A suite of 30 primarily estrogenic organic wastewater contaminants was measured in several influent/effluent wastewater samples from four municipal wastewater treatment plants and effluents from one ...bleached kraft pulp mill (BKME) using an ultra-trace analytical method based on gas chromatography–high resolution mass spectroscopy (GC–HRMS).
In vitro recombinant yeast assay detection of the estrogenic equivalent (EEq) on whole and solid phase extracted (SPE) and fractionated wastewater was also performed. 19-Norethindrone was the most frequently detected and abundant (26–224 ng/L) of all the synthetic estrogens/progesterones in the influent samples. 17α-Ethinylestradiol was the more frequently detected synthetic estrogen/progesterone in the effluents occurring at or below 5 ng/L with some sporadic occurrences of up to 178 ng/L. The greatest levels of steroidal estrogens in municipal effluents were E1
>
E2
>
E3 which were all <
20 ng/L. Nonylphenol and di(2-ethylhexyl) phthalate were found to be the highest non-steroidal synthetic compounds surveyed in both municipal influent and effluent samples, both occurring at 6–7 μg/L in municipal effluents. BKME contained relatively large amounts of the plant sterol stigmasterol (4 μg/L) but low amounts of fecal sterols, and steroidal estrogens (E2 only at 6 ng/L) when compared to the municipal effluents.
In vitro EEq in the wastewater surveyed ranged from 9–106 ng E2/L and ranked from municipal influent
>
municipal effluent
≈
BKME, with most of the estrogenicity fractionating in the 100% methanol SPE fraction followed by a secondary amount in the diethyl ether (for municipal) or methyl-
tert butyl ether (for BKME) SPE fractions. Most correlations between chemical and
in vitro estrogenic equivalency were weak (
p
>
0.05 in most cases). Unexpected inverse correlations between
in vitro estrogenic activity and concentrations of the estrogenic contaminant bisphenol A were found which likely contributed to the weakness of these correlations.
A modified toxicity identification and evaluation procedure was continued with the SPE extracts from the more potent 100% methanol SPE fractions of municipal effluent. High performance liquid chromatography band elution retention times, based on
in vitro estrogen detection, indicated that steroidal estrogens such as E2 were responsible for most of the estrogenicity of the samples. Subsequent collection and GC–MS analysis of active bands did not confirm the presence of steroidal estrogens, but expanded the possibility of phthalate esters (i.e. dibutyl phthalate) and natural sterols (i.e. β-sitosterol) contributing to the overall estrogenic load.
Sexual minority men are at increased risk for anal squamous cell carcinoma. Our objective was to compare screening engagement among individuals randomized to self‐collect an anal canal specimen at ...home or to attend a clinic appointment. Specimen adequacy was then assessed for human papillomavirus (HPV) DNA genotyping. A randomized trial recruited cisgendered sexual minority men and transgender people in the community and assigned them to use a home‐based self‐collection swabbing kit or attend a clinic‐based swabbing. Swabs were sent for HPV genotyping. The proportions of participants completing screening in each study arm and the adequacy of their specimens for HPV genotyping were assessed. Relative risks were estimated for factors associated with screening. A total of 240 individuals were randomized. Age (median, 46 years) and HIV status (27.1% living with HIV) did not differ by study arm. A total of 89.2% and 74.2% of home‐arm and clinic‐arm individuals returned the swab, respectively (P = .003), difference between groups, 15.0% (95% CI 5.4%‐24.6%). Among black individuals, 96.2% and 63.2% in the home and clinic arms screened (P = .006). Among individuals with HIV, 89.5% and 51.9% in the home and clinic arms screened (P < .001). Self‐collected swabs and clinician‐collected swabs were comparable in adequacy for HPV genotyping (96.3% and 93.3%, respectively). People at highest risk for anal cancer may be more likely to screen if they are able to self‐collect swabs at home rather than attend a clinic.
What's new?
While risk for anal squamous cell carcinoma (ASCC) is elevated among sexual minority men, guidelines for screening remain unclear. In our study, the authors assessed the utility of anal canal self‐sampling among sexual and gender minorities with and without HIV, comparing results from home‐based self‐sampling with clinician sampling. Participants were more likely to engage in home‐based self‐sampling vs clinic‐based screening. This was especially the case among black individuals and those living with HIV. Specimen adequacy for human papillomavirus genotyping was greater than 90% across groups. The findings highlight the importance of home‐based self‐sampling for ASCC screening in high‐risk populations.
Metabolic basis to Sherpa altitude adaptation Horscroft, James A.; Kotwica, Aleksandra O.; Laner, Verena ...
Proceedings of the National Academy of Sciences - PNAS,
06/2017, Letnik:
114, Številka:
24
Journal Article
Recenzirano
Odprti dostop
The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison ...to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature.
