Selective cleavage of lignin β-O-4 aryl ether bond by β-etherase of the white-rot fungus Dichomitus squalens.

Production of value-added compounds from a renewable aromatic polymer, lignin, has proven to be challenging. Chemical procedures, involving harsh reaction conditions, are costly and often result in nonselective degradation of lignin linkages. Therefore, enzymatic catalysis with selective cleavage of lignin bonds provides a sustainable option for lignin valorization. In this study, we describe the first functionally characterized fungal intracellular beta-etherase from the wood-degrading white-rot basidiomycete Dichomitus squalens. This enzyme, Ds-GST1, from the glutathione-Stransferase superfamily selectively cleaved the beta-O-4 aryl ether bond of a dimeric lignin model compound in a glutathionedependent reaction. Ds-GST1 also demonstrated activity on polymeric synthetic lignin fractions, shown by a decrease in molecular weight distribution of the lactase -oxidized guaiacyl dehydrogenation polymer. In addition to a possible role of DsGST1 in intracellular catabolism of lignin-derived aromatic compounds, the cleavage of the most abundant linkages in lignin under mild reaction conditions makes this biocatalyst an attractive green alternative in biotechnological applications.Peer reviewe

Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML

We sought to identify drugs that could counteract cytarabine resistance in acute myeloid leukemia (AML) by generating eight resistant variants from MOLM-13 and SHI-1 AML cell lines by long-term drug treatment. These cells were compared with 66 ex vivo chemorefractory samples from cytarabine-treated AML patients. The models and patient cells were subjected to genomic and transcriptomic profiling and high-throughput testing with 250 emerging and clinical oncology compounds. Genomic profiling uncovered deletion of the deoxycytidine kinase (DCK) gene in both MOLM-13- and SHI-1-derived cytarabine-resistant variants and in an AML patient sample. Cytarabine-resistant SHI-1 variants and a subset of chemorefractory AML patient samples showed increased sensitivity to glucocorticoids that are often used in treatment of lymphoid leukemia but not AML. Paired samples taken from AML patients before treatment and at relapse also showed acquisition of glucocorticoid sensitivity. Enhanced glucocorticoid sensitivity was only seen in AML patient samples that were negative for the FLT3 mutation (P = 0.0006). Our study shows that development of cytarabine resistance is associated with increased sensitivity to glucocorticoids in a subset of AML, suggesting a new therapeutic strategy that should be explored in a clinical trial of chemorefractory AML patients carrying wild-type FLT3.Peer reviewe

Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors

Tyrosine kinase inhibitors (TKI) are the mainstay treatment of BCR-ABL1-positive leukemia and virtually all patients with chronic myeloid leukemia in chronic phase (CP CML) respond to TKI therapy. However, there is limited information on the cellular mechanisms of response and particularly on the effect of cell differentiation state to TKI sensitivity in vivo and ex vivo/in vitro. We used multiple, independent high-throughput drug sensitivity and resistance testing platforms that collectively evaluated 295 oncology compounds to characterize ex vivo drug response profiles of primary cells freshly collected from newly-diagnosed patients with BCR-ABL1positive leukemia (n = 40) and healthy controls (n = 12). In contrast to the highly TKI-sensitive cells from blast phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, primary CP CML cells were insensitive to TKI therapy ex vivo. Despite maintaining potent BCR-ABL1 inhibitory activity, ex vivo viability of cells was unaffected by TKIs. These findings were validated in two independent patient cohorts and analysis platforms. All CP CML patients under study responded to TKI therapy in vivo. When CP CML cells were sorted based on CD34 expression, the CD34-positive progenitor cells showed good sensitivity to TKIs, whereas the more mature CD34-negative cells were markedly less sensitive. Thus in CP CML, TKIs predominantly target the progenitor cell population while the differentiated leukemic cells (mostly cells from granulocytic series) are insensitive to BCR-ABL1 inhibition. These findings have implications for drug discovery in CP CML and indicate a fundamental biological difference between CP CML and advanced forms of BCR-ABL1-positive leukemia.Peer reviewe

Men, Mental Health and Elite Sport: a Narrative Review

Mental health in elite sport is receiving more publicity due to an increase in male athletes sharing their personal experiences. Sports injury is recognised as the major risk factor for psychological distress amongst male athletes, although anecdotally this may be that athletes are more likely to discuss their emotional wellbeing when related to the injury they are experiencing. Stress can be amplified within elite sport and the pressure they experience in relation to competition and performance can be exacerbated by adverse life events. This ongoing stress does not end when their sporting career does, it can follow them into retirement. The physical and psychological demands placed upon them by the sporting environment may predispose athletes to developing depression. As an athlete's symptoms of mental illness intensify, their performance can be negatively affected leaving them vulnerable and exposed to further symptoms of common mental disorders. The pressure of performance can also expose male athletes to overtraining syndrome which can be difficult to distinguish from depression. Male athletes are more vulnerable to eating disorders compared with males in the general population and they do have anxieties, particularly around their bodies, but find it difficult to disclose their concerns. In addition to this, male athletes are more likely to use substances, including opioids to improve both sport and non-sport performance.Despite the prevalence of common mental disorders in male athletes, stigma still exists, and although some athletes discuss their issues publicly after their career has ended, the majority of athletes prefer to remain silent. There remains a view that athletes who seek help for psychological problems may be seen as weak. Although there is an improvement in help-seeking attitudes within elite sport, further research and education is needed to encourage men to talk about their mental health, share their experiences and to enjoy a greater sense of emotional wellbeing

The Kolumbo submarine volcano of Santorini island is a large pool of bacterial strains with antimicrobial activity

Microbes in hydrothermal vents with their unique secondary metabolism may represent an untapped potential source of new natural products. In this study, samples were collected from the hydrothermal field of Kolumbo submarine volcano in the Aegean Sea, in order to isolate bacteria with antimicrobial activity. Eight hundred and thirty-two aerobic heterotrophic bacteria were isolated and then differentiated through BOX-PCR analysis at the strain level into 230 genomic fingerprints, which were screened against 13 different type strains (pathogenic and nonpathogenic) of Gram-positive, Gram-negative bacteria and fungi. Forty-two out of 176 bioactive-producing genotypes (76 %) exhibited antimicrobial activity against at least four different type strains and were selected for 16S rDNA sequencing and screening for nonribosomal peptide (NRPS) and polyketide (PKS) synthases genes. The isolates were assigned to genus Bacillus and Proteobacteria, and 20 strains harbored either NRPS, PKS type I or both genes. This is the first report on the diversity of culturable mesophilic bacteria associated with antimicrobial activity from Kolumbo area; the extremely high proportion of antimicrobial-producing strains suggested that this unique environment may represent a potential reservoir of novel bioactive compounds