Synthesis, structure, and photophysical properties of platinum(II) (N, C, N) pincer complexes derived from purine nucleobases

The synthesis of a series of Pt{κ3-N,C,N′-[L]}X (X = Cl, RC≡C) pincer complexes derived from purine and purine nucleosides is reported. In these complexes, the 6-phenylpurine skeleton provides the N,C-cyclometalated fragment, whereas an amine, imine, or pyridine substituent of the phenyl ring supplies the additional N′-coordination point to the pincer complex. The purine N,C-fragment has two coordination positions with the metal (N1 and N7), but the formation of the platinum complexes is totally regioselective. Coordination through the N7 position leads to the thermodynamically favored [6.5]-Pt{κ3-N7,C,N′-[L]}X complexes. However, the coordination through the N1 position is preferred by the amino derivatives, leading to the isomeric kinetic [5.5]-Pt{κ3-N1,C,N′-[L]}X complexes. Extension of the reported methodology to complexes having both pincer and acetylide ligands derived from nucleosides allows the preparation of novel heteroleptic bis-nucleoside compounds that could be regarded as organometallic models of Pt-induced interstrand cross-link. Complexes having amine or pyridine arms are green phosphorescence emitters upon photoexcitation at low concentrations in CH2Cl2 solution and in poly(methyl methacrylate) (PMMA) films. They undergo self-quenching at high concentrations due to molecular aggregation. The presence of intermolecular π–π stacking and weak Pt···Pt interactions was also observed in the solid state by X-ray diffraction analysis

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

The ALHAMBRA survey: reliable morphological catalogue of 22 051 early- and late-type galaxies

Advanced Large Homogeneous Area Medium Band Redshift Astronomical (ALHAMBRA) is photometric survey designed to trace the cosmic evolution and cosmic variance. It covers a large area of ~4 deg2 in eight fields, where seven fields overlap with other surveys, allowing us to have complementary data in other wavelengths. All observations were carried out in 20 continuous, medium band (30 nm width) optical and 3 near-infrared (JHK) bands, providing the precise measurements of photometric redshifts. In addition, morphological classification of galaxies is crucial for any kind of galaxy formation and cosmic evolution studies, providing the information about star formation histories, their environment and interactions, internal perturbations, etc. We present a morphological classification of >40 000 galaxies in the ALHAMBRA survey. We associate to every galaxy a probability to be early type using the automated Bayesian code GALSVM. Despite of the spatial resolution of theALHAMBRAimages (~1 arcsec), for 22 051 galaxies, we obtained the contamination by other type of less than 10 per cent. Of those, 1640 and 10 322 galaxies are classified as early-(down to redshifts ~0.5) and late-type (down to redshifts ~1.0), respectively, with magnitudes F613W ≤ 22.0. In addition, for magnitude range 22.0 < F613W ≤ 23.0, we classified other 10 089 late-type galaxies with redshifts ≤1.3.We show that the classified objects populate the expected regions in the colour-mass and colour-magnitude planes. The presented data set is especially attractive given the homogeneous multiwavelength coverage available in the ALHAMBRA fields, and is intended to be used in a variety of scientific applications. The low-contamination catalogue (<10 per cent) is made publicly available with this paper. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.This research was supported by the Junta de Andalucía through projects PO8-TIC-03531 and TIC114, the Spanish Ministry of Economy and Competitiveness (MINECO) through projects AYA2006-14046, AYA2010-15169, AYA2010-22111-C03-02, AYA2011-29517-C03-01, and the Generalitat Valenciana through project GV/Prometeo 2009/064. MP acknowledges financial support from JAE-Doc program of the Spanish National Research Council (CSIC), co-funded by the European Social Fund.Peer Reviewe

SEVA 4.0: an update of the Standard European Vector Architecture database for advanced analysis and programming of bacterial phenotypes

10 Pág.The SEVA platform (https://seva-plasmids.com) was launched one decade ago, both as a database (DB) and as a physical repository of plasmid vectors for genetic analysis and engineering of Gram-negative bacteria with a structure and nomenclature that follows a strict, fixed architecture of functional DNA segments. While the current update keeps the basic features of earlier versions, the platform has been upgraded not only with many more ready-to-use plasmids but also with features that expand the range of target species, harmonize DNA assembly methods and enable new applications. In particular, SEVA 4.0 includes (i) a sub-collection of plasmids for easing the composition of multiple DNA segments with MoClo/Golden Gate technology, (ii) vectors for Gram-positive bacteria and yeast and [iii] off-the-shelf constructs with built-in functionalities. A growing collection of plasmids that capture part of the standard-but not its entirety-has been compiled also into the DB and repository as a separate corpus (SEVAsib) because of its value as a resource for constructing and deploying phenotypes of interest. Maintenance and curation of the DB were accompanied by dedicated diffusion and communication channels that make the SEVA platform a popular resource for genetic analyses, genome editing and bioengineering of a large number of microorganisms.The SEVA repository has been developed and maintained with funds of the SYCOLIM [ERA-COBIOTECH 2018-PCI2019-111859-2] Project of the Spanish Ministry of Science and Innovation, SYNBIO4FLAV [H2020-NMBP-TR-IND/H2020-NMBP-BIO-2018-814650]; MIX-UP [MIX-UP H2020-BIO-CN-2019-870294] Contracts of the European Union; BIOSINT-CM [Y2020/TCS-6555] Project of the Comunidad de Madrid-European Structural and Investment Funds (FSE, FECER); P.I.N. acknowledges financial support by the Novo Nordisk Foundation [NNF20CC0035580, TARGET (NNF21OC0067996]; European Union's Horizon 2020 Research and Innovation Programme [814418 (SinFonia)]; M.H.H.N. acknowledges funding by the Novo Nordisk Foundation [NNF20CC0035580]; P.D. was funded by Czech Science Foundation Project 22-12505S; A.G.M. was supported by the Grants BioSinT-CM [Y2020/TCS-6555]; CONTEXT (Atracción de Talento Program) [2019-T1/BIO-14053] Projects of the Comunidad de Madrid, MULTI-SYSBIO [PID2020-117205GA-I00]; Severo Ochoa Program for Centres of Excellence in R&D [CEX2020-000999-S] funded by MCIN/AEI/10.13039/501100011033 and the ECCO (ERC-2021-COG-101044360) Contract of the EU. Funding for open access charge: European Commission Grant SYNBIO4FLAV [H2020-NMBP-TR-IND/H2020-NMBP-BIO-2018-814650].With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2020‐000999‐S) .Peer reviewe

Systemic pro-inflammatory response identifies patients with cancer with adverse outcomes from SARS-CoV-2 infection: the OnCovid Inflammatory Score

Background: Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study. Methods: In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets. Results: We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p<0.01), recovering in survivors to pre-COVID-19 levels. Patients in poorer risk categories for each index except the PLR exhibited higher mortality rates (p<0.001) and shorter median overall survival in the training and validation sets (p<0.01). Multivariable analyses revealed the OIS to be most independently predictive of survival (validation set HR 2.48, 95% CI 1.47 to 4.20, p=0.001; adjusted concordance index score 0.611). Conclusions: Systemic inflammation is a validated prognostic domain in SARS-CoV-2-infected patients with cancer and can be used as a bedside predictor of adverse outcome. Lymphocytopenia and hypoalbuminemia as computed by the OIS are independently predictive of severe COVID-19, supporting their use for risk stratification. Reversal of the COVID-19-induced proinflammatory state is a putative therapeutic strategy in patients with cancer

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60&nbsp;years old

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life