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The Antarctic Circumpolar Current (ACC) represents the world’s largest ocean-current system and affects global ocean circulation, climate and Antarctic ice-sheet stability1–3. Today, ACC dynamics are controlled by atmospheric forcing, oceanic density gradients and eddy activity4. Whereas palaeoceanographic reconstructions exhibit regional heterogeneity in ACC position and strength over Pleistocene glacial–interglacial cycles5–8, the long-term evolution of the ACC is poorly known. Here we document changes in ACC strength from sediment cores in the Pacific Southern Ocean. We find no linear long-term trend in ACC flow since 5.3 million years ago (Ma), in contrast to global cooling9and increasing global ice volume10. Instead, we observe a reversal on a million-year timescale, from increasing ACC strength during Pliocene global cooling to a subsequent decrease with further Early Pleistocene cooling. This shift in the ACC regime coincided with a Southern Ocean reconfiguration that altered the sensitivity of the ACC to atmospheric and oceanic forcings11–13. We find ACC strength changes to be closely linked to 400,000-year eccentricity cycles, probably originating from modulation of precessional changes in the South Pacific jet stream linked to tropical Pacific temperature variability14. A persistent link between weaker ACC flow, equatorward-shifted opal deposition and reduced atmospheric CO2during glacial periods first emerged during the Mid-Pleistocene Transition (MPT). The strongest ACC flow occurred during warmer-than-present intervals of the Plio-Pleistocene, providing evidence of potentially increasing ACC flow with future climate warming.

The fossil record of cetaceans documents how terrestrial animals acquired extreme adaptations and transitioned to a fully aquatic lifestyle1,2. In whales, this is associated with a substantial increase in maximum body size. Although an elongate body was acquired early in cetacean evolution3, the maximum body mass of baleen whales reflects a recent diversification that culminated in the blue whale4. More generally, hitherto known gigantism among aquatic tetrapods evolved within pelagic, active swimmers. Here we describe Perucetus colossus—a basilosaurid whale from the middle Eocene epoch of Peru. It displays, to our knowledge, the highest degree of bone mass increase known to date, an adaptation associated with shallow diving5. The estimated skeletal mass of P. colossusexceeds that of any known mammal or aquatic vertebrate. We show that the bone structure specializations of aquatic mammals are reflected in the scaling of skeletal fraction (skeletal mass versus whole-body mass) across the entire disparity of amniotes. We use the skeletal fraction to estimate the body mass of P. colossus, which proves to be a contender for the title of heaviest animal on record. Cetacean peak body mass had already been reached around 30 million years before previously assumed, in a coastal context in which primary productivity was particularly high.

The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS–STING (cyclic GMP-AMP synthase–signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma.

Strata of Chilcatay and Pisco formations exposed in the Ica Desert (East Pisco Basin, southern Peru) preserve one of the most complete and rich records of Miocene marine vertebrates of the world. Despite its exceptional importance, the chronostratigraphy of these fossil-bearing deposits has been only sporadically studied in the literature until recently. This work presents a detailed reconstruction of the chronostratigraphic framework, achieved by mapping and logging of seven sections of the Miocene Chilcatay and Pisco formations along the western side of the Ica River. The Chilcatay Formation consists of two allomembers, namely Ct1 and Ct2, bounded at the base by unconformities CE0.1 and CE0.2, respectively. Similarly, the immediately overlying Pisco Formation is divided into allomembers P0, P1, and P2, bounded at the base by unconformities PE0.0, PE0.1 and PE0.2, respectively. The new 39Ar–40Ar results presented here, combined with ages of previous work, provide precise constraints on the age of several stratigraphically referenced volcanic ash layers intercalated in the studied fossil-bearing succession, placing its vertebrate fossil fauna within a refined temporal framework and laying the solid ground for its detailed regional and global comparison. The ages of the allomembers, and thus their associated faunas, can be reliably estimated by the combination of 39Ar–40Ar dating on tephra layers with diatom biostratigraphy. In the study area, the two methods are mutually consistent and constrain the deposition of the Chilcatay Formation between 19.2 and 18.0 Ma, that of P1 between 9.5 and 8.6 Ma, and that of P2 between 8.4 and 6.7 Ma. In the absence of direct dating of the P0 allomember, which lacks both preserved tephra suitable for 39Ar–40Ar dating and microfossils, its age can be constrained to the temporal gap between the youngest age available from the underlying Chilcatay strata (18.0 Ma) and the oldest age available from the overlying P1 strata (9.5 Ma).

Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters.

Natural gas hydrate is ice‐like mixture of gas (mostly methane) and water that is widely found in sediments along the world's continental margins and within and beneath permafrost and glaciers in a near‐surface depth interval where the pressure is sufficiently high and temperature sufficiently low for gas hydrate to be stable. We categorize the myriad of geological gas hydrate deposits into five characteristic types. We then review the multiple quantitative models that have proposed to describe the genesis of these deposits and describe how each may have formed. We emphasize the importance of coupling multiphase flow (free gas and liquid water) and multicomponent reactive transport with geological history to describe the dynamical processes of gas hydrate formation and evolution in geological systems. A better insight into the kinetics of methane formation from microbial biogenesis and the processes of multiphase flow at the pore scale will advance our knowledge of how these systems form. By understanding the generation and evolution of gas hydrate through time, we will better decipher the role of gas hydrate in the carbon cycle, its potential to contribute to climate change and geohazards, and how to design optimal strategies for gas production from hydrate reservoirs. Scientific drillings and geophysical investigations have revealed various occurrences of gas hydrate under the seafloor and within and beneath permafrost. We summarize their key features and categorize their occurrences into five major types. We then review the different quantitative models that have been developed to explain their formation in the field and link different models to field observations. We identify the key advances achieved, the major remaining challenges, and the efforts required to further understand the formation of gas hydrate in geological systems. This knowledge can help us learn the role of gas hydrate in natural environments. Geological gas hydrate deposits can be categorized into five major types and tied to six different formation mechanismsFree gas flow and capillary pressure play significant roles in forming many concentrated hydrate depositsA better understanding of microbial methanogenesis will illuminate how methane hydrate deposits are formed in geological systems

During wound repair, branching morphogenesis and carcinoma dissemination, cellular rearrangements are fostered by a solid-to-liquid transition, known as unjamming. The biomolecular machinery behind unjamming and its pathophysiological relevance remain, however, unclear. Here, we study unjamming in a variety of normal and tumorigenic epithelial two-dimensional (2D) and 3D collectives. Biologically, the increased level of the small GTPase RAB5A sparks unjamming by promoting non-clathrin-dependent internalization of epidermal growth factor receptor that leads to hyperactivation of the kinase ERK1/2 and phosphorylation of the actin nucleator WAVE2. This cascade triggers collective motility effects with striking biophysical consequences. Specifically, unjamming in tumour spheroids is accompanied by persistent and coordinated rotations that progressively remodel the extracellular matrix, while simultaneously fluidizing cells at the periphery. This concurrent action results in collective invasion, supporting the concept that the endo-ERK1/2 pathway is a physicochemical switch to initiate collective invasion and dissemination of otherwise jammed carcinoma.

Detector stochastic deviations from an ideal response can hamper the measurement of quantum properties of light, especially in the mesoscopic regime where photon-number resolution is required. We demonstrate that, by proper analysis of the output signal, nonclassicality of twin-beam states can be detected and exploited with commercial and cost-effective silicon-based photon-number-resolving detectors.

We applied a cyclostratigraphic analysis to a late Albian – late Cenomanian Tethyan section (Monte Petrano) from the Umbria-Marche Basin. Starting from a high-resolution (mm-scale) lithological log, estimated calcium carbonate contents were used as input data for cyclostratigraphy. The orbital tuning was based on long and short eccentricity, obliquity and precessional components and was tied to a radiometric age of 93.9 ± 0.15 Ma (2s) of the Cenomanian/Turonian boundary. The estimated variations in sedimentation rates allowed for constructing an anchored astrochronology of the composite Albian – Cenomanian d13C record. Our estimates of the total duration of the Albian and Cenomanian stages are about 14.20 ± 0.86 Myr and about 4.94 ± 0.35 Myr, respectively. The Aptian/Albian boundary lies at 113.04 ± 0.94 Ma and the Albian/Cenomanian boundary at 98.84 ± 0.35 Ma. Moreover, according to our results, OAE1d lasted about 1.21 ± 0.17 Myr (from 100.11 ± 0.41 Ma to 98.90 ± 0.35 Ma). We obtained an astronomical tuned age of 96.28 ± 0.28 Ma to 96.12 ± 0.27 Ma for the MCE I with a total duration of the event of about 166 ± 20 kyr. Astronomical cyclicities and climatic conditions exerted a direct influence on the depositional style of the studied geological record. Orbitally-paced variation in insolation controlled the variability in monsoon intensity, with maximum in monsoon strength during insolation maxima. Under humid climatic conditions, the orbitally-paced variations in summer monsoon precipitation controlled the amount of runoff and transportation of fine-grained detrital sediments in the basin, thus modulating the alternate deposition of marls and carbonate-rich sediments. During arid climate periods, the fluctuations in winter monsoon intensity controlled the variations in wind-blown dust availability and the fluctuations in ocean fertilization with times of enhanced siliceous productivity under eutrophic conditions and carbonate productivity under oligotrophic conditions.

We hypothesized that in glioblastoma recurring after radiotherapy, a condition whereby the brain endothelium undergoes radiation-induced senescence, tumor cells with endothelial phenotype may be relevant for tumor neovascularization. Matched glioblastoma samples obtained at primary surgery and at surgery for tumor recurrence after radiotherapy, all expressing epidermal growth factor receptor variant III (EGFRvIII), were assessed by a technique that combines fluorescent in situ hybridization (FISH) for the EGFR/CEP7chromosomal probe with immunostaining for endothelial cells (CD31) and activated pericytes (α Smooth Muscle Actin). Five EGFRvIII-expressing paired primary/recurrent glioblastoma samples, in which the tumor cells showed EGFR/CEP7amplification, were then assessed by CD31 and α Smooth Muscle Actin immunofluorescence. In glomeruloid bodies, the ratio between CD31+ cells with amplified EGFR/CEP7signal and the total CD31+ cells was 0.23 ± 0.09 (mean ± sem) and 0.63 ± 0.07 in primary tumors and in recurrent ones, respectively (p< 0.002, Student-ttest). In capillaries, the ratio of CD31+ cells with amplified EGFR/CEP7over the total CD31+ cells lining the capillary lumen was 0.21 ± 0.06 (mean ± sem) and 0.42 ± 0.07 at primary surgery and at recurrence, respectively (p< 0.005, Student-ttest). Expression of α Smooth Muscle Actin by cells with EGFR/CEP7amplification was not observed. Then, in glioblastoma recurring after radiotherapy, where the brain endothelium suffers from radiation-induced cell senescence, tumor-derived endothelium plays a role in neo-vascularization.

We hypothesized that in glioblastoma recurring after radiotherapy, a condition whereby the brain endothelium undergoes radiation-induced senescence, tumor cells with endothelial phenotype may be relevant for tumor neovascularization. Matched glioblastoma samples obtained at primary surgery and at surgery for tumor recurrence after radiotherapy, all expressing epidermal growth factor receptor variant III (EGFRvIII), were assessed by a technique that combines fluorescent in situ hybridization (FISH) for the EGFR/CEP7chromosomal probe with immunostaining for endothelial cells (CD31) and activated pericytes (α Smooth Muscle Actin). Five EGFRvIII-expressing paired primary/recurrent glioblastoma samples, in which the tumor cells showed EGFR/CEP7amplification, were then assessed by CD31 and α Smooth Muscle Actin immunofluorescence. In glomeruloid bodies, the ratio between CD31+ cells with amplified EGFR/CEP7signal and the total CD31+ cells was 0.23 ± 0.09 (mean ± sem) and 0.63 ± 0.07 in primary tumors and in recurrent ones, respectively (p< 0.002, Student-ttest). In capillaries, the ratio of CD31+ cells with amplified EGFR/CEP7over the total CD31+ cells lining the capillary lumen was 0.21 ± 0.06 (mean ± sem) and 0.42 ± 0.07 at primary surgery and at recurrence, respectively (p< 0.005, Student-ttest). Expression of α Smooth Muscle Actin by cells with EGFR/CEP7amplification was not observed. Then, in glioblastoma recurring after radiotherapy, where the brain endothelium suffers from radiation-induced cell senescence, tumor-derived endothelium plays a role in neo-vascularization.

