A robust, semi-automated approach for counting cementum increments imaged with synchrotron X-ray computed tomography

Cementum, the tissue attaching mammal tooth roots to the periodontal ligament, grows appositionally throughout life, displaying a series of circum-annual incremental features. These have been studied for decades as a direct record of chronological lifespan. The majority of previous studies on cementum have used traditional thin-section histological methods to image and analyse increments. However, several caveats have been raised in terms of studying cementum increments in thin-sections. Firstly, the limited number of thin-sections and the two-dimensional perspective they impart provide an incomplete interpretation of cementum structure, and studies often struggle or fail to overcome complications in increment patterns that complicate or inhibit increment counting. Increments have been repeatedly shown to both split and coalesce, creating accessory increments that can bias increment counts. Secondly, identification and counting of cementum increments using human vision is subjective, and it has led to inaccurate readings in several experiments studying individuals of known age. Here, we have attempted to optimise a recently introduced imaging modality for cementum imaging; X-ray propagation-based phase-contrast imaging (PPCI). X-ray PPCI was performed for a sample of rhesus macaque (Macaca mulatta) lower first molars (n = 10) from a laboratory population of known age. PPCI allowed the qualitative identification of primary/annual versus intermittent secondary increments formed by splitting/coalescence. A new method for semi-automatic increment counting was then integrated into a purpose-built software package for studying cementum increments, to count increments in regions with minimal complications. Qualitative comparison with data from conventional cementochronology, based on histological examination of tissue thin-sections, confirmed that X-ray PPCI reliably and non-destructively records cementum increments (given the appropriate preparation of specimens prior to X-ray imaging). Validation of the increment counting algorithm suggests that it is robust and provides accurate estimates of increment counts. In summary, we show that our new increment counting method has the potential to overcome caveats of conventional cementochronology approaches, when used to analyse three-dimensional images provided by X-ray PPCI.Peer reviewe

Ageing enhances cellular immunity to myeloperoxidase and experimental anti-myeloperoxidase glomerulonephritis

OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disease characterised by small blood vessel inflammation, commonly affecting the kidneys and respiratory tract. It is unclear why the incidence of this condition increases with age. Previous studies in a passive antibody transfer system in aged mice have implicated innate effectors. To test the hypothesis that autoimmunity to myeloperoxidase, an autoantigen responsible for ANCA-associated vasculitis, increases with age, anti-myeloperoxidase autoimmunity was studied in murine models of active autoimmunity and disease induced by cellular immunity. METHODS: Young (8 weeks) and aged (either 15 or 22 month) mice were immunised with whole proteins or peptides from ovalbumin, as a model foreign antigen, or myeloperoxidase protein or peptides. Mice were subjected to a model of active anti-myeloperoxidase glomerulonephritis. Cellular and humoral immune responses and tissue inflammation were assessed. RESULTS: While cellular immunity to ovalbumin was diminished in aged mice, cellular autoimmunity to myeloperoxidase and its immunodominant CD4+ and CD8+ T cell epitopes was increased after immunization with either MPO peptides or whole MPO protein, assessed by peptide and antigen specific production of the pro-inflammatory cytokines interferon-γ and interleukin-17A. MPO-ANCA titres were not increased in aged mice compared with young mice. In experimental anti-MPO glomerulonephritis, cell mediated injury was increased, likely due to CD4+ and CD8+ T cells, innate immunity and the increased vulnerability of aged kidneys. CONCLUSION: Heightened cellular immunity to MPO develops with ageing in mice and may contribute to the increased incidence and severity of ANCA-associated vasculitis in older people

HLA and kidney disease: from associations to mechanisms

Since the first association between HLA and diseases of native kidneys was described almost 50 years ago, technological and conceptual advances in HLA biology and typing, together with better case ascertainment, have led to an improved understanding of HLA associations with a variety of renal diseases. A substantial body of evidence now supports the existence of HLA genetic associations in the field of renal disease beyond the role of HLA in allogeneic responses in transplant recipients. Allomorphs of HLA have emerged as important risk factors in most immune-mediated renal diseases, which, together with other genetic and environmental factors, lead to loss of tolerance and autoimmune-mediated renal inflammation. HLA associations have also been described for renal diseases that are less traditionally seen as autoimmune or immune-mediated. Here, we review essential concepts in HLA biology and the association of HLA with diseases of the native kidneys, and describe the current understanding of the epistatic and mechanistic bases of HLA-associated kidney disease. Greater understanding of the relationship between HLA and kidney function has the potential not only to further the understanding of immune renal disease at a fundamental level but also to lead to the development and application of more effective, specific and less toxic therapies for kidney diseases

Regulation of the androgen receptor by SET9-mediated methylation

The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors that plays a critical role in regulating expression of genes involved in prostate development and transformation. Upon hormone binding, the AR associates with numerous co-regulator proteins that regulate the activation status of target genes via flux to the post-translational modification status of histones and the receptor. Here we show that the AR interacts with and is directly methylated by the histone methyltransferase enzyme SET9. Methylation of the AR on lysine 632 is necessary for enhancing transcriptional activity of the receptor by facilitating both inter-domain communication between the N- and C-termini and recruitment to androgen-target genes. We also show that SET9 is pro-proliferative and anti-apoptotic in prostate cancer cells and demonstrates up-regulated nuclear expression in prostate cancer tissue. In all, our date indicate a new mechanism of AR regulation that may be therapeutically exploitable for prostate cancer treatment

Reply to: Revisiting life history and morphological proxies for early mammaliaform metabolic rates

Non peer reviewe

Reptile-like physiology in Early Jurassic stem-mammals

Despite considerable advances in knowledge of the anatomy, ecology and evolution of early mammals, far less is known about their physiology. Evidence is contradictory concerning the timing and fossil groups in which mammalian endothermy arose. To determine the state of metabolic evolution in two of the earliest stem-mammals, the Early Jurassic Morganucodon and Kuehneotherium, we use separate proxies for basal and maximum metabolic rate. Here we report, using synchrotron X-ray tomographic imaging of incremental tooth cementum, that they had maximum lifespans considerably longer than comparably sized living mammals, but similar to those of reptiles, and so they likely had reptilian-level basal metabolic rates. Measurements of femoral nutrient foramina show Morganucodon had blood flow rates intermediate between living mammals and reptiles, suggesting maximum metabolic rates increased evolutionarily before basal metabolic rates. Stem mammals lacked the elevated endothermic metabolism of living mammals, highlighting the mosaic nature of mammalian physiological evolution. Modern mammals are endothermic, but it has not been clear when this type of metabolism evolved. Here, Newham et al. analyse tooth and bone structure in Early Jurassic stem-mammal fossils to estimate lifespan and blood flow rates, which inform about basal and maximum metabolic rates, respectively, and show these stem-mammals had metabolic rates closer to modern ectothermic reptiles than to endothermic mammals.Peer reviewe

Youth, mobility and mobile phones in Africa: findings from a three-country study

he penetration of mobile phones into sub-Saharan Africa has occurred with amazing rapidity: for many young people, they now represent a very significant element of their daily life. This paper explores usage and perceived impacts among young people aged c. 9–18 years in three countries: Ghana, Malawi and South Africa. Our evidence comes from intensive qualitative research with young people, their parents, teachers and other key informants (in-depth interviews, focus groups and school essays) and a follow-up questionnaire survey administered to nearly 3000 young people in 24 study sites. The study was conducted in eight different sites in each country (i.e. urban, peri-urban, rural and remote rural sites in each of two agro-ecological zones), enabling comparison of experiences in diverse spatial contexts. The evidence, collected within a broader research study of child mobility, allows us to examine current patterns of usage among young people with particular attention to the way these are emerging in different locational contexts and to explore connections between young people's phone usage, virtual and physical mobilities and broader implications for social change. The issues of gender and inter-generational relations are important elements in this account

Multiple pathways of SARS-CoV-2 nosocomial transmission uncovered by integrated genomic and epidemiological analyses during the second wave of the COVID-19 pandemic in the UK

IntroductionThroughout the global COVID-19 pandemic, nosocomial transmission has represented a major concern for healthcare settings and has accounted for many infections diagnosed within hospitals. As restrictions ease and novel variants continue to spread, it is important to uncover the specific pathways by which nosocomial outbreaks occur to understand the most suitable transmission control strategies for the future.MethodsIn this investigation, SARS-CoV-2 genome sequences obtained from 694 healthcare workers and 1,181 patients were analyzed at a large acute NHS hospital in the UK between September 2020 and May 2021. These viral genomic data were combined with epidemiological data to uncover transmission routes within the hospital. We also investigated the effects of the introduction of the highly transmissible variant of concern (VOC), Alpha, over this period, as well as the effects of the national vaccination program on SARS-CoV-2 infection in the hospital.ResultsOur results show that infections of all variants within the hospital increased as community prevalence of Alpha increased, resulting in several outbreaks and super-spreader events. Nosocomial infections were enriched amongst older and more vulnerable patients more likely to be in hospital for longer periods but had no impact on disease severity. Infections appeared to be transmitted most regularly from patient to patient and from patients to HCWs. In contrast, infections from HCWs to patients appeared rare, highlighting the benefits of PPE in infection control. The introduction of the vaccine at this time also reduced infections amongst HCWs by over four-times.DiscussionThese analyses have highlighted the importance of control measures such as regular testing, rapid lateral flow testing alongside polymerase chain reaction (PCR) testing, isolation of positive patients in the emergency department (where possible), and physical distancing of patient beds on hospital wards to minimize nosocomial transmission of infectious diseases such as COVID-19

Exposure-based Interventions for the management of individuals with high levels of needle fear across the lifespan: a clinical practice guideline and call for further research

Needle fear typically begins in childhood and represents an important health-related issue across the lifespan. Individuals who are highly fearful of needles frequently avoid health care. Although guidance exists for managing needle pain and fear during procedures, the most highly fearful may refuse or abstain from such procedures. The purpose of a clinical practice guideline (CPG) is to provide actionable instruction on the management of a particular health concern; this guidance emerges from a systematic process. Using evidence from a rigorous systematic review interpreted by an expert panel, this CPG provides recommendations on exposure-based interventions for high levels of needle fear in children and adults. The AGREE-II, GRADE, and Cochrane methodologies were used. Exposure-based interventions were included. The included evidence was very low quality on average. Strong recommendations include the following. In vivo (live/in person) exposure-based therapy is recommended (vs. no treatment) for children seven years and older and adults with high levels of needle fear. Non-in vivo (imaginal, computer-based) exposure (vs. no treatment) is recommended for individuals (over seven years of age) who are unwilling to undergo in vivo exposure. Although there were no included trials which examined children \u3c 7 years, exposure-based interventions are discussed as good clinical practice. Implementation considerations are discussed and clinical tools are provided. Utilization of these recommended practices may lead to improved health outcomes due to better health care compliance. Research on the understanding and treatment of high levels of needle fear is urgently needed; specific recommendations are provided