Detection and characterisation of Eemian marine tephra layers within the sapropel S5 sediments of the Aegean and Levantine Seas

The Eemian was the last interglacial period (~130 to 115 ka BP) to precede the current interglacial. In Eastern Mediterranean marine sediments, it is marked by a well-developed and organic-rich “sapropel” layer (S5), which is thought to reflect an intensification and northward migration of the African monsoon rain belt over orbital timescales. However, despite the importance of these sediments, very little proxy-independent stratigraphic information is available to enable rigorous correlation of these sediments across the region. This paper presents the first detailed study of visible and non-visible (cryptotephra) layers found within these sediments at three marine coring sites: ODP Site 967B (Levantine Basin), KL51 (South East of Crete) and LC21 (Southern Aegean Sea). Major element analyses of the glass component were used to distinguish four distinct tephra events of Santorini (e.g., Vourvoulos eruption) and possible Anatolian provenance occurring during the formation of S5. Interpolation of core chronologies provides provisional eruption ages for the uppermost tephra (unknown Santorini, 121.8 ± 2.9 ka) and lowermost tephra (Anatolia or Kos/Yali/Nisyros, 126.4 ± 2.9 ka). These newly characterised tephra deposits have also been set into the regional tephrostratigraphy to illustrate the potential to precisely synchronise marine proxy records with their terrestrial counterparts, and also contribute to the establishment of a more detailed volcanic history of the Eastern Mediterranean

An evaluation of Minor Groove Binders as anti-lung cancer therapeutics

A series of 47 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for anti-lung cancer activity by screening against the melanoma cancer cell line B16-F10. Five compounds have been found to possess significant activity, more so than a standard therapy, Gemcitabine. Moreover, one compound has been found to have an activity around 70-fold that of Gemcitabine and has a favourable selectivity index of greater than 125. Furthermore, initial studies have revealed this compound to be metabolically stable and thus it represents a lead for further optimisation towards a novel treatment for lung cance

Advancing Santorini’s tephrostratigraphy: new glass geochemical data and improved marine-terrestrial tephra correlations for the past ∼360 kyrs

The island of Santorini in the Aegean Sea is one of the world’s most violent active volcanoes. Santorini has produced numerous highly explosive eruptions over at least the past ∼360 kyrs that are documented by the island’s unique proximal tephra record. However, the lack of precise eruption ages and comprehensive glass geochemical datasets for proximal tephras has long hindered the development of a detailed distal tephrostratigraphy for Santorini eruptions. In light of these requirements, this study develops a distal tephrostratigraphy for Santorini covering the past ∼360 kyrs, which represents a major step forward towards the establishment of a tephrostratigraphic framework for the Eastern Mediterranean region. We present new EPMA glass geochemical data of proximal tephra deposits from twelve Plinian and numerous Inter-Plinian Santorini eruptions and use this dataset to establish assignments of 28 distal marine tephras from three Aegean Sea cores (KL49, KL51 and LC21) to specific volcanic events. Based on interpolation of sapropel core chronologies we provide new eruption age estimates for correlated Santorini tephras, including dates for major Plinian eruptions, Upper Scoriae 1 (80.8 ± 2.9 ka), Vourvoulos (126.5 ± 2.9 ka), Middle Pumice (141.0 ± 2.6 ka), Cape Thera (156.9 ± 2.3 ka), Lower Pumice 2 (176.7 ± 0.6 ka), Lower Pumice 1 (185.7 ± 0.7 ka), and Cape Therma 3 (200.2 ± 0.9 ka), but also for 17 Inter-Plinian events. Older Plinian and Inter-Plinian activity between ∼310 ka and 370 ka, documented in the distal terrestrial setting of Tenaghi Philippon (NE Greece), is independently dated by palynostratigraphy and complements the distal Santorini tephrostratigraphic record

Penultimate deglacial warming across the Mediterranean Sea revealed by clumped isotopes in foraminifera

The variability of seawater temperature through time is a critical measure of climate change, yet its reconstruction remains problematic in many regions. Mg/Ca and oxygen isotope (δ^18 Oc) measurements in foraminiferal carbonate shells can be combined to reconstruct seawater temperature and δ^18 O (δ^18 OSW). The latter is a measure of changes in local hydrology (e.g., precipitation/evaporation, freshwater inputs) and global ice volume. But diagenetic processes may affect foraminiferal Mg/Ca. This restricts its potential in many places, including the Mediterranean Sea, a strategic region for deciphering global climate and sea-level changes. High alkalinity/salinity conditions especially bias Mg/Ca temperatures in the eastern Mediterranean (eMed). Here we advance the understanding of both western Mediterranean (wMed) and eMed hydrographic variability through the penultimate glacial termination (TII) and last interglacial, by applying the clumped isotope (Δ47) paleothermometer to planktic foraminifera with a novel data-processing approach. Results suggest that North Atlantic cooling during Heinrich stadial 11 (HS11) affected surface-water temperatures much more in the wMed (during winter/spring) than in the eMed (during summer). The method’s paired Δ47 and δ^18 Oc data also portray δ^18 OSW. These records reveal a clear HS11 freshwater signal, which attenuated toward the eMed, and also that last interglacial surface warming in the eMed was strongly amplified by water-column stratification during the deposition of the organic-rich (sapropel) interval known as S5.Tis study was supported by Swiss National Science Foundation projects SNSF 200020_160046 and IZK0Z2_160377, ETH project No. ETH-33 14-1, ANZIC-IODP project ARIES30735 (K.M.G. & L.R.-S.), and Australian Research Council Australian Laureate Fellowship FL120100050 (E.J.R)

Asynchronous Antarctic and Greenland ice-volume contributions to the last interglacial sea-level highstand

The last interglacial (LIG; ~130 to ~118 thousand years ago, ka) was the last time global sea level rose well above the present level. Greenland Ice Sheet (GrIS) contributions were insufficient to explain the highstand, so that substantial Antarctic Ice Sheet (AIS) reduction is implied. However, the nature and drivers of GrIS and AIS reductions remain enigmatic, even though they may be critical for understanding future sea-level rise. Here we complement existing records with new data, and reveal that the LIG contained an AIS-derived highstand from ~129.5 to ~125 ka, a lowstand centred on 125–124 ka, and joint AIS + GrIS contributions from ~123.5 to ~118 ka. Moreover, a dual substructure within the first highstand suggests temporal variability in the AIS contributions. Implied rates of sea-level rise are high (up to several meters per century; m c−1), and lend credibility to high rates inferred by ice modelling under certain ice-shelf instability parameterisations.Universidade de VigoAustralian Research Council Laureate Fellowship | Ref. FL120100050RCN project THRESHOLDS | Ref. 2549

Leadership and the media: Gendered framings of Julia Gillard's ‘sexism and misogyny’ speech

This article analyses Australian media portrayals of former Australian Prime Minister Julia Gillard's ‘sexism and misogyny’ speech to parliament in October 2012. Our analysis reveals that coverage of the speech comprised three principal gendered framings: strategic attack, uncontrolled emotional outpouring and hypocrisy. We argue that these framings demonstrate the role the media plays as a gendered mediator, perpetuating the gender double bind that constrains female political leaders, as they negotiate the demand to demonstrate masculine leadership attributes without tarnishing the feminine qualities expected of them. In this instance, gendered media framings limited the saliency of Gillard's speech, curtailed calls for wider introspection on Australian political culture and further disassociated women from political leadership

Accurately calibrated X-ray fluorescence core scanning (XRF-CS) record of Ti ∕ Al reveals Early Pleistocene aridity and humidity variability over North Africa and its close relationship to low-latitude insolation

In eastern Mediterranean sediments, the titanium-to-aluminum ratio (Ti/Al) captures relative variability in eolian to river-derived material and predominantly integrates climate signals over the Saharan and Sahel regions. Long Ti/Al time series can, therefore, provide valuable records of North African humidity and aridity changes. X-ray fluorescence core scanning (XRF-CS) can generate near-continuous Ti/Al records with relatively modest effort and in an acceptable amount of time, provided that accurate Ti/Al values are acquired. Calibration of raw XRF-CS data to those of established analytical methods is an important pathway for obtaining the required accuracy. We assess how to obtain reliable XRF-CS Ti/Al calibration by using different calibration reference sample sets for a long sediment record from ODP Site 967 (eastern Mediterranean Sea). The accuracy of reference concentrations and the number of reference samples are important for reliable calibration. Our continuous Ti/Al record allows detailed time series analysis over the past 3g€¯Myr. Near-direct control of low-latitude insolation on the timing and amplitude of North African aridity and humidity is observed from 3 to g1/4g€¯1.2g€¯Ma. In our Ti/Al record, most arid North African intervals (i.e., with the longest period and highest amplitude) occur after the mid-Pleistocene transition (MPT; g1/4g€¯1.2-0.7g€¯Ma), when ice ages intensified. We also observe a subdued relationship between low-latitude insolation and North African climate after the MPT. These findings support the growing consensus that African climate became more sensitive to remote high-latitude climate when a threshold ice volume was reached during the MPT

Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells

During chronic liver injury hepatic stellate cells (HSCs), the principal source of extracellular matrix in the fibrotic liver, transdifferentiate into pro-fibrotic myofibroblast-like cells - a process potentially regulated by microRNAs (miRNAs). Recently, we found serum miRNA-25-3p (miR-25) levels were upregulated in children with Cystic Fibrosis (CF) without liver disease, compared to children with CF-associated liver disease and healthy individuals. Here we examine the role of miR-25 in HSC biology. MiR-25 was detected in the human HSC cell line LX-2 and in primary murine HSCs, and increased with culture-induced activation. Transient overexpression of miR-25 inhibited TGF-β and its type 1 receptor (TGFBR1) mRNA expression, TGF-β-induced Smad2 phosphorylation and subsequent collagen1α1 induction in LX-2 cells. Pull-down experiments with biotinylated miR-25 revealed Notch signaling (co-)activators ADAM-17 and FKBP14 as miR-25 targets in HSCs. NanoString analysis confirmed miR-25 regulation of Notch- and Wnt-signaling pathways. Expression of Notch signaling pathway components and endogenous Notch1 signaling was downregulated in miR-25 overexpressing LX-2 cells, as were components of Wnt signaling such as Wnt5a. We propose that miR-25 acts as a negative feedback anti-fibrotic control during HSC activation by reducing the reactivity of HSCs to TGF-β-induced collagen expression and modulating the cross-talk between Notch, Wnt and TGF-β signaling

Profiling sulfur(VI) fluorides as reactive functionalities for chemical biology tools and expansion of the ligandable proteome

Here, we report a comprehensive profiling study of sulfur(VI) fluorides (SVI-F) in the context of multiple chemical biology applications and illustrate that these motifs present an exciting opportunity to develop tools for a wide scope of protein targets. SVI-Fs are reactive functionalities that offer utility for targeting almost any protein, as they can modify multiple residues including Lys, Tyr, His and Ser. A panel of SVI-F functionalities were studied with respect to hydrolytic stability and reactivity with nucleophilic amino acids. Subsequently, the reactivity of SVI-Fs with CAII and kinase proteins was investigated, in the context of both fragment binders and optimized probes. Finally, the performance of the SVI-F panel in chemoproteomic workflows was analyzed. The studies provided an in-depth understanding of the hydrolytic stability, protein reactivity and chemoproteomic utility of SVI-F functionalities that are suitable for direct incorporation into chemical tools. Such insights offer a valuable guide for the prospective design of SVI-F-containing ligands for various chemical biology workflows and demonstrate the wide range of proteins that SVI-Fs can capture, thus highlighting the opportunity for SVI-Fs to expand the liganded proteome

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis