Evidence for ligand- and solvent-induced disproportionation of uranium(IV)

Disproportionation, where a chemical element converts its oxidation state to two different ones, one higher and one lower, underpins the fundamental chemistry of metal ions. The overwhelming majority of uranium disproportionations involve uranium(III) and (V), with a singular example of uranium(IV) to uranium(V/III) disproportionation known, involving a nitride to imido/triflate transformation. Here, we report a conceptually opposite disproportionation of uranium(IV)-imido complexes to uranium(V)-nitride/uranium(III)-amide mixtures. This is facilitated by benzene, but not toluene, since benzene engages in a redox reaction with the uranium(III)-amide product to give uranium(IV)-amide and reduced arene. These disproportionations occur with potassium, rubidium, and cesium counter cations, but not lithium or sodium, reflecting the stability of the corresponding alkali metal-arene by-products. This reveals an exceptional level of ligand- and solvent-control over a key thermodynamic property of uranium, and is complementary to isolobal uranium(V)-oxo disproportionations, suggesting a potentially wider prevalence possibly with broad implications for the chemistry of uranium

Exceptional uranium(VI)-nitride triple bond covalency from ¹⁵N nuclear magnetic resonance spectroscopy and quantum chemical analysis.

From Europe PMC via Jisc Publications RouterHistory: ppub 2021-09-01, epub 2021-09-24Publication status: PublishedFunder: RCUK | Engineering and Physical Sciences Research Council (EPSRC); Grant(s): EP/M027015/1, EP/K024000/1, EP/S033181/1Funder: European Research Council; Grant(s): 612724Determining the nature and extent of covalency of early actinide chemical bonding is a fundamentally important challenge. Recently, X-ray absorption, electron paramagnetic, and nuclear magnetic resonance spectroscopic studies have probed actinide-ligand covalency, largely confirming the paradigm of early actinide bonding varying from ionic to polarised-covalent, with this range sitting on the continuum between ionic lanthanide and more covalent d transition metal analogues. Here, we report measurement of the covalency of a terminal uranium(VI)-nitride by 15N nuclear magnetic resonance spectroscopy, and find an exceptional nitride chemical shift and chemical shift anisotropy. This redefines the 15N nuclear magnetic resonance spectroscopy parameter space, and experimentally confirms a prior computational prediction that the uranium(VI)-nitride triple bond is not only highly covalent, but, more so than d transition metal analogues. These results enable construction of general, predictive metal-ligand 15N chemical shift-bond order correlations, and reframe our understanding of actinide chemical bonding to guide future studies

Association between maternal micronutrient status, oxidative stress and common genetic variants in antioxidant enzymes at 15 weeks’ gestation in nulliparous women who subsequently develop pre-eclampsia

Aims: Pre-eclampsia is a pregnancy-specific condition affecting 2-7% of women and a leading cause of perinatal and maternal morbidity and mortality. Deficiencies of specific micronutrient antioxidant activities associated with copper, selenium, zinc and manganese, have previously been linked to pre-eclampsia at time of disease. Our aims were to investigate whether maternal plasma micronutrient concentrations and related antioxidant enzyme activities are altered prior to pre-eclampsia onset and to examine the dependence on genetic variations in these antioxidant enzymes. Methods: Pre-disease plasma samples (15+1 weeks’ gestation) were obtained from women enrolled in the international SCreening fOr Pregnancy Endpoints (SCOPE) study who subsequently developed pre-eclampsia (n=244), and age- and BMI-matched normotensive controls (n=472). Micronutrient concentrations were measured by inductively coupled plasma mass spectrometry; associated antioxidant enzyme activities, selenoprotein-P, caeruloplasmin concentrations and activities, antioxidant capacity and markers of oxidative stress were measured by colorimetric assays. Sixty four tagSNPs within genes encoding the antioxidant enzymes and selenoprotein-P were genotyped using allele-specific competitive PCR. Results: Plasma copper and caeruloplasmin concentrations were modestly, but significantly elevated in women who subsequently developed pre-eclampsia (both P<0.001) compared to controls (median [IQR], copper: 1957.4 [1787, 2177.5] vs. 1850.0 [1663.5, 2051.5] µg/L; caeruloplasmin: 2.5[1.4, 3.2] vs. 2.2[1.2, 3.0] µg/ml). There were no differences in other micronutrients or enzymes between groups. No relationship was observed between genotype for single nucleotide polymorphisms (SNPs) and antioxidant enzyme activity. Conclusions: This analysis of a prospective cohort study reports maternal micronutrient concentrations in combination with associated antioxidant enzymes and SNPs in their encoding genes in women at 15 weeks’ gestation that subsequently developed pre-eclampsia. The modest elevation in copper may contribute to oxidative stress, later in pregnancy, in those women that go on to develop pre-eclampsia. The lack of evidence to support the hypothesis that functional SNPs influence antioxidant enzyme activity in pregnant women argues against a role for these genes in the aetiology of pre-eclampsia

