Tubular epithelial cells in renal clear cell carcinoma express high RIPK1/3 and show increased susceptibility to TNF receptor 1-induced necroptosis.

We previously reported that renal clear cell carcinoma cells (RCC) express both tumor necrosis factor receptor (TNFR)-1 and -2, but that, in organ culture, a TNF mutein that only engages TNFR1, but not TNFR2, causes extensive cell death. Some RCC died by apoptosis based on detection of cleaved caspase 3 in a minority TUNEL-positive cells but the mechanism of death in the remaining cells was unexplained. Here, we underpin the mechanism of TNFR1-induced cell death in the majority of TUNEL-positive RCC cells, and show that they die by necroptosis. Malignant cells in high-grade tumors displayed threefold to four fold higher expression of both receptor-interacting protein kinase (RIPK)1 and RIPK3 compared with non-tumor kidney tubular epithelium and low-grade tumors, but expression of both enzymes was induced in lower grade tumors in organ culture in response to TNFR1 stimulation. Furthermore, TNFR1 activation induced significant MLKL(Ser358) and Drp1(Ser616) phosphorylation, physical interactions in RCC between RIPK1-RIPK3 and RIPK3-phospho-MLKL(Ser358), and coincidence of phospho-MLKL(ser358) and phospho-Drp1(Ser616) at mitochondria in TUNEL-positive RCC. A caspase inhibitor only partially reduced the extent of cell death following TNFR1 engagement in RCC cells, whereas three inhibitors, each targeting a different step in the necroptotic pathway, were much more protective. Combined inhibition of caspases and necroptosis provided additive protection, implying that different subsets of cells respond differently to TNF-α, the majority dying by necroptosis. We conclude that most high-grade RCC cells express increased amounts of RIPK1 and RIPK3 and are poised to undergo necroptosis in response to TNFR1 signaling.National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre , Kidney Research UK and NIH grant R01-HL36003.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Nature Publishing Group

Trends in oral anticoagulant prescribing in individuals with type 2 diabetes mellitus: a population-based study in the UK

OBJECTIVE: To evaluate oral anticoagulant (OAC) prescribing trends in type 2 diabetes mellitus (T2DM) in the UK from 2001 to 2015. DESIGN: A cross-sectional drug utilisation study. SETTING: Electronic health records from The Health Improvement Network primary care database in the UK. PARTICIPANTS: Individuals with T2DM who received a record of OAC prescription. OUTCOME MEASURES: The prescribing trends of OAC medications in individuals with T2DM were examined from 2001 to 2015, stratified by age, gender and therapeutic classifications. RESULTS: A total of 361 635 individuals with T2DM were identified, of whom 36 570 were prescribed OAC from 2001 to 2015. The prevalence of OAC prescribing increased by 50.0%, from 1781 individuals receiving OAC prescriptions (IROACP) (4.4 (95% CI 4.2 to 4.6) per 100 persons) in 2001, to 17 070 IROACP (6.6 (95% CI 6.5 to 6.7) per 100 persons) in 2015. The prevalence of warfarin prescribing decreased by 14.0%, from 1761 individuals receiving warfarin prescriptions (IRWP) (98.9 (95% CI 98.4 to 99.4) per 100 persons) in 2001, to 14 533 IRWP (85.1 (95% CI 84.6 to 85.7) per 100 persons) in 2015. This corresponded with increased prescribing of direct oral anticoagulants (DOACs), from 18 individuals receiving DOAC prescriptions (IRDOACP) (0.1 (95% CI 0.08 to 0.23) per 100 persons) in 2010, to 3016 IRDOACP (17.6 (95% CI 17.1 to 18.2) per 100 persons) in 2015, during the same period. CONCLUSIONS: Prescribing of OACs in individuals with T2DM increased from 2001 to 2015. Since the introduction of DOACs, there has been a clear shift in prescribing towards these agents. Future studies are needed to assess the safety of coadministration of OAC medications and antidiabetic therapy with T2DM

Entanglement Zoo II: Examples in Physics and Cognition

We have recently presented a general scheme enabling quantum modeling of different types of situations that violate Bell's inequalities. In this paper, we specify this scheme for a combination of two concepts. We work out a quantum Hilbert space model where 'entangled measurements' occur in addition to the expected 'entanglement between the component concepts', or 'state entanglement'. We extend this result to a macroscopic physical entity, the 'connected vessels of water', which maximally violates Bell's inequalities. We enlighten the structural and conceptual analogies between the cognitive and physical situations which are both examples of a nonlocal non-marginal box modeling in our classification.Comment: 11 page

Seeing the baby, doing family: commercial ultrasound as family practice?

