Transitory FGF treatment results in the long-lasting suppression of the proliferative response to repeated FGF stimulation.

FGF applied as a single growth factor to quiescent mouse fibroblasts induces a round of DNA replication, however continuous stimulation results in arrest in the G1 phase of the next cell cycle. We hypothesized that FGF stimulation induces the establishment of cell memory, which prevents the proliferative response to repeated or continuous FGF application. When a 2-5 day quiescence period was introduced between primary and repeated FGF treatments, fibroblasts failed to efficiently replicate in response to secondary FGF application. The establishment of “FGF memory” during the first FGF stimulation did not require DNA synthesis, but was dependent on the activity of FGF receptors, MEK, p38 MAPK and NFκB signaling, and protein synthesis. While secondary stimulation resulted in strongly decreased replication rate, we did not observe any attenuation of morphological changes, Erk1/2 phosphorylation and cyclin D1 induction. However, secondary FGF stimulation failed to induce the expression of cyclin A, which is critical for the progression from G1 to S phase. Treatment of cells with a broad range histone deacetylase inhibitor during the primary FGF stimulation rescued the proliferative response to the secondary FGF treatment suggesting that the establishment of “FGF memory” may be based on epigenetic changes. We suggest that “FGF memory” can prevent the hyperplastic response to cell damage and inflammation, which are associated with an enhanced FGF production and secretion. “FGF memory” may present a natural obstacle to the efficient application of recombinant FGFs for the treament of ulcers, ischemias and wounds

Perceptions on artificial intelligence-based decision making for coexisting multiple long-term health conditions: A protocol for a qualitative study with patients and healthcare professionals

IntroductionCoexisting multiple health conditions is common among older people, a population that is increasing globally. The potential for polypharmacy, adverse events, drug interactions and causing additional health conditions complicates prescribing decisions for these patients. Artificial Intelligence (AI)-generated decision-making tools may help guide clinical decisions in the context of multiple health conditions, by determining which of multiple medication options is best. This study aims to explore the perceptions of healthcare professionals (HCPs) and patients on the use of AI in the management of multiple health conditions.Methods and analysis A qualitative study will be conducted using semi-structured interviews. Adults (≥18 years) with multiple health conditions living in the West Midlands of England and HCPs with experience in caring for patients with multiple health conditions will be eligible and purposively sampled. Patients will be identified from Clinical Practice Research Datalink (CPRD) Aurum; CPRD will contact general practitioners who will in turn, send a letter to patients inviting them to take part. Eligible HCPs will be recruited through British healthcare professional bodies and known contacts. Up to 30 patients and 30 HCPs will be recruited, until data saturation is achieved. Interviews will be in-person or virtual, audio recorded and transcribed verbatim. The topic guide was designed to explore participants’ attitudes towards AI-informed clinical decision-making to augment clinician-directed decision-making, the perceived advantages and disadvantages of both methods and attitudes toward risk management. Case vignettes comprising a common decision pathway for patients with multiple health conditions will be presented during each interview to invite participants’ opinions on how their experiences compare. Data will be analysed thematically using the Framework method.Ethics and dissemination This study has been approved by the National Health Service Research Ethics Committee (Reference: 22/SC/0210). Written informed consent or verbal consent will be obtained prior to each interview. The findings from this study will be disseminated through peer- reviewed publications, conferences and lay summaries.<br/

Molecular spectroscopy for ground-state transfer of ultracold RbCs molecules

We perform one- and two-photon high resolution spectroscopy on ultracold samples of RbCs Feshbach molecules with the aim to identify a suitable route for efficient ground-state transfer in the quantum-gas regime to produce quantum gases of dipolar RbCs ground-state molecules. One-photon loss spectroscopy allows us to probe deeply bound rovibrational levels of the mixed excited (A1{\Sigma}+ - b3{\Pi}0) 0+ molecular states. Two-photon dark state spectroscopy connects the initial Feshbach state to the rovibronic ground state. We determine the binding energy of the lowest rovibrational level |v"=0,J"=0> of the X1{\Sigma}+ ground state to be DX 0 = 3811.5755(16) 1/cm, a 300-fold improvement in accuracy with respect to previous data. We are now in the position to perform stimulated two-photon Raman transfer to the rovibronic ground state.Comment: Submitted to PCCP themed issue: Physics and Chemistry of Cold Molecule

The lack of star formation gradients in galaxy groups up to z~1.6

In the local Universe, galaxy properties show a strong dependence on environment. In cluster cores, early type galaxies dominate, whereas star-forming galaxies are more and more common in the outskirts. At higher redshifts and in somewhat less dense environments (e.g. galaxy groups), the situation is less clear. One open issue is that of whether and how the star formation rate (SFR) of galaxies in groups depends on the distance from the centre of mass. To shed light on this topic, we have built a sample of X-ray selected galaxy groups at 0<z<1.6 in various blank fields (ECDFS, COSMOS, GOODS). We use a sample of spectroscopically confirmed group members with stellar mass M >10^10.3 M_sun in order to have a high spectroscopic completeness. As we use only spectroscopic redshifts, our results are not affected by uncertainties due to projection effects. We use several SFR indicators to link the star formation (SF) activity to the galaxy environment. Taking advantage of the extremely deep mid-infrared Spitzer MIPS and far-infrared Herschel PACS observations, we have an accurate, broad-band measure of the SFR for the bulk of the star-forming galaxies. We use multi-wavelength SED fitting techniques to estimate the stellar masses of all objects and the SFR of the MIPS and PACS undetected galaxies. We analyse the dependence of the SF activity, stellar mass and specific SFR on the group-centric distance, up to z~1.6, for the first time. We do not find any correlation between the mean SFR and group-centric distance at any redshift. We do not observe any strong mass segregation either, in agreement with predictions from simulations. Our results suggest that either groups have a much smaller spread in accretion times with respect to the clusters and that the relaxation time is longer than the group crossing time.Comment: Accepted for publication in MNRA