Chemical carcinogenicity revisited 2: Current knowledge of carcinogenesis shows that categorization as a carcinogen or non-carcinogen is not scientifically credible

Abstract Developments in the understanding of the etiology of cancer have undermined the 1970s concept that chemicals are either "carcinogens" or "non-carcinogens". The capacity to induce cancer should not be classified in an inflexible binary manner as present (carcinogen) or absent (non-carcinogen). Chemicals may induce cancer by three categories of mode of action: direct interaction with DNA or DNA replication including DNA repair and epigenetics; receptor-mediated induction of cell division; and non-specific induction of cell division. The long-term rodent bioassay is neither appropriate nor efficient to evaluate carcinogenic potential for humans and to inform risk management decisions. It is of questionable predicitiveness, expensive, time consuming, and uses hundreds of animals. Although it has been embedded in practice for over 50 years, it has only been used to evaluate less than 5% of chemicals that are in use. Furthermore, it is not reproducible because of the probabilisitic nature of the process it is evaluating combined with dose limiting toxicity, dose selection, and study design. The modes of action that lead to the induction of tumors are already considered under other hazardous property categories in classification (Mutagenicity/Genotoxicity and Target Organ Toxicity); a separate category for Carcinogenicity is not required and provides no additional public health protection

Seroprevalence of Trypanosoma cruzi in Rural Ecuador and Clustering of Seropositivity within Households

We performed a cross-sectional study of Trypanosoma cruzi seroprevalence in 14 communities in three provinces of Ecuador and estimated the magnitude of the association of seropositive individuals within households. A total of 3,286 subjects from 997 households were included. Seroprevalence was 5.7%, 1.0%, and 3.6% in subjects in the Manabí, Guayas, and Loja provinces, respectively. Seroprevalence increased with increasing age in Manabí and Guayas, whereas in Loja, the highest prevalence occurred in children ≤ 10 years of age. In the coastal provinces, clustering of seropositives within households was not observed after adjustment for other household factors. However, in the Andean province of Loja, the odds of seropositivity were more than two times greater for an individual living in a household with another seropositive person. Our results indicate that transmission of T. cruzi is ongoing in Ecuador, although intensity of transmission and mechanisms of interaction between humans and the insect vectors of disease vary between geographic regions

Chemical carcinogenicity revisited 3: Risk assessment of carcinogenic potential based on the current state of knowledge of carcinogenesis in humans

Abstract Over 50 years, we have learned a great deal about the biology that underpins cancer but our approach to testing chemicals for carcinogenic potential has not kept up. Only a small number of chemicals has been tested in animal-intensive, time consuming, and expensive long-term bioassays in rodents. We now recommend a transition from the bioassay to a decision-tree matrix that can be applied to a broader range of chemicals, with better predictivity, based on the premise that cancer is the consequence of DNA coding errors that arise either directly from mutagenic events or indirectly from sustained cell proliferation. The first step is in silico and in vitro assessment for mutagenic (DNA reactive) activity. If mutagenic, it is assumed to be carcinogenic unless evidence indicates otherwise. If the chemical does not show mutagenic potential, the next step is assessment of potential human exposure compared to the threshold for toxicological concern (TTC). If potential human exposure exceeds the TTC, then testing is done to look for effects associated with the key characteristics that are precursors to the carcinogenic process, such as increased cell proliferation, immunosuppression, or significant estrogenic activity. Protection of human health is achieved by limiting exposures to below NOEALs for these precursor effects. The decision tree matrix is animal-sparing, cost effective, and in step with our growing knowledge of the process of cancer formation

Chemical carcinogenicity revisited 1: A unified theory of carcinogenicity based on contemporary knowledge

