppm N). The N rates had statistically significant affected root density and root surface from 40 to 120 days after treatment (DAT) with highest values at 100 DAT and 90 ppm N, 52.54 cm of root 100 cm-3 and 27.59 cm2 of root 100 cm-3 , respectively. The root volume was significantly affected by N fertilizer from 40 to 100 DAT and highest value was 13.18 cm3 of root 100 cm-3 soil in the 90 ppm at 120 DAT. The plant leaf area was significantly affected by the highest rate of N. Yield per plant had not statistically significant difference with the 60 and with the 90 and highest weight per plant 292.25 g plant-1 in 90 ppm. In conclusion, Ν fertilization significantly affected growth or camelina’s root system after 40 DAT. Plant growth was significantly affected by fertilization and the highest yield and 1,000 seed weight were recorded with the highest amount of N

GEOCHEMICAL INVESTIGATION OF AQUIFER POLLUTION FROM WASTE MANAGEMENT. THE CASE OF KOMOTINI LANDFILL (GREECE)

According to European legislation, environmental control and monitoring of landfills has become of crucial importance. This study includes a thorough geochemical approach aiming to evaluate the environmental impact of the landfill of Komotini, N. Greece. Samples of waters were taken from inside the working landfill as well as from the area of the neighbouring old landfill. The waters were analyzed chemically (major elements and heavy metals) and isotopically (D and 18O). Also, biogas flow was measured and the ratio CH4/CO2. Based on the geomorphological, hydrogeological and land use data of the area, we proceeded to analyses of waters both from the area of the landfill and from the wider region (drainage basin). The obtained results were used to construct digital maps (GIS) in order to determine the special dispersion of the polluted aquifers. The biogas flow in the old and new garbage burial sites was measured by accumulation chamber device for methane and carbon dioxide ratio determination. The obtained results show an important agent of pollution in the water samples downstream from the landfill and in a distance more than 2km, along the dispersion of the leachate. The land use of the area was taken into account to evaluate the importance and the criticality of the situation

The antimalarial drug amodiaquine stabilizes p53 through ribosome biogenesis stress, independently of its autophagy-inhibitory activity

Pharmacological inhibition of ribosome biogenesis is a promising avenue for cancer therapy. Herein, we report a novel activity of the FDA-approved antimalarial drug amodiaquine which inhibits rRNA transcription, a rate-limiting step for ribosome biogenesis, in a dose-dependent manner. Amodiaquine triggers degradation of the catalytic subunit of RNA polymerase I (Pol I), with ensuing RPL5/RPL11-dependent stabilization of p53. Pol I shutdown occurs in the absence of DNA damage and without the subsequent ATM-dependent inhibition of rRNA transcription. RNAseq analysis revealed mechanistic similarities of amodiaquine with BMH-21, the first-in-class Pol I inhibitor, and with chloroquine, the antimalarial analog of amodiaquine, with well-established autophagy-inhibitory activity. Interestingly, autophagy inhibition caused by amodiaquine is not involved in the inhibition of rRNA transcription, suggesting two independent anticancer mechanisms. In vitro, amodiaquine is more efficient than chloroquine in restraining the proliferation of human cell lines derived from colorectal carcinomas, a cancer type with predicted susceptibility to ribosome biogenesis stress. Taken together, our data reveal an unsuspected activity of a drug approved and used in the clinics for over 30 years, and provide rationale for repurposing amodiaquine in cancer therapy

Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET.

We would like to thank M.Oren (Weizmann Institute of Science) for kindly providing the MDM2 antibodies, the core facility for Bioinformatics and Expression Analysis (BEA, Karolinska, Huddinge) for assisting in massive parallel sequencing and computational infrastructure, as well as E Dratkiewicz, AS Nilsson, and JF Martinez for excellent technical assistance.Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that the disulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregase to suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxic effects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, and mechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diverse human cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed by features of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein and its functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomics profiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolonged exposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneous pharmacological inhibition of RiBi and/or autophagy that further enhanced CuET's tumor cytotoxicity, using both cell culture and zebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET's anti-cancer activity, inform about the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in light of cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET in oncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, rather than old, approved drugs with their, often complex, metabolic profiles.This work was funded by the following grants: the Swedish Cancer Society (grant number: 170176), the Swedish Research Council (VR-MH 2014-46602-117891-30), Novo Nordisk Foundation (NNF20OC0060590), Danish National Research Foundation (project CARD, DNRF 125), the Danish Cancer Society (R204-A12617-B153), DFF 1026-00241B (all granted to JB), and the Grant agency of the Czech Republic: GACR 20-28685S (granted to ZS and MM). Open access funding provided by Karolinska Institute.S

Endogenous viral elements in shrew genomes provide insights into Pestivirus ancient history

