How to make a 350-m-thick lowstand systems tract in 17,000 years: The Late Pleistocene Po River (Italy) lowstand wedge

The 350-m-thick succession of the Po River lowstand wedge (Italy) associated with the Last Glacial Maximum (deposited over ~17 k.y) contains stratal architecture at a physical scale commonly attributed to much longer time scales, with complex, systematically varying internal clinothem characteristics. This study investigated clinothem stacking patterns and controls through the integration of seismic reflection data with sediment attributes, micropaleontology, regional climate, eustacy, and high-resolution age control possible only in Quaternary sequences. Three clinothem types are differentiated based on topset geometry, shelf-edge and onlap-point trajectory, internal seismic facies, and interpreted bottomset deposits: type A has moderate topset aggradation, ascending shelf-edge trajectory, and mass-transport bottomset deposits; type B has eroded topset, descending shelf-edge trajectory, and bottomset distributary channel-lobe complexes; and type C has maximal topset aggradation, ascending shelf-edge trajectory, and concordant bottomsets. Type A and C clinothems exhibit reduced sediment bypass and delivery to the basin, whereas type B clinothems are associated with short intervals of increased sediment export from the shelf to deeper water. Clinothems individually span a range of 0.4–4.7 k.y., contemporaneous with significant eustatic and climate changes, but their stacking patterns resemble those found in ancient successions and ascribed to significantly longer durations, indicating that (1) the response time of ancient continental margin–scale systems to high-frequency variations in accommodation and sediment supply could be as short as centuries, (2) even millennial- to centennial-scale stratal units can record substantial influence of allogenic controls, and (3) sandy deposits can be compartmentalized even in a short-duration lowstand systems tract

Large-scale response of the Eastern Mediterranean thermohaline circulation to African monsoon intensification during sapropel S1 formation

The formation of Eastern Mediterranean sapropels has periodically occurred during intensification of northern hemisphere monsoon precipitation over North Africa. However, the large-scale response of the Eastern Mediterranean thermohaline circulation during these monsoon-fuelled freshening episodes is poorly constrained. Here, we investigate the formation of the youngest sapropel (S1) along an across-slope transect in the Adriatic Sea. Foraminifera-based oxygen index, redox-sensitive elements and biogeochemical parameters reveal – for the first time – that the Adriatic S1 was synchronous with the deposition of south-eastern Mediterranean S1 beds. Proxies of paleo thermohaline currents indicate that the bottom-hugging North Adriatic Dense Water (NAdDW) suddenly decreased at the sapropel onset simultaneously with the maximum freshening of the Levantine Sea during the African Humid Period. We conclude that the lack of the “salty” Levantine Intermediate Water hampered the preconditioning of the northern Adriatic waters necessary for the NAdDW formation prior to the winter cooling. Consequently, a weak NAdDW limited in turn the Eastern Mediterranean Deep Water (EMDWAdriatic) formation with important consequences for the ventilation of the Ionian basin as well. Our results highlight the importance of the Adriatic for the deep water ventilation and the interdependence among the major eastern Mediterranean water masses whose destabilization exerted first-order control on S1 deposition

Large-scale response of the Eastern Mediterranean thermohaline circulation to African monsoon intensification during sapropel S1 formation

This study was supported by Shell International Exploration and Production Inc. We thank the R/V URANIA crew for at sea assistance. This is the ISMAR contribution n. 1914. We thank Dr. L. Capotondi and Dr. L. Vigliotti for their constructive comments on the first draft of the manuscript. We also thank Dr. Daria Pasqual (University of Padova, Dept. of Geosciences) for her assistance in XRF analyses. We thank two anonymous reviewers and the Editor H. Bauch for their constructive comments. We also acknowledge Prof. Gerhard Schmiedl (Universität Hamburg) and Associate Prof. Syee Weldeab (Earth Science, UC Santa Barbara) for providing published data used in this study.Peer reviewedPostprin

The Late Pleistocene Po River lowstand wedge in the Adriatic Sea: Controls on architecture variability and sediment partitioning

