Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5′-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5′-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5′-monophosphate, which is further transformed to the active 5′-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan’s research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents

How young radiologists use contrast media and manage adverse reactions: an international survey

Objectives: To collect real-world data about the knowledge and self-perception of young radiologists concerning the use of contrast media (CM) and the management of adverse drug reactions (ADR). Methods: A survey (29 questions) was distributed to residents and board-certified radiologists younger than 40 years to investigate the current international situation in young radiology community regarding CM and ADRs. Descriptive statistics analysis was performed. Results: Out of 454 respondents from 48 countries (mean age: 31.7 ± 4 years, range 25–39), 271 (59.7%) were radiology residents and 183 (40.3%) were board-certified radiologists. The majority (349, 76.5%) felt they were adequately informed regarding the use of CM. However, only 141 (31.1%) received specific training on the use of CM and 82 (18.1%) about management ADR during their residency. Although 266 (58.6%) knew safety protocols for handling ADR, 69.6% (316) lacked confidence in their ability to manage CM-induced ADRs and 95.8% (435) expressed a desire to enhance their understanding of CM use and handling of CM-induced ADRs. Nearly 300 respondents (297; 65.4%) were aware of the benefits of contrast-enhanced ultrasound, but 249 (54.8%) of participants did not perform it. The preferred CM injection strategy in CT parenchymal examination and CT angiography examination was based on patient’s lean body weight in 318 (70.0%) and 160 (35.2%), a predeterminate fixed amount in 79 (17.4%) and 116 (25.6%), iodine delivery rate in 26 (5.7%) and 122 (26.9%), and scan time in 31 (6.8%) and 56 (12.3%), respectively. Conclusion: Training in CM use and management ADR should be implemented in the training of radiology residents. Critical relevance statement: We highlight the need for improvement in the education of young radiologists regarding contrast media; more attention from residency programs and scientific societies should be focused on training about contrast media use and the management of adverse drug reactions. Key points: • This survey investigated training of young radiologists about use of contrast media and management adverse reactions. • Most young radiologists claimed they did not receive dedicated training. • An extreme heterogeneity of responses was observed about contrast media indications/contraindications and injection strategy. Graphical Abstract: (Figure presented.

Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia

Copyright © 2021 The Authors. Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans (n = 7175) and used Mendelian randomization (MR) to evaluate potential causality (n = 173,480). The results showed evidence for lower Hb levels being associated with lower body mass index, better glucose tolerance and other metabolic profiles, lower inflammatory load, and blood pressure. Expression of the key HIF target genes SLC2A4 and Slc2a1 in skeletal muscle and adipose tissue, respectively, associated with systolic blood pressure in MR analyses and body weight, liver weight, and adiposity in mice. Last, manipulation of murine Hb levels mediated changes to key metabolic parameters. In conclusion, low-end normal Hb levels may be favorable for metabolic health involving mild chronic activation of the HIF response.Academy of Finland grants 266719 and 308009; S. Jusélius Foundation; Emil Aaltonen Foundation; Jane and Aatos Erkko Foundation; Academy of Finland Profi 5 funding for mathematics and AI: data insight for high-dimensional dynamics and the Academy of Finland Project 312123; British Heart Foundation Centre of Research Excellence (RE/18/4/34215); National Institute for Health Research Clinical Lectureship (CL-2020-16-001) at St. George’s, University of London. NFBC1966; University of Oulu grant nos. 65354 and 24000692; Oulu University Hospital grant nos. 2/97, 8/97, and 24301140; Ministry of Health and Social Affairs grant nos. 23/251/97, 160/97, and 190/97; National Institute for Health and Welfare, Helsinki grant no. 54121; Regional Institute of Occupational Health, Oulu, Finland grant nos. 50621 and 54231; ERDF European Regional Development Fund grant no. 539/2010 A31592; the European Union’s Horizon 2020 research and innovation programme grant agreement nos. 633595 (DynaHEALTH), 733206 (LifeCycle), 643774 (iHEALTH-T2D), 824989 (EUCAN Connect), and 721567 (EU H2020-MSCA-ITN-2016 CAPICE Marie Sklodowska-Curie), and grant nos. MR/M013138/1, MRC/BBSRC, and MR/S03658X/1 (the Medical Research Council, UK, JPI HDHL); and Academy of Finland, University Hospital Oulu, and NHLBI grant 5R01HL087679-02 through the STAMPEED program; The Young Finns Study has been financially supported by the Academy of Finland: grants 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere, and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; and Diabetes Research Foundation of Finnish Diabetes Association; European Union’s Horizon 2020 research and innovation programme under grant agreement no. 848146; grant agreement 755320 for TAXINOMISIS; European Research Council (grant 742927 for MULTIEPIGEN project); and Tampere University Hospital Supporting Foundation and Finnish Society of Clinical Chemistry

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Inbred wild type mouse strains have distinct spontaneous morphological phenotypes.