Medical sociologists and anthropologists have studied the social significance of obstetric ultrasound for families but little is known about how women and families make use of commercially available ultrasound scans. This article draws on interviews with women who booked a scan with a commercial company in the UK. For some women, commercial ultrasound can be understood as a family practice. We investigate this theme by examining who accompanies women to commercial scan appointments, how scan images are shared and how sonograms are used as prompts to resemblance talk. We argue that commercial scans are more than an additional opportunity to acquire ‘baby’s first picture’ and offer a flexible resource to do family, creating and affirming family relationships and rehearsing roles as parents, siblings and grandparents. Our findings confirm the importance of imagination in doing family and raise questions about the role of technology and commercial interests in shaping family practices

Hospital admission trends due to respiratory diseases in England and Wales between 1999 and 2019: an ecologic study

BACKGROUND: Identifying trends of hospital admissions for respiratory diseases is crucial for public health and research to guide future clinical improvements for better outcomes. This study aims to define the trends of respiratory disease-related hospital admissions (RRHA) in England and Wales between 1999 and 2019. METHODS: An ecological study was conducted using hospital admission data taken from the Hospital Episode Statistics database in England and the Patient Episode Database for Wales. Hospital admissions data for respiratory diseases were extracted for the period between April 1999 and March 2019. The trend in hospital admissions was assessed using a Poisson model. RESULTS: Hospital admission rate increased by 104.7% [from 1535.05 (95% CI 1531.71–1538.38) in 1999 to 3142.83 (95% CI 3138.39–3147.26) in 2019 per 100,000 persons, trend test, p < 0.01]. The most common causes were influenza and pneumonia, chronic lower respiratory diseases, other acute lower respiratory infections, which accounted for 26.6%, 26.4%, and 14.9%, respectively. The age group 75 years and above accounted for 34.1% of the total number of hospital admissions. Males contributed to 50.5% of the total number of hospital admissions. Hospital admission rate in females increased by 119.8% [from 1442.18 (95% CI 1437.66–1446.70) in 1999 to 3169.38 (95% CI 3163.11–3175.64) in 2019 per 100,000 persons, trend test, p < 0.001]. Hospital admission rate increased by 92.9% in males [from 1633.25 (95% CI 1628.32–1638.17) in 1999 to 3149.78 (95% CI 3143.46–3156.09) in 2019 per 100,000 persons, trend test, p < 0.001]. CONCLUSION: During the study period, hospital admissions rate due to respiratory diseases increased sharply. The rates of hospital admissions were higher among males for the vast majority of respiratory diseases. Further observational studies are warranted to identify risk factors for these hospital admissions and to offer relevant interventions to mitigate the risk

Monitoring iron chelation effect in hearts of thalassaemia patients with improved sensitivity using reduced transverse relaxation rate (RR2)

Posters - Myocardial Viability: Human Models: No. 3660Accurate MRI characterization of myocardial iron is needed to improve the diagnosis and management of thalassaemia patients with transfusional iron overload. This study aimed to demonstrate that a new transverse relaxation index, the reduced R2 (RR2) that is estimated from non-monoexponential multi-echo CPMG signal decay and sensitive to ferritin iron, could detect the myocardial iron changes immediately following 1-week iron chelation suspension in thalassaemia patients at 3T.postprin

Neutron star envelopes and thermal radiation from the magnetic surface

The thermal structure of neutron star envelopes is discussed with emphasis on analytic results. Recent progress on the effect of chemical constitution and high magnetic fields on the opacities and the thermal structure is further reviewed in view of the application to pulsar cooling and magnetars

Timing the extant avian radiation: The rise of modern birds, and the importance of modeling molecular rate variation

Unravelling the phylogenetic relationships among the major groups of living birds has been described as the greatest outstanding problem in dinosaur systematics. Recent work has identified portions of the avian tree of life that are particularly challenging to reconstruct, perhaps as a result of rapid cladogenesis early in crown bird evolutionary history (specifically, the interval immediately following the end-Cretaceous mass extinction). At face value this hypothesis enjoys support from the crown bird fossil record, which documents the first appearances of most major crown bird lineages in the early Cenozoic—in line with a model of rapid post-extinction niche filling among surviving avian lineages. However, molecular-clock analyses have yielded strikingly variable estimates for the age of crown birds, and conflicting inferences on the impact of the end-Cretaceous mass extinction on the extant bird radiation. This uncertainty has often been ascribed to a patchy avian fossil record, but the possibility of model misspecification in molecular divergence time analyses represents an important and relatively underexplored alternative hypothesis. Here, we highlight the necessity of further developing and using models that account for coordinated variation in rates of molecular evolution across a phylogeny (e.g. molecular early bursts) as a means of assessing support for a rapid post-Cretaceous radiation of crown birds. We discuss how relationships between life-history and substitution rates can mislead divergence time studies that do not account for directional changes in substitution rates over time, and suggest that these effects might have caused some of the variation in existing molecular date estimates for birds. We suggest multiple paths forward that could help resolve this and similar conflicts within other major eukaryotic clades.</jats:p