Pollen-based reconstruction of Holocene vegetation and climate in Southern Italy: the case of Lago di Trifoglietti

International audienceA high-resolution pollen record from Lago Trifoglietti in Calabria (southern Italy) provides new insights into the paleoenvironmental and palaeoclimatic changes which characterise the Holocene period in the southern Italy. The chronology is based on 11 AMS radiocarbon dates from terrestrial organic material. The Holocene history of the vegetation cover shows the persistence of an important and relatively stable Fagus forest present over that entire period, offering a rare example of a beech woodstand able to withstand climate changes for more than 11 000 yr. Probably in relation with early Holocene dry climate conditions which affected southern Italy, the Trifoglietti pollen record supports a southward delay in thermophyllous forest expansion dated to ca. 13 500 cal BP at Monticchio, ca. 11 000 cal BP at Trifoglietti, and finally ca. 9800 cal BP in Sicily. Regarding the human impact history, the Trifoglietti pollen record shows only poor imprints of agricultural activities and anthopogenic indicators, apart from those indicating pastoralism activities beneath forest cover. The selective exploitation of Abies appears to have been the strongest human impact on the Trifoglietti surroundings. On the basis of (1) a specific ratio between hygrophilous and terrestrial taxa, and (2) the Modern Analogue Technique, the pollen data collected at Lago Trifoglietti led to the establishment of two palaeoclimatic records tracing changes in (1) lake depth and (2) annual precipitation. On a millennial scale, these records give evidence of increasing moisture from ca. 11 000 to ca. 9400 cal BP and maximum humidity from ca. 9400 to ca. 6200 cal BP, prior to a general trend towards the drier climate conditions that have prevailed up to the present. In addition, several successive centennial-scale oscillations appear to have punctuated the entire Holocene. The identification of a cold dry event around 11 300 cal BP, responsible for a marked decline in timberline altitude and possibly equivalent to the PBO, remains to be confirmed by further investigations verifying both chronology and magnitude. Two cold and possibly drier Boreal oscillations developed at ca. 9800 and 9200 cal BP. At Trifoglietti, the 8.2 kyr event corresponds to the onset of cooler and drier climatic conditions which persisted until ca. 7500 cal BP. Finally, the second half of the Holocene was characterised by dry phases at ca. 6100–5200, 4400–3500, and 2500–1800 cal BP, alternating with more humid phases at ca. 5200–4400 and ca. 3500–2500 cal BP. Considered as a whole, these millennial-scale trends and centennial-scale climatic oscillations support contrasting patterns of palaeohydrological changes recognised between the north- and south-central Mediterranean

Multiscale molecular profiling of pathological bone resolves sexually dimorphic control of extracellular matrix composition.

Collagen assembly during development is essential for successful matrix mineralisation, which determines bone quality and mechanocompetence. However, the biochemical and structural perturbations that drive pathological skeletal collagen configuration remain unclear. Deletion of vascular endothelial growth factor (VEGF) in bone forming osteoblasts (OBs) induces sex-specific alterations in extracellular matrix (ECM) conformation and mineralisation coupled to vascular changes, which are augmented in males. Whether this phenotypic dimorphism arises as a result of the divergent control of ECM composition and its subsequent arrangement is unknown and is the focus of this study. Herein, we have used a murine osteocalcin-specific Vegf knockout (OcnVEGFKO) and performed ex vivo multiscale analysis at the tibiofibular junction of both sexes. Furthermore, we also deleted Vegf in vitro in OBs extracted from male and female mice in an attempt to link sex-specific matrix signatures to deviations in gene expression. Label-free and non-destructive polarisation-resolved second harmonic generation microscopy (p-SHG) revealed a reduction in collagen fibre number in males following the loss of VEGF, complemented by observable defects in matrix organisation by backscattered electron scanning electron microscopy. This was accompanied only in males by localised divergence in collagen orientation, determined by p-SHG anisotropy measurements, as a result of OcnVEGFKO. Raman spectroscopy confirmed the effect on collagen was linked to molecular dimorphic VEGF effects on collagen-specific proline and hydroxyproline, and collagen intra-stand stability, in addition to matrix carbonation and mineralisation. Vegf deletion in male and female murine OB cultures in vitro further highlighted divergence in genes regulating local ECM structure including Adamts2, Spp1, Mmp9 and Lama1 The current results demonstrate the utility of macromolecular imaging and spectroscopic modalities for the detection of collagen arrangement and ECM composition in pathological bone. Linking the sex-specific genetic regulators to matrix signatures could be important for treatment of dimorphic bone disorders which clinically manifest in both pathological nano and macro-level disorganisation

