Transforming growth factor-beta enables NFATc1 expression during osteoclastogenesis.

Osteoclastogenesis is dependent on distinct stimuli that prime and activate osteoclast differentiation. One cytokine needed to prime monocytes for osteoclastogenesis is TGF-beta, which enables and augments RANKL and TNF-alpha-induced osteoclast differentiation. However, the precise time-period during which this occurs and the molecular mechanism mediating this action are unknown. We report here TGF-beta prime monocytes for osteoclast formation within 24h by regulating expression of NFATc1, a key osteoclastic transcription factor. TGF-beta directly induces cytoplasmic NFATc1 expression within 24h, but is unable to stimulate NFATc1 nuclear translocation. Furthermore, RANKL-induced NFATc1 expression is dependent on the presence of TGF-beta during the early stages of osteoclastogenesis. Similarly, TNF-alpha activates osteoclastogenesis by stimulating translocation of TGF-beta-induced NFATc1. In light of these findings, it is apparent that osteoclast formation is dependent on coordinated interactions between TGF-beta and RANKL/TNF-alpha that regulate the expression and intracellular distribution of NFATc1 during early stages of osteoclast differentiation

Effect of health messages on alcohol attitudes and intentions in a sample of 16- & 17-year-old underage drinkers

Background. Responsible drinking messages (RDMs) are a key component of many education-based interventions for reducing alcohol harms. The evidence base for the effectiveness of RDMs is extremely limited, with some recent research suggesting iatrogenic effects of such messages. Objective. To examine the effects of exposure to health messages on attitudes towards drinking and drunkenness, and intentions to drink and get drunk, amongst underage drinkers. Methods. Ninety-four underage drinkers were recruited from colleges in the UK. Participants were either actively or passively exposed to one of two health messages (RDM or general wellbeing). Measures of attitudes and intentions towards drinking and drunkenness were obtained one week before and immediately after participation in the study. A unit estimation task was also included. Results. Active exposure to RDMs led to more positive attitude towards drunkenness, while passive exposure led to more negative attitudes. Passive RDM exposure led to increased intentions to get drunk in future. Wellbeing posters produced the opposite effect in some but not all of these measures. Conclusions. Exposure to RDMs may have some beneficial effects in terms of creating more negative attitudes towards alcohol consumption, but we also identified potential iatrogenic effects regarding attitudes and intentions towards drunkenness amongst an underage sample of drinkers. Further research is required to better understand optimal ways of framing RDMs to produce positive changes in attitudes, intentions and prospective drinking behaviour

Prevalence, incidence, and outcomes across cardiovascular diseases in homeless individuals using national linked electronic health records

AIMS: The risk and burden of cardiovascular disease (CVD) are higher in homeless than in housed individuals but population-based analyses are lacking. The aim of this study was to investigate prevalence, incidence and outcomes across a range of specific CVDs among homeless individuals. METHODS AND RESULTS: Using linked UK primary care electronic health records (EHRs) and validated phenotypes, we identified homeless individuals aged ≥16 years between 1998 and 2019, and age- and sex-matched housed controls in a 1:5 ratio. For 12 CVDs (stable angina; unstable angina; myocardial infarction; sudden cardiac death or cardiac arrest; unheralded coronary death; heart failure; transient ischaemic attack; ischaemic stroke; subarachnoid haemorrhage; intracerebral haemorrhage; peripheral arterial disease; abdominal aortic aneurysm), we estimated prevalence, incidence, and 1-year mortality post-diagnosis, comparing homeless and housed groups. We identified 8492 homeless individuals (32 134 matched housed individuals). Comorbidities and risk factors were more prevalent in homeless people, e.g. smoking: 78.1% vs. 48.3% and atrial fibrillation: 9.9% vs. 8.6%, P < 0.001. CVD prevalence (11.6% vs. 6.5%), incidence (14.7 vs. 8.1 per 1000 person-years), and 1-year mortality risk [adjusted hazard ratio 1.64, 95% confidence interval (CI) 1.29-2.08, P < 0.001] were higher, and onset was earlier (difference 4.6, 95% CI 2.8-6.3 years, P < 0.001), in homeless, compared with housed people. Homeless individuals had higher CVD incidence in all three arterial territories than housed people. CONCLUSION: CVD in homeless individuals has high prevalence, incidence, and 1-year mortality risk post-diagnosis with earlier onset, and high burden of risk factors. Inclusion health and social care strategies should reflect this high preventable and treatable burden, which is increasingly important in the current COVID-19 context

A fixed-target platform for serial femtosecond crystallography in a hydrated environment.

For serial femtosecond crystallography at X-ray free-electron lasers, which entails collection of single-pulse diffraction patterns from a constantly refreshed supply of microcrystalline sample, delivery of the sample into the X-ray beam path while maintaining low background remains a technical challenge for some experiments, especially where this methodology is applied to relatively low-ordered samples or those difficult to purify and crystallize in large quantities. This work demonstrates a scheme to encapsulate biological samples using polymer thin films and graphene to maintain sample hydration in vacuum conditions. The encapsulated sample is delivered into the X-ray beam on fixed targets for rapid scanning using the Roadrunner fixed-target system towards a long-term goal of low-background measurements on weakly diffracting samples. As a proof of principle, we used microcrystals of the 24 kDa rapid encystment protein (REP24) to provide a benchmark for polymer/graphene sandwich performance. The REP24 microcrystal unit cell obtained from our sandwiched in-vacuum sample was consistent with previously established unit-cell parameters and with those measured by us without encapsulation in humidified helium, indicating that the platform is robust against evaporative losses. While significant scattering from water was observed because of the sample-deposition method, the polymer/graphene sandwich itself was shown to contribute minimally to background scattering

Computational biomechanical modelling of the rabbit cranium during mastication

Although a functional relationship between bone structure and mastication has been shown in some regions of the rabbit skull, the biomechanics of the whole cranium during mastication have yet to be fully explored. In terms of cranial biomechanics, the rabbit is a particularly interesting species due to its uniquely fenestrated rostrum, the mechanical function of which is debated. In addition, the rabbit processes food through incisor and molar biting within a single bite cycle, and the potential influence of these bite modes on skull biomechanics remains unknown. This study combined the in silico methods of multi-body dynamics and finite element analysis to compute musculoskeletal forces associated with a range of incisor and molar biting, and to predict the associated strains. The results show that the majority of the cranium, including the fenestrated rostrum, transmits masticatory strains. The peak strains generated over all bites were found to be attributed to both incisor and molar biting. This could be a consequence of a skull shape adapted to promote an even strain distribution for a combination of infrequent incisor bites and cyclic molar bites. However, some regions, such as the supraorbital process, experienced low peak strain for all masticatory loads considered, suggesting such regions are not designed to resist masticatory forces

The foot posture index, ankle lunge test, Beighton scale and the lower limb assessment score in healthy children: a reliability study

<p>Abstract</p> <p>Background</p> <p>Outcome measures are important when evaluating treatments and physiological progress in paediatric populations. Reliable, relevant measures of foot posture are important for such assessments to be accurate over time. The aim of the study was to assess the intra- and inter-rater reliability of common outcome measures for paediatric foot conditions.</p> <p>Methods</p> <p>A repeated measures, same-subject design assessed the intra- and inter-rater reliability of measures of foot posture, joint hypermobility and ankle range: the Foot Posture Index (FPI-6), the ankle lunge test, the Beighton scale and the lower limb assessment scale (LLAS), used by two examiners in 30 healthy children (aged 7 to 15 years). The Oxford Ankle Foot Questionnaire (OxAFQ-C) was completed by participants and a parent, to assess the extent of foot and ankle problems.</p> <p>Results</p> <p>The OxAFQ-C demonstrated a mean (SD) score of 6 (6) in adults and 7(5) for children, showing good agreement between parents and children, and which indicates mid-range (transient) disability. Intra-rater reliability was good for the FPI-6 (ICC = 0.93 - 0.94), ankle lunge test (ICC = 0.85-0.95), Beighton scale (ICC = 0.96-0.98) and LLAS (ICC = 0.90-0.98). Inter-rater reliability was largely good for each of the: FPI-6 (ICC = 0.79), ankle lunge test (ICC = 0.83), Beighton scale (ICC = 0.73) and LLAS (ICC = 0.78).</p> <p>Conclusion</p> <p>The four measures investigated demonstrated adequate intra-rater and inter-rater reliability in this paediatric sample, which further justifies their use in clinical practice.</p

Things change: Women’s and men’s marital disruption dynamics in Italy during a time of social transformations, 1970-2003

We study women’s and men’s marital disruption in Italy between 1970 and 2003. By applying an event-history analysis to the 2003 Italian variant of the Generations and Gender Survey we found that the spread of marital disruption started among middle-highly educated women. Then in recent years it appears that less educated women have also been able to dissolve their unhappy unions. Overall we can see the beginning of a reversed educational gradient from positive to negative. In contrast the trend in men’s marital disruption risk appears as a change over time common to all educational groups, although with persisting educational differentials.determinants, educational differences, event history analysis, gender difference, Italy, marital disruption

Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

Multifactorial mechanisms underlying late-onset Alzheimer’s disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system’s integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions