Molecular Pathobiology of the Cerebrovasculature in Aging and in Alzheimers Disease Cases With Cerebral Amyloid Angiopathy

Cerebrovascular dysfunction and cerebral amyloid angiopathy (CAA) are hallmark features of Alzheimer's disease (AD). Molecular damage to cerebrovessels in AD may result in alterations in vascular clearance mechanisms leading to amyloid deposition around blood vessels and diminished neurovascular-coupling. The sequelae of molecular events leading to these early pathogenic changes remains elusive. To address this, we conducted a comprehensive in-depth molecular characterization of the proteomic changes in enriched cerebrovessel fractions isolated from the inferior frontal gyrus of autopsy AD cases with low (85.5 ± 2.9 yrs) vs. high (81 ± 4.4 yrs) CAA score, aged-matched control (87.4 ± 1.5 yrs) and young healthy control (47 ± 3.3 yrs) cases. We employed a 10-plex tandem isobaric mass tag approach in combination with our ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method. Enriched cerebrovascular fractions showed very high expression levels of proteins specific to endothelial cells, mural cells (pericytes and smooth muscle cells), and astrocytes. We observed 150 significantly regulated proteins in young vs. aged control cerebrovessels. The top pathways significantly modulated with aging included chemokine, reelin, HIF1α and synaptogenesis signaling pathways. There were 213 proteins significantly regulated in aged-matched control vs. high CAA cerebrovessels. The top three pathways significantly altered from this comparison were oxidative phosphorylation, Sirtuin signaling pathway and TCA cycle II. Comparison between low vs. high CAA cerebrovessels identified 84 significantly regulated proteins. Top three pathways significantly altered between low vs. high CAA cerebrovessels included TCA Cycle II, Oxidative phosphorylation and mitochondrial dysfunction. Notably, high CAA cases included more advanced AD pathology thus cerebrovascular effects may be driven by the severity of amyloid and Tangle pathology. These descriptive proteomic changes provide novel insights to explain the age-related and AD-related cerebrovascular changes contributing to AD pathogenesis. Particularly, disturbances in energy bioenergetics and mitochondrial biology rank among the top AD pathways altered in cerebrovessels. Targeting these failed mechanisms in endothelia and mural cells may provide novel disease modifying targets for developing therapeutic strategies against cerebrovascular deterioration and promoting cerebral perfusion in AD. Our future work will focus on interrogating and validating these novel targets and pathways and their functional significance

Using ice core measurements from Taylor Glacier, Antarctica, to calibrate in situ cosmogenic 14 C production rates by muons

Cosmic rays entering the Earth’s atmosphere produce showers of secondary particles such as protons, neutrons, and muons. The interaction of these particles with oxygen-16 (16O) in minerals such as ice and quartz can produce carbon-14 (14C). In glacial ice, 14C is also incorporated through trapping of 14C-containing atmospheric gases (14CO2, 14CO, and 14CH4). Understanding the production rates of in situ cosmogenic 14C is important to deconvolve the in situ cosmogenic and atmospheric 14C signals in ice, both of which contain valuable paleoenvironmental information. Unfortunately, the in situ 14C production rates by muons (which are the dominant production mechanism at depths of > 6m solid ice equivalent) are uncertain. In this study, we use measurements of in situ 14C in ancient ice (> 50 ka) from the Taylor Glacier, an ablation site in Antarctica, in combination with a 2D ice flow model to better constrain the compound-specific rates of 14C production by muons and the partitioning of in situ 14C between CO2, CO, and CH4. Our measurements show that 33.7% (11.4%; 95% confidence interval) of the produced cosmogenic 14C forms 14CO and 66.1% (11.5%; 95% confidence interval) of the produced cosmogenic 14C forms 14CO2. 14CH4 represents a very small fraction (< 0.3%) of the total. Assuming that the majority of in situ muogenic 14C in ice forms 14CO2, 14CO, and 14CH4, we also calculated muogenic 14C production rates that are lower by factors of 5.7 (3.6–13.9; 95% confidence interval) and 3.7 (2.0–11.9; 95% confidence interval) for negative muon capture and fast muon interactions, respectively, when compared to values determined in quartz from laboratory studies (Heisinger et al., 2002a, b) and in a natural setting (Lupker et al., 2015). This apparent discrepancy in muogenic 14C production rates in ice and quartz currently lacks a good explanation and requires further investigation

Developing an Australian Melanoma Clinical Outcomes Registry (MelCOR): a protocol paper

Introduction Australia has the highest incidence of melanoma in the world with variable care provided by a diverse range of clinicians. Clinical quality registries aim to identify these variations in care and provide anonymised, benchmarked feedback to clinicians and institutions to improve patient outcomes. The Australian Melanoma Clinical Outcomes Registry (MelCOR) aims to collect population-wide, clinical-level data for the early management of cutaneous melanoma and provide anonymised feedback to healthcare providers. Methods and analysis A modified Delphi process will be undertaken to identify key clinical quality indicators for inclusion in the MelCOR pilot. MelCOR will prospectively collect data relevant to these quality indicators, initially for all people over the age of 18 years living in Victoria and Queensland with a melanoma diagnosis confirmed by histopathology, via a two-stage recruitment and consent process. In stage 1, existing State-based cancer registries contact the treating clinician and provide an opportunity for them to opt themselves or their patients out of direct contact with MelCOR. After stage 1, re-identifiable clinical data are provided to the MelCOR under a waiver of consent. In stage 2, the State-based cancer registry will approach the patient directly and invite them to opt in to MelCOR and share identifiable data. If a patient elects to opt in, MelCOR will be able to contact patients directly to collect patient-reported outcome measures. Aggregated data will be used to provide benchmarked, comparative feedback to participating institutions/clinicians. Ethics and dissemination Following the successful collection of pilot data, the feasibility of an Australia-wide roll out will be evaluated. Key quality indicator data will be the core of the MelCOR dataset, with additional data points added later. Annual reports will be issued, first to the relevant stakeholders followed by the public. MelCOR is approved by the Alfred Ethics Committee (58280/127/20)