Macrosystems ecology: Understanding ecological patterns and processes at continental scales

Macrosystems ecology is the study of diverse ecological phenomena at the scale of regions to continents and their interactions with phenomena at other scales. This emerging subdiscipline addresses ecological questions and environmental problems at these broad scales. Here, we describe this new field, show how it relates to modern ecological study, and highlight opportunities that stem from taking a macrosystems perspective. We present a hierarchical framework for investigating macrosystems at any level of ecological organization and in relation to broader and finer scales. Building on well-established theory and concepts from other subdisciplines of ecology, we identify feedbacks, linkages among distant regions, and interactions that cross scales of space and time as the most likely sources of unexpected and novel behaviors in macrosystems. We present three examples that highlight the importance of this multiscaled systems perspective for understanding the ecology of regions to continents

Genetic Variation at the FTO Locus Influences RBL2 Gene Expression

OBJECTIVE - Genome-wide association studies that compare the statistical association between thousands of DNA variations and a human trait have detected 958 loci across 127 different diseases and traits. However, these statistical associations only provide evidence for genomic regions likely to harbor a causal gene(s) and do not directly identify such genes. We combined gene variation and expression data in a human cohort to identify causal genes. RESEARCH DESIGN AND METHODS - Global gene transcription activity was obtained for each individual in a large human cohort (n = 1,240). These quantitative transcript data were tested for correlation with genotype data generated from the same individuals to identify gene expression patterns influenced by the variants. RESULTS - Variant rs8050136 lies within intron 1 of the FTO gene on chromosome 16 and marks a locus strongly associated with type 2 diabetes and obesity and widely replicated across many populations. We report that genetic variation at this locus does not influence FTO gene expression levels (P = 0.38), but is strongly correlated with expression of RBL2 (P = 2.7 × 10-5), ~270,000 base pairs distant to FTO. CONCLUSIONS - These data suggest that variants at FTO influence RBL2 gene expression at large genetic distances. This observation underscores the complexity of human transcriptional regulation and highlights the utility of large human cohorts in which both genetic variation and global gene expression data are available to identify disease genes. Expedient identification of genes mediating the effects of genome-wide association study - identified loci will enable mechanism-of-action studies and accelerate understanding of human disease processes under genetic influence. © 2010 by the American Diabetes Association

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2,3,4,5,6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation

Characteristics of non-randomised studies using comparisons with external controls submitted for regulatory approval in the USA and Europe: a systematic review