Although facies and stratal geometries of continental margin successions can be defined in detail based on subsurface and outcrop studies, most studies lack the high-resolution age control needed to constrain the time scale of formation of such successions and infer their external forcing mechanisms. Our work on the Po River Lowstand Wedge (PRLW) indicates that deposition rates are surprisingly high with the entire 350-m-thick succession being deposited in less than 17,000 years, and with individual clinothems recording time periods ranging from 400 to 4700 years. The PRLW preserves a high-resolution record of stacked, deltaic shelf-edge clinothems deposited during the Last Glacial Maximum (31.8–14.4 ky BP) in the Adriatic basin (Mediterranean Sea). We investigated clinothem internal geometry, stacking patterns, and facies distributions to infer the main controls on their growth by integrating seismic reflection data with seismic facies attributes and paleoenvironmental proxies. The stratigraphic framework of the shelf-edge clinothems was then related to major paleoenvironmental shifts during the last glacial cycle and driven by eustatic and climatic changes. Within the PRLW, we recognized three distinctive types of 100's-m-high shelf-edge clinothems, type A, type B and type C, each with diagnostic topset geometries, shelf-edge trajectories, and associated distal basin-fill deposits. These elemental clinothem types stack into two Clinothem Sets. Clinothem Set 1, with essentially flat to slightly descending shelf-edge trajectory, is composed of stacked types A and B clinothems, and records the direct influence of river flux leading to dysoxic conditions on the bottom of the basin. In particular, clinothem accumulation rates were as much as 200 km3/ky in some of the type B clinothems. Clinothem Set 2, showing ascending shelf-edge trajectory, records an aggradational stacking coupled with a retreat of the river-entry points with benthic fauna assemblages that reflect the influence of peaks in freshwater discharge. Whereas Clinothem Set 1 developed under perturbations of river supply linked to the multi-scale waxing and waning of glaciers during an interval dominated by eustatic fall, Clinothem Set 2 reflects the main thawing of glaciers concomitant to the first phase of the eustatic rise. From a sequence stratigraphic perspective, Clinothem Set 1 is interpreted as staked high-frequency sequences, while Clinothem Set 2 represents a stack of high-frequency parasequences. The high-resolution age control from boreholes and seismic data enabled us to relate stratal character to independently constrained environmental proxies: this revealed how the evolution of a shelf-edge system intricately convolves the influences of both global (eustacy) and regional (climate-driven supply fluctuations) controls, both at sub-Milankovitch scales. Finally, the thickness, geometry, and stacking patterns of the centennial to millennial clinothems of the PRLW vary in systematic ways resulting in geometries that closely resemble those of ancient shelf-edge systems, and offering the PRLW as a sub-modern analogue. Our observations also reinforce the focus of the classic sequence-stratigraphic approach on analyzing surfaces and their geometric relations and not on time duration or formation mechanisms

VKORC1 mutation in European populations of Rattus norvegicus with first data for Italy and the report of a new amino acidic substitution

In the Norway rat, Rattus norvegicus, anticoagulant rodenticide resistance is mainly associated with mutations in the third exon of the Vitamin K epoxide reductase complex subunit 1 (VKORC1). Identification of the resistant wild populations is very important to improve the control practices and to limit the damages due to inadequate use of the anticoagulant rodenticide. In this study, we determined the distribution of the third exon mutations in poorly investigated areas of Africa, Europe and the Middle East. In particular, we investigated the phenomenon for the first time in the Italian peninsula. We obtained sequences of the third exon for 133 Norway rats from 37 localities in Africa, Europe and the Middle East. For additional analysis, we retrieved information in literature on amino acid substitution in 1136 third exon sequences of Norway rats from Europe, the Far East, North America and South America. However, we found third exon mutations only in Europe and the Far East with the Y139F mutation shared between the two areas. Europe has the higher number of mutant individuals and Y139C mutation prevails. In Italy, we found a single missense mutation (I123S) in a Venetian locality. This homozygote mutation, is not know in literature to be associated with resistance, but it is very similar to a mutation that confers resistance in humans (I123N). This similarity and its high local frequency makes it a good candidate for future testing. Our results provide useful data to better understand the resistance phenomenon and to plan targeted control actions

Survival Risk Scores for Real-Life Relapsed/Refractory Multiple Myeloma Patients Receiving Elotuzumab or Carfilzomib In Combination With Lenalidomide and Dexamethasone as Salvage Therapy: Analysis of 919 Cases Outside Clinical Trials

The present study aimed to develop two survival risk scores (RS) for overall survival (OS, SRSKRd/EloRd) and progression-free survival (PFS, PRSKRd/EloRd) in 919 relapsed/refractory multiple myeloma (RRMM) patients who received carfilzomib, lenalidomide, and dexamethasone (KRd)/elotuzumab, lenalidomide, and dexamethasone (EloRd). The median OS was 35.4 months, with no significant difference between the KRd arm versus the EloRd arm. In the multivariate analysis, advanced ISS (HR = 1.31; P = 0.025), interval diagnosis–therapy (HR = 1.46; P = 0.001), number of previous lines of therapies (HR = 1.96; P < 0.0001), older age (HR = 1.72; P < 0.0001), and prior lenalidomide exposure (HR = 1.30; P = 0.026) remained independently associated with death. The median PFS was 20.3 months, with no difference between the two strategies. The multivariate model identified a significant progression/death risk increase for ISS III (HR = 1.37; P = 0.002), >3 previous lines of therapies (HR = 1.67; P < 0.0001), older age (HR = 1.64; P < 0.0001), and prior lenalidomide exposure (HR = 1.35; P = 0.003). Three risk SRSKRd/EloRd categories were generated: low-risk (134 cases, 16.5%), intermediate-risk (467 cases, 57.3%), and high-risk categories (213 cases, 26.2%). The 1- and 2-year OS probability rates were 92.3% and 83.8% for the low-risk (HR = 1, reference category), 81.1% and 60.6% (HR = 2.73; P < 0.0001) for the intermediate-risk, and 65.5% and 42.5% (HR = 4.91; P < 0.0001) for the high-risk groups, respectively. Notably, unlike the low-risk group, which did not cross the median timeline, the OS median values were 36.6 and 18.6 months for the intermediate- and high-risk cases, respectively. Similarly, three PRSKRd/EloRd risk categories were engendered. Based on such grouping, 338 (41.5%) cases were allocated in the low-, 248 (30.5%) in the intermediate-, and 228 (28.0%) in the high-risk groups. The 1- and 2-year PFS probability rates were 71.4% and 54.5% for the low-risk (HR = 1, reference category), 68.9% and 43.7% (HR = 1.95; P < 0.0001) for the intermediate-risk, and 48.0% and 27.1% (HR = 3.73; P < 0.0001) for the high-risk groups, respectively. The PFS median values were 29.0, 21.0, and 11.7 months for the low-, intermediate-, and high-risk cases. This analysis showed 2.7- and 4.9-fold increased risk of death for the intermediate- and high-risk cases treated with KRd/EloRd as salvage therapy. The combined progression/death risks of the two categories were increased 1.3- and 2.2-fold compared to the low-risk group. In conclusion, SRSKRd/EloRd and PRSKRd/EloRd may represent accessible and globally applicable models in daily clinical practice and ultimately represent a prognostic tool for RRMM patients who received KRd or EloRd