Tandem DNA repeats vary in the size and sequence of each unit (motif). When expanded, these tandem DNA repeats have been associated with more than 40 monogenic disorders
. Their involvement in ...disorders with complex genetics is largely unknown, as is the extent of their heterogeneity. Here we investigated the genome-wide characteristics of tandem repeats that had motifs with a length of 2-20 base pairs in 17,231 genomes of families containing individuals with autism spectrum disorder (ASD)
and population control individuals
. We found extensive polymorphism in the size and sequence of motifs. Many of the tandem repeat loci that we detected correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated expansions of tandem repeats that were rare among population control individuals were significantly more prevalent among individuals with ASD than their siblings without ASD, particularly in exons and near splice junctions, and in genes related to the development of the nervous system and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in children with ASD compared with 20.7% in children without ASD, which suggests that tandem repeat expansions make a collective contribution to the risk of ASD of 2.6%. These rare tandem repeat expansions included previously undescribed ASD-linked expansions in DMPK and FXN, which are associated with neuromuscular conditions, and in previously unknown loci such as FGF14 and CACNB1. Rare tandem repeat expansions were associated with lower IQ and adaptive ability. Our results show that tandem DNA repeat expansions contribute strongly to the genetic aetiology and phenotypic complexity of ASD.
Mutations in genes involved in lipid metabolism have increasingly been associated with various subtypes of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative motor ...neuron disorders characterized by spastic paraparesis. Here, we report an unusual autosomal recessive neurodegenerative condition, best classified as a complicated form of hereditary spastic paraplegia, associated with mutation in the ethanolaminephosphotransferase 1 (EPT1) gene (now known as SELENOI), responsible for the final step in Kennedy pathway forming phosphatidylethanolamine from CDP-ethanolamine. Phosphatidylethanolamine is a glycerophospholipid that, together with phosphatidylcholine, constitutes more than half of the total phospholipids in eukaryotic cell membranes. We determined that the mutation defined dramatically reduces the enzymatic activity of EPT1, thereby hindering the final step in phosphatidylethanolamine synthesis. Additionally, due to central nervous system inaccessibility we undertook quantification of phosphatidylethanolamine levels and species in patient and control blood samples as an indication of liver phosphatidylethanolamine biosynthesis. Although this revealed alteration to levels of specific phosphatidylethanolamine fatty acyl species in patients, overall phosphatidylethanolamine levels were broadly unaffected indicating that in blood EPT1 inactivity may be compensated for, in part, via alternate biochemical pathways. These studies define the first human disorder arising due to defective CDP-ethanolamine biosynthesis and provide new insight into the role of Kennedy pathway components in human neurological function.
SP/KLF (Specificity protein/Krüppel-like factor) transcription factors comprise an emerging group of proteins that may behave as tumour suppressors. Incidentally, many cancers that display ...alterations in certain KLF proteins are also associated with a high incidence of KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue) mutations. Therefore in the present paper we investigate whether SP/KLF proteins suppress KRAS-mediated cell growth, and more importantly, the potential mechanisms underlying these effects. Using a comprehensive family-wide screening of the 24 SP/KLF members, we discovered that SP5, SP8, KLF2, KLF3, KLF4, KLF11, KLF13, KLF14, KLF15 and KLF16 inhibit cellular growth and suppress transformation mediated by oncogenic KRAS. Each protein in this subset of SP/KLF members individually inhibits BrdU (5-bromo-2-deoxyuridine) incorporation in KRAS oncogenic-mutant cancer cells. SP5, KLF3, KLF11, KLF13, KLF14 and KLF16 also increase apoptosis in these cells. Using KLF11 as a representative model for mechanistic studies, we demonstrate that this protein inhibits the ability of cancer cells to form both colonies in soft agar and tumour growth in vivo. Molecular studies demonstrate that these effects of KLF11 are mediated, at least in part, through silencing cyclin A via binding to its promoter and leading to cell-cycle arrest in S-phase. Interestingly, similar to KLF11, KLF14 and KLF16 mechanistically share the ability to modulate the expression of cyclin A. Collectively, the present study stringently defines a distinct subset of SP/KLF proteins that impairs KRAS-mediated cell growth, and that mechanistically some members of this subset accomplish this, at least in part, through regulation of the cyclin A promoter.
Glioblastoma is a highly lethal brain cancer that frequently recurs in proximity to the original resection cavity. We explored the use of oncolytic virus therapy against glioblastoma with Zika virus ...(ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile virus indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a mouse-adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs; thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients.
Three-dimensional whole-heart T2 mapping at 3T Ding, Haiyan; Fernandez-de-Manuel, Laura; Schär, Michael ...
Magnetic resonance in medicine,
September 2015, Letnik:
74, Številka:
3
Journal Article
In this millennium, global drylands face a myriad of problems that present tough research, management, and policy challenges. Recent advances in dryland development, however, together with the ...integrative approaches of global change and sustainability science, suggest that concerns about land degradation, poverty, safeguarding biodiversity, and protecting the culture of 2.5 billion people can be confronted with renewed optimism. We review recent lessons about the functioning of dryland ecosystems and the livelihood systems of their human residents and introduce a new synthetic framework, the Drylands Development Paradigm (DDP). The DDP, supported by a growing and well-documented set of tools for policy and management action, helps navigate the inherent complexity of desertification and dryland development, identifying and synthesizing those factors important to research, management, and policy communities.
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