Abstract Developments in the understanding of the etiology of cancer have profound implications for the way the carcinogenicity of chemicals is addressed. This paper proposes a unified theory of carcinogenesis that will illuminate better ways to evaluate and regulate chemicals. In the last four decades, we have come to understand that for a cell and a group of cells to begin the process of unrestrained growth that is defined as cancer, there must be changes in DNA that reprogram the cell from normal to abnormal. Cancer is the consequence of DNA coding errors that arise either directly from mutagenic events or indirectly from cell proliferation especially if sustained. Chemicals that act via direct interaction with DNA can induce cancer because they cause mutations which can be carried forward in dividing cells. Chemicals that act via non-genotoxic mechanisms must be dosed to maintain a proliferative environment so that the steps toward neoplasia have time to occur. Chemicals that induce increased cellular proliferation can be divided into two categories: those which act by a cellular receptor to induce cellular proliferation, and those which act via non-specific mechanisms such as cytotoxicity. This knowledge has implications for testing chemicals for carcinogenic potential and risk management

Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment

Pituitary tumor transforming gene (PTTG)-binding factor (PBF or PTTG1IP) is a little characterized protooncogene that has been implicated in the etiology of breast and thyroid tumors. In this study, we created a murine transgenic model to target PBF expression to the thyroid gland (PBF-Tg mice) and found that these mice exhibited normal thyroid function, but a striking enlargement of the thyroid gland associated with hyperplastic and macrofollicular lesions. Expression of the sodium iodide symporter (NIS), a gene essential to the radioiodine ablation of thyroid hyperplasia, neoplasia, and metastasis, was also potently inhibited in PBF-Tg mice. Critically, iodide uptake was repressed in primary thyroid cultures from PBF-Tg mice, which could be rescued by PBF depletion. PBF-Tg thyroids exhibited upregulation of Akt and the TSH receptor (TSHR), each known regulators of thyrocyte proliferation, along with upregulation of the downstream proliferative marker cyclin D1. We extended and confirmed findings from the mouse model by examining PBF expression in human multinodular goiters (MNG), a hyperproliferative thyroid disorder, where PBF and TSHR was strongly upregulated relative to normal thyroid tissue. Furthermore, we showed that depleting PBF in human primary thyrocytes was sufficient to increase radioiodine uptake. Together, our findings indicate that overexpression of PBF causes thyroid cell proliferation, macrofollicular lesions, and hyperplasia, as well as repression of the critical therapeutic route for radioiodide uptake

Evidence for ligand- and solvent-induced disproportionation of uranium(IV)

From Springer Nature via Jisc Publications RouterHistory: received 2020-05-14, accepted 2021-07-21, registration 2021-07-28, pub-electronic 2021-08-10, online 2021-08-10, collection 2021-12Publication status: PublishedFunder: RCUK | Engineering and Physical Sciences Research Council (EPSRC); doi: https://doi.org/10.13039/501100000266; Grant(s): EP/K024000/1, EP/M027015/1, EP/P001386/1, EP/S033181/1Funder: Leverhulme Trust; doi: https://doi.org/10.13039/501100000275; Grant(s): RF-2018-545\4Funder: Royal Society; doi: https://doi.org/10.13039/501100000288; Grant(s): UF110005Abstract: Disproportionation, where a chemical element converts its oxidation state to two different ones, one higher and one lower, underpins the fundamental chemistry of metal ions. The overwhelming majority of uranium disproportionations involve uranium(III) and (V), with a singular example of uranium(IV) to uranium(V/III) disproportionation known, involving a nitride to imido/triflate transformation. Here, we report a conceptually opposite disproportionation of uranium(IV)-imido complexes to uranium(V)-nitride/uranium(III)-amide mixtures. This is facilitated by benzene, but not toluene, since benzene engages in a redox reaction with the uranium(III)-amide product to give uranium(IV)-amide and reduced arene. These disproportionations occur with potassium, rubidium, and cesium counter cations, but not lithium or sodium, reflecting the stability of the corresponding alkali metal-arene by-products. This reveals an exceptional level of ligand- and solvent-control over a key thermodynamic property of uranium, and is complementary to isolobal uranium(V)-oxo disproportionations, suggesting a potentially wider prevalence possibly with broad implications for the chemistry of uranium