Autism in England: assessing underdiagnosis in a population-based cohort study of prospectively collected primary care data

Background: Autism has long been viewed as a paediatric condition, meaning that many autistic adults missed out on a diagnosis as children when autism was little known. We estimated numbers of diagnosed and undiagnosed autistic people in England, and examined how diagnostic rates differed by socio-demographic factors. / Methods: This population-based cohort study of prospectively collected primary care data from IQVIA Medical Research Data (IMRD) compared the prevalence of diagnosed autism to community prevalence to estimate underdiagnosis. 602,433 individuals registered at an English primary care practice in 2018 and 5,586,100 individuals registered between 2000 and 2018 were included. / Findings: Rates of diagnosed autism in children/young people were much higher than in adults/older adults. As of 2018, 2.94% of 10- to 14-year-olds had a diagnosis (1 in 34), vs. 0.02% aged 70+ (1 in 6000). Exploratory projections based on these data suggest that, as of 2018, 463,500 people (0.82% of the English population) may have been diagnosed autistic, and between 435,700 and 1,197,300 may be autistic and undiagnosed (59–72% of autistic people, 0.77%–2.12% of the English population). Age-related inequalities were also evident in new diagnoses (incidence): c.1 in 250 5- to 9-year-olds had a newly-recorded autism diagnosis in 2018, vs. c.1 in 4000 20- to 49-year-olds, and c.1 in 18,000 people aged 50+. / Interpretation: Substantial age-related differences in the proportions of people diagnosed suggest an urgent need to improve access to adult autism diagnostic services

Sociodemographic characteristics and longitudinal progression of multimorbidity:A multistate modelling analysis of a large primary care records dataset in England

BackgroundMultimorbidity, characterised by the coexistence of multiple chronic conditions in an individual, is a rising public health concern. While much of the existing research has focused on cross-sectional patterns of multimorbidity, there remains a need to better understand the longitudinal accumulation of diseases. This includes examining the associations between important sociodemographic characteristics and the rate of progression of chronic conditions.Methods and findingsWe utilised electronic primary care records from 13.48 million participants in England, drawn from the Clinical Practice Research Datalink (CPRD Aurum), spanning from 2005 to 2020 with a median follow-up of 4.71 years (IQR: 1.78, 11.28). The study focused on 5 important chronic conditions: cardiovascular disease (CVD), type 2 diabetes (T2D), chronic kidney disease (CKD), heart failure (HF), and mental health (MH) conditions. Key sociodemographic characteristics considered include ethnicity, social and material deprivation, gender, and age. We employed a flexible spline-based parametric multistate model to investigate the associations between these sociodemographic characteristics and the rate of different disease transitions throughout multimorbidity development. Our findings reveal distinct association patterns across different disease transition types. Deprivation, gender, and age generally demonstrated stronger associations with disease diagnosis compared to ethnic group differences. Notably, the impact of these factors tended to attenuate with an increase in the number of preexisting conditions, especially for deprivation, gender, and age. For example, the hazard ratio (HR) (95% CI; p-value) for the association of deprivation with T2D diagnosis (comparing the most deprived quintile to the least deprived) is 1.76 ([1.74, 1.78]; p ConclusionsOur results indicate that early phases of multimorbidity development could warrant increased attention. The potential importance of earlier detection and intervention of chronic conditions is underscored, particularly for MH conditions and higher-risk populations. These insights may have important implications for the management of multimorbidity

Sequencing of 15 622 Gene-bearing BACs Clarifies the Gene-dense Regions of the Barley Genome

Barley (Hordeum vulgare L.) possesses a large and highly repetitive genome of 5.1 Gb that has hindered the development of a complete sequence. In 2012, the International Barley Sequencing Consortium released a resource integrating whole-genome shotgun sequences with a physical and genetic framework. However, because only 6278 bacterial artificial chromosome (BACs) in the physical map were sequenced, fine structure was limited. To gain access to the gene-containing portion of the barley genome at high resolution, we identified and sequenced 15 622 BACs representing the minimal tiling path of 72 052 physical-mapped gene-bearing BACs. This generated ~1.7 Gb of genomic sequence containing an estimated 2/3 of all Morex barley genes. Exploration of these sequenced BACs revealed that although distal ends of chromosomes contain most of the gene-enriched BACs and are characterized by high recombination rates, there are also gene-dense regions with suppressed recombination. We made use of published map-anchored sequence data from Aegilops tauschii to develop a synteny viewer between barley and the ancestor of the wheat D-genome. Except for some notable inversions, there is a high level of collinearity between the two species. The software HarvEST:Barley provides facile access to BAC sequences and their annotations, along with the barley–Ae. tauschii synteny viewer. These BAC sequences constitute a resource to improve the efficiency of marker development, map-based cloning, and comparative genomics in barley and related crops. Additional knowledge about regions of the barley genome that are gene-dense but low recombination is particularly relevant