Objectives: Non-randomised clinical trial designs involving comparisons against external controls or specific standards can be used to support regulatory submissions for indications in diseases that are rare, with high unmet need, without approved therapies and/or where placebo is considered unethical. The objective of this review was to summarise the characteristics of non-randomised trials submitted to the European Medicines Agency (EMA) or Food and Drug Administration (FDA) for indications in haematological cancers, haematological non-malignant conditions, stem cell transplants or rare metabolic diseases. // Methods: We conducted systematic searches of EMA databases of conditional approvals, exceptional circumstances, or orphan drug designations and FDA inventories of orphan drug designations, accelerated approvals, breakthrough therapy, fast-track and priority approvals. Products were included if reviewed by at least one agency between 2005 and 2017, the primary evidence base was non-randomised trial(s) and the indication was for haematological cancers, stem cell transplantation, haematological conditions or rare metabolic conditions. // Results: We identified 43 eligible indication-specific products using non-randomised study designs involving comparisons with external controls, submitted to the EMA (n=34) and/or FDA (n=41). Of the 43 indication-specific products, 4 involved matching external controls to the population of a non-randomised interventional study using individual patient-level data (IPD), 12 referred to external controls without IPD and 27 did not explicitly reference external controls. The FDA approved 98% of submissions, with 56% accelerated approvals; most required postapproval confirmatory randomised controlled trials (RCT). The EMA approved 79% of submissions, with a quarter of approvals conditional on completion of a postapproval RCT or additional non-randomised trials. // Conclusions: There has been a large increase in submissions to the EMA and FDA using non-randomised study designs involving comparisons with external controls in recent years. This study demonstrated that regulators may be willing to approve such submissions, although approvals are often conditional on further confirmatory evidence from postapproval studies

A linkage study of candidate loci in familial Parkinson's Disease

BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Most cases are sporadic, however familial cases do exist. We examined 12 families with familial Parkinson's disease ascertained at the Movement Disorder clinic at the Oregon Health Sciences University for genetic linkage to a number of candidate loci. These loci have been implicated in familial Parkinson's disease or in syndromes with a clinical presentation that overlaps with parkinsonism, as well as potentially in the pathogenesis of the disease. METHODS: The examined loci were PARK3, Parkin, DRD (dopa-responsive dystonia), FET1 (familial essential tremor), BDNF (brain-derived neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), Ret, DAT1 (the dopamine transporter), Nurr1 and Synphilin-1. Linkage to the α-synuclein gene and the Frontotemporal dementia with parkinsonism locus on chromosome 17 had previously been excluded in the families included in this study. Using Fastlink, Genehunter and Simwalk both parametric and model-free non-parametric linkage analyses were performed. RESULTS: In the multipoint parametric linkage analysis lod scores were below -2 for all loci except FET1 and Synphilin-1 under an autosomal dominant model with incomplete penetrance. Using non-parametric linkage analysis there was no evidence for linkage, although linkage could not be excluded. A few families showed positive parametric and non-parametric lod scores indicating possible genetic heterogeneity between families, although these scores did not reach any degree of statistical significance. CONCLUSIONS: We conclude that in these families there was no evidence for linkage to any of the loci tested, although we were unable to exclude linkage with both parametric and non-parametric methods

Penal Agnosis and Historical Denial: Problematising ‘Common Sense’ Understandings of Prison Officers and Violence in Prison

The aim of this chapter is to consider if the much-publicised ‘causal relationship’ between prison officer numbers and prisoner violence is a form of ‘penal agnosis’: the cultural production of penal ignorance (Proctor, Agnotology: a missing term to describe the cultural production of ignorance. In R. Proctor & L. Schiebinger (Eds.), Agnotology: the making and unmaking of ignorance. Stanford: Stanford University Press, 2008). My use of penal agnosis draws directly from the writings of Cohen (States of denial. Cambridge: Polity, 2001) and Mathiesen (Silently silenced. Winchester: Waterside Press, 2004). Silencing techniques deployed in everyday life help to keep people quiet and neutralise criticism. Whilst these are varied, of particular concern here is when an event becomes “isolated in the present” (Mathiesen, Silently silenced. Winchester: Waterside Press, 2004: 42), specifically contemporary media and political discussions of prison officers and prison violence. This chapter provides a theoretical context to the invisibility of historical evidence regarding the deeply embedded harms and violence of penal confinement. It focuses on how the narrative of prison staffing levels is not only time-locked but also how the current understandings of the relationship with violence are derived primarily from the perspective of prison officers. Through critique of this approach an alternative space is opened for thinking differently about how to best respond to the current harms and violence of incarceration