The mouse is the most commonly used animal for modelling human disease. New approaches for generating genetically manipulated mouse models to represent human disease, as well as target the function of specific genes, has increased the importance of mice in biomedical science. For the correct interpretation of alterations in mouse phenotype the basic morphology of background mouse strains must be known. Despite on-going efforts to create publicly available baseline phenotypic data, the information concerning spontaneous lesions in wild-type mice is incomplete and scattered so far, and further studies are needed. We addressed this problem by screening haematoxylin-eosin stained sections of brain, reproductive organs, urinary bladder, kidney, thyroid, parathyroid, heart, lung, spleen, thymus, lymph nodes, adrenal glands, stomach, intestine, liver, skin and pancreas of six commonly used inbred mouse strains (C57BL6/J, C57BL6/NTac, C3HeB/FeJ, BALB/cByJ, 129P2/OlaHsd and FVB/N) for inherent spontaneous morphological lesions. Interesting spontaneous phenotypes were seen in morphology of the liver, pancreas, adrenal glands, lungs, intestines and heart. In conclusion, care should be taken when choosing the background mouse strain for genetic manipulations, since different mouse strains harbour different inherent lesions that can affect the function of targeted genes, interpretation of results and translation of results to model human disease

Mechanism of benzo(a)pyrene-induced accumulation of p53 tumour suppressor protein in mouse

Abstract The tumour suppressor gene TP53 is the most commonly mutated gene in human cancers. The protein it codes, p53, becomes activated as a response to stress signals. When activated, p53 binds to DNA and affects the transcription of its target genes. They then cause cell cycle arrest, DNA repair and/or induction of programmed cell death, thus preventing mutations and cancer. Specific mutations in TP53 are associated with exposure to certain carcinogens, such as polycyclic aromatic hydrocarbons (PAHs). These environmental chemical carcinogens are formed through incomplete combustion of organic material. Benzo(a)pyrene (BP) is commonly used as a model compound for PAH carcinogenesis. BP causes accumulation of p53, but the mechanism of accumulation is not known. The aim of this study was to gain more insight into the p53 protein in the first phases of PAH carcinogenesis in vivo in mouse, using BP as the model compound. Mice from the inbred C57BL/6 strain were treated topically or intraperitoneally with BP or were exposed to cigarette smoke inhalation. The amount of p53 protein was studied by immunoblotting, immunohistochemistry and immuno electron microscopy, and the mdm2, p21 and p19ARF proteins were studied by immunoblotting. The binding of BP to DNA was measured by synchronous fluorescence spectrophotometry. The p53 protein was induced in vivo in skin and lung after BP treatment and in lung after cigarette smoke treatment. An increase in p53 was associated with an increase in the amount of BP-DNA adducts. In skin, the induction of p53 was accompanied by induction of the p21 and mdm2 proteins, which are transcriptional targets of p53. This indicates that the in vivo induced p53 is a wild-type protein and functional. In lungs, the induction of p53 was accompanied by a decrease of mdm2 and an increase of p19ARF. These results confirm that BP is metabolized and binds to DNA in mouse tissues and indicate that BP-DNA adducts are the trigger for p53 protein induction. The in vivo regulation of the p53 protein is different in different tissues of C57BL/6 mouse

Vacuum ultraviolet absorption in silica samples

Optical absorption analysis in the ultraviolet and vacuum ultraviolet region from 4.0 to 9.0 eV has been performed on di\u80erent silica materials. We analysed natural and synthetic silica samples, both as grown and irradiated with di\u80erent irradiations, neutrons, c, and ultraviolet photons. Regardless of irradiation we always observed in the spectrum of irradiated samples the growth of the band at 5.8 eV, a band attributed to the E0 paramagnetic center. Comparing this absorption under di\u80erent irradiation, we suggest the B2 and E absorption bands are not correlated and therefore cannot be assigned to the same defect