Metabolomics with LC-QTOF-MS Permits the Prediction of Disease Stage in Aortic Abdominal Aneurysm Based on Plasma Metabolic Fingerprint

Abdominal aortic aneurysm (AAA) is a permanent and localized aortic dilation, defined as aortic diameter ≥3 cm. It is an asymptomatic but potentially fatal condition because progressive enlargement of the abdominal aorta is spontaneously evolving towards rupture

Identification of Synaptic Targets of Drosophila Pumilio

Drosophila Pumilio (Pum) protein is a translational regulator involved in embryonic patterning and germline development. Recent findings demonstrate that Pum also plays an important role in the nervous system, both at the neuromuscular junction (NMJ) and in long-term memory formation. In neurons, Pum appears to play a role in homeostatic control of excitability via down regulation of para, a voltage gated sodium channel, and may more generally modulate local protein synthesis in neurons via translational repression of eIF-4E. Aside from these, the biologically relevant targets of Pum in the nervous system remain largely unknown. We hypothesized that Pum might play a role in regulating the local translation underlying synapse-specific modifications during memory formation. To identify relevant translational targets, we used an informatics approach to predict Pum targets among mRNAs whose products have synaptic localization. We then used both in vitro binding and two in vivo assays to functionally confirm the fidelity of this informatics screening method. We find that Pum strongly and specifically binds to RNA sequences in the 3′UTR of four of the predicted target genes, demonstrating the validity of our method. We then demonstrate that one of these predicted target sequences, in the 3′UTR of discs large (dlg1), the Drosophila PSD95 ortholog, can functionally substitute for a canonical NRE (Nanos response element) in vivo in a heterologous functional assay. Finally, we show that the endogenous dlg1 mRNA can be regulated by Pumilio in a neuronal context, the adult mushroom bodies (MB), which is an anatomical site of memory storage

IL21R expressing CD14+CD16+ monocytes expand in multiple myeloma patients leading to increased osteoclasts

Bone marrow monocytes are primarily committed to osteoclast formation. It is, however, unknown whether potential primary alterations are specifically present in bone marrow monocytes of multiple myeloma patients, smoldering myeloma or monoclonal gammopathy of uncertain significance. Herein, we analyzed the immunophenotypic and transcriptional profiles of bone marrow CD14+ monocytes in a cohort of patients with different types of monoclonal gammopathies to identify alterations involved in myeloma-enhanced osteoclastogenesis. A higher number of bone marrow CD14+CD16+ cells was found in patients with active myeloma as compared to those with smoldering myeloma and monoclonal gammopathy of uncertain significance. Interestingly, sorted bone marrow CD14+CD16+ cells from myeloma patients were more pro-osteoclastogenic than CD14+CD16- cells in cultures ex vivo. Moreover, transcriptional analysis demonstrated that bone marrow multiple myeloma (but neither monoclonal gammopathy of uncertain significance nor smoldering myeloma) CD14+ cells significantly upregulated genes involved in osteoclast formation, including IL21R. IL21R mRNA over-expression by bone marrow CD14+ cells was independent from the presence of IL-21. Consistently, IL-21 production by T cells as well as IL-21 bone marrow levels were not significantly different among monoclonal gammopathies. Thereafter, we showed that IL21R over-expression in CD14+ cells increased osteoclast formation. Consistently, IL-21R signaling inhibition by Janex 1 suppressed osteoclast differentiation from bone marrow CD14+ cells of myeloma patients. Our results indicated that multiple myeloma patients showed distinct bone marrow monocyte features compared to those with indolent monoclonal gammopathies, supporting the role of IL21R over-expression by bone marrow CD14+ cells in enhanced osteoclast formation