School composition, school culture and socioeconomic inequalities in young people's health: multi-level analysis of the Health Behaviour in School-aged Children (HBSC) survey in Wales

Health inequalities emerge during childhood and youth, before widening in adulthood. Theorising, testing and interrupting the mechanisms through which inequalities are perpetuated and sustained is vital. Schools are viewed as settings through which inequality in young people's health may be addressed, but few studies examine the social processes via which institutional structures reproduce or mitigate health inequalities. Informed by Markham and Aveyard's theory of human functioning and school organisation, including their concept of institutional boundaries, critical theories of marketisation and the concept of micro-political practices within schools, this paper presents analysis of student survey data (N = 9055) from 82 secondary schools in Wales. It examines the role of socioeconomic composition, social relationships at school and institutional priorities in mitigating or perpetuating health inequality. It finds that affluent schools were most unequal in terms of student health behaviours and subjective wellbeing. In relation to health behaviours, students from affluent families accrue a disproportionate benefit. For wellbeing, students from poorer families reported lower subjective wellbeing where attending more affluent schools. Student–staff relationships appear to be a key mechanism underpinning these effects: poor relationships with staff were predicted by a pupil's position within schools’ socioeconomic hierarchy and associated with worse health outcomes. That is, students from the poorest families reported better relationships with teachers where attending less affluent schools. Universal approaches engaging with these social processes are needed to reduce health inequalities

Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland.

Recent lineage tracing studies have revealed that mammary gland homeostasis relies on unipotent stem cells. However, whether and when lineage restriction occurs during embryonic mammary development, and which signals orchestrate cell fate specification, remain unknown. Using a combination of in vivo clonal analysis with whole mount immunofluorescence and mathematical modelling of clonal dynamics, we found that embryonic multipotent mammary cells become lineage-restricted surprisingly early in development, with evidence for unipotency as early as E12.5 and no statistically discernable bipotency after E15.5. To gain insights into the mechanisms governing the switch from multipotency to unipotency, we used gain-of-function Notch1 mice and demonstrated that Notch activation cell autonomously dictates luminal cell fate specification to both embryonic and basally committed mammary cells. These functional studies have important implications for understanding the signals underlying cell plasticity and serve to clarify how reactivation of embryonic programs in adult cells can lead to cancer.Wellcome Trus

Late Quaternary sea-level change and early human societies in the central and eastern Mediterranean Basin : an interdisciplinary review

This article reviews key data and debates focused on relative sea-level changes since the Last Interglacial (approximately the last 132,000 years) in the Mediterranean Basin, and their implications for past human populations. Geological and geomorphological landscape studies are critical to archaeology. Coastal regions provide a wide range of resources to the populations that inhabit them. Coastal landscapes are increasingly the focus of scholarly discussions from the earliest exploitation of littoral resources and early hominin cognition, to the inundation of the earliest permanently settled fishing villages and eventually, formative centres of urbanisation. In the Mediterranean, these would become hubs of maritime transportation that gave rise to the roots of modern seaborne trade. As such, this article represents an original review of both the geo-scientific and archaeological data that specifically relate to sea-level changes and resulting impacts on both physical and cultural landscapes from the Palaeolithic until the emergence of the Classical periods. Our review highlights that the interdisciplinary links between coastal archaeology, geomorphology and sea-level changes are important to explain environmental impacts on coastal human societies and human migration. We review geological indicators of sea level and outline how archaeological features are commonly used as proxies for measuring past sea levels, both gradual changes and catastrophic events. We argue that coastal archaeologists should, as a part of their analyses, incorporate important sea-level concepts, such as indicative meaning. The interpretation of the indicative meaning of Roman fishtanks, for example, plays a critical role in reconstructions of late Holocene Mediterranean sea levels. We identify avenues for future work, which include the consideration of glacial isostatic adjustment (GIA) in addition to coastal tectonics to explain vertical movements of coastlines, more research on Palaeolithic island colonisation, broadening of Palaeolithic studies to include materials from the entire coastal landscape and not just coastal resources, a focus on rescue of archaeological sites under threat by coastal change, and expansion of underwater archaeological explorations in combination with submarine geomorphology. This article presents a collaborative synthesis of data, some of which have been collected and analysed by the authors, as the MEDFLOOD (MEDiterranean sea-level change and projection for future FLOODing) community, and highlights key sites, data, concepts and ongoing debates

Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis.

Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Orbitally-Tuned Sr Isotope Chemostratigraphy for the Late Middle to Late Miocene

We present a Sr chemostratigraphic reference section for the late middle to late Miocene (14-5 Ma) from Ocean Drilling Program site 926 on the Ceara Rise. This site combines a precise, orbitally tuned timescale with a high sedimentation rate (15 m/m.y.), continuous deposition, and excellent biostratigraphic control. The Sr isotope curve is based on measurements of cleaned, planktonic foraminifera at 100-200 kyr sample intervals and it illustrates periods of rapid change in Sr-87/Sr-86 alternating with periods of little change. Chemostratigraphically-defined ages for these intervals can be determined within +/-0.8 m.y. and +/-1.6 m.y, respectively. There is excellent correlation with the published curve for site 588 [Hodell and Woodruff, 1994]; however the curve for site 747 [Oslick et al., 1994] exhibits less structure, which may be due to small errors in age estimates related to slow sedimentation rates, high-latitude fauna and an interval of complicated magnetics. Late Miocene data compare favorably with data from site 758 [Farrell et al., 1995]