As viral genomic imprints in host genomes, endogenous viral elements (EVEs) shed light on the deep evolutionary history of viruses, ancestral host ranges, and ancient viral-host interactions. In addition, they may provide crucial information for calibrating viral evolutionary timescales. In this study, we conducted a comprehensive in silico screening of a large dataset of available mammalian genomes for EVEs deriving from members of the viral family Flaviviridae, an important group of viruses including well-known human pathogens, such as Zika, dengue, or hepatitis C viruses. We identified two novel pestivirus-like EVEs in the reference genome of the Indochinese shrew (Crocidura indochinensis). Homologs of these novel EVEs were subsequently detected in vivo by molecular detection and sequencing in 27 shrew species, including 26 species representing a wide distribution within the Crocidurinae subfamily and one in the Soricinae subfamily on different continents. Based on this wide distribution, we estimate that the integration event occurred before the last common ancestor of the subfamily, about 10.8 million years ago, attesting to an ancient origin of pestiviruses and Flaviviridae in general. Moreover, we provide the first description of Flaviviridae-derived EVEs in mammals even though the family encompasses numerous mammal-infecting members. This also suggests that shrews were past and perhaps also current natural reservoirs of pestiviruses. Taken together, our results expand the current known Pestivirus host range and provide novel insight into the ancient evolutionary history of pestiviruses and the Flaviviridae family in general

The tribulations of trials: Lessons learnt recruiting 777 older adults into REtirement in ACTion (REACT), a trial of a community, group-based active ageing intervention targeting mobility disability

This is the author accepted manuscriptBackground: Challenges of recruitment to randomised controlled trials (RCTs) and successful strategies to overcome them should be clearly reported to improve recruitment into future trials. REtirement in ACTion (REACT) is a UK-based multi-centre RCT recruiting older adults at high risk of mobility disability to a 12-month group-based exercise and behaviour maintenance programme or to a minimal Healthy Ageing control intervention. Methods:The recruitment target was 768 adults, aged 65 years and older scoring 4 to 9 on the Short Physical Performance Battery (SPPB). Recruitment methods included: a) invitations mailed by General Practitioners (GPs); b) invitations distributed via third sector organisations; c) public relations (PR) campaign. Yields, efficiency and costs were calculated. Results: The study recruited 777 (33.9% men) community-dwelling, older adults (mean age 77.55 years (SD 6.79), mean SPPB score 7.37 (SD 1.56)), 95.11% white (n=739) and broadly representative of UK quintiles of deprivation. Over a 20-month recruitment period, 25,559 invitations were issued. Eighty-eight percent of participants were recruited via GP invitations, 5.4% via the PR campaign, 3% via word-of-mouth and 2.5% via third sector organisations. Mean recruitment cost per participant was £78.47, with an extra £26.54 per recruit paid to GPs to cover research costs. Conclusions: REACT successfully recruited to target. Response rates were lower than initially predicted and recruitment timescales required adjustment. Written invitations from General Practitioners were the most efficient method for recruiting older adults at risk of mobility disability. Targeted efforts could achieve more ethnically diverse cohorts. All trials should be required to provide recruitment data to enable evidence-based planning of future trials.National Institute for Health Research, Public Health Research Programm

The effectiveness of the active cycle of breathing technique in patients with chronic respiratory diseases: A systematic review

Background: Active cycle breathing technique (ACBT), which includes cycle of breathing control, thoracic expansion exercises and forced expiratory technique (FET), appears to have beneficial effects in patients with a variety of respiratory diseases. This systematic review provides an update on the new related studies, expanding the evidence base through the last 12 years and specifically evaluating the effectiveness of ACBT on pulmonary function-related outcome variables in patients with chronic respiratory diseases. Methods: MEDLINE/Pubmed, PEDro, and Cochrane Library for Randomized Controlled Trials were searched between September 2008 and December 2021, in continuance of a previous systematic review, to identify randomized clinical trials and/or crossover studies comparing ACBT to other respiratory treatment techniques in patients with chronic obstructive pulmonary diseases, cystic fibrosis, or bronchiectasis. Results: Eleven studies were included and the quality of most of them was moderate to good. The outcomes most frequently assessed were forced expiratory volume in 1 s (FEV1), sputum wet weight, forced vital capacity (FVC), and peak expiratory flow rate. Secondary outcomes were quality of life and dyspnea. Various comparators were identified and most of them assessed the ACBT as an effective method in comparison with other respiratory treatment modalities. Most studies revealed that ACBT/FET had at least an equally beneficial short-term effect on sputum wet weight, FEV1 and FVC compared to other treatment methods. Conclusion: The results of this updating review reinforced the data of a previous systematic review regarding the beneficial impact of ACBT for the short-term improvement in respiratory tract secretions clearance and pulmonary function. ACBT is effective in increasing the expectorated sputum volume, in reducing viscoelasticity of the secretion and in relieving symptoms such as dyspnea. © 202