In geophysical inverse problems, the distribution of physical properties in an Earth model is inferred from a set of measured data. A necessary step is to select data that are best suited to the problem at hand. This step is performed ahead of solving the inverse problem, generally on the basis of expert knowledge. However, expert‐opinion can introduce bias based on pre‐conceptions. Here we apply a trans‐dimensional algorithm to automatically weigh data on the basis of how consistent they are with the fundamental hypotheses made to solve the inverse problem. We demonstrate this approach by inverting arrival times for the location of a seismic source in an elastic half‐space, assuming a point‐source and uniform weights in concentric shells. The key advantage is that the data do no longer need to be selected by an expert, but they are assigned varying weights during the inversion procedure. In the Big data era, automated approaches to data evaluation are needed for two main reasons: to be able to process a large amount of data in a limited time, and to avoid bias introduced by data analysists. In this study we present a novel approach to data analysis, where the data themselves measure their consistency with our hypotheses. The approach is applied to earthquake location in mines, where millions of seismic events occur every year, and automatic processing of seismic data is mandatory. We demonstrate that our approach outperforms standard ones when almost nothing is known about the data and their measurement errors. We develop a novel approach for automatic weighting of data in geophysical inverse problems, based on a trans‐dimensional algorithmWe apply the novel approach to seismic event location in mines, obtaining consistent results compared to a more standard methodOur approach outperforms standard seismic monitoring approaches, when limited information are available on local seismic structure We develop a novel approach for automatic weighting of data in geophysical inverse problems, based on a trans‐dimensional algorithm We apply the novel approach to seismic event location in mines, obtaining consistent results compared to a more standard method Our approach outperforms standard seismic monitoring approaches, when limited information are available on local seismic structure

The black-box nature of most artificial intelligence (AI) models encourages the development of explainability methods to engender trust into the AI decision-making process. Such methods can be broadly categorized into two main types: post hoc explanations and inherently interpretable algorithms. We aimed at analyzing the possible associations between COVID-19 and the push of explainable AI (XAI) to the forefront of biomedical research. We automatically extracted from the PubMed database biomedical XAI studies related to concepts of causality or explainability and manually labeled 1,603 papers with respect to XAI categories. To compare the trends pre- and post-COVID-19, we fit a change point detection model and evaluated significant changes in publication rates. We show that the advent of COVID-19 in the beginning of 2020 could be the driving factor behind an increased focus concerning XAI, playing a crucial role in accelerating an already evolving trend. Finally, we present a discussion with future societal use and impact of XAI technologies and potential future directions for those who pursue fostering clinical trust with interpretable machine learning models.

Methane hydrates in fine‐grained continental slope sediments often occupy isolated depth intervals surrounded by hydrate‐free sediments. As they are not connected to deep gas sources, these hydrate deposits have been interpreted as sourced by in situ microbial methane. We investigate here the hypothesis that these isolated hydrate accumulations form preferentially in sediments deposited during Pleistocene glacial lowstands that contain relatively large amounts of labile particulate organic carbon, leading to enhanced microbial methanogenesis. To test this hypothesis, we apply an advection‐diffusion‐reaction model with a time‐dependent organic carbon deposition controlled by glacioeustatic sea level variations. In the model, hydrate forms in sediments with greater organic carbon content deposited during the penultimate glacial cycle (~120–240 ka). The model predictions match hydrate‐bearing intervals detected in three sites drilled on the northern Gulf of Mexico continental slope, supporting the hypothesis of hydrate formation driven by enhanced organic carbon burial during glacial lowstands. Natural methane hydrates, ice‐like compounds of water and methane, are widespread in continental margin sediments. We show here evidence for the hypothesis that methane hydrates form preferentially in sediments deposited during glacial periods, which contain more organic matter that is converted to methane by microbes. Methane hydrates within continental slope sediments often occupy isolated depth intervalsHydrate‐bearing intervals may be formed by enhanced methanogenesis in organic carbon‐rich sediments deposited during glacial lowstandsModeling driven by higher organic carbon deposition during lowstands matches hydrate‐bearing intervals observed in Gulf of Mexico boreholes

The Mio – Pliocene Pisco Formation, Peru, is a world renowned Konservat-Lagerstätte. Beside its potential in preserving important information on the history of the Pacific Ocean during the Miocene, the Pisco Fm. provides palaeontologists with the unique opportunity to study in detail the evolution of marine vertebrate fauna during the Neogene. Because diatomites are one of the main lithologies of the Pisco Fm., previous authors have hypothesised exceptionally high sedimentation rates related to the deposition of diatom frustules as the main cause leading to the formation of the Lagerstätte. However, sedimentation rates were never calculated. With the perspective to build a solid stratigraphic framework for the whole Pisco Fm., we started to investigate two important fossiliferous sites: Cerro Colorado and Cerro Los Quesos. Within these two areas, measurement of multiple stratigraphic sections combined with extensive field mapping of a number of distinct marker beds was carried out, which allowed a high-resolution correlation and creation of a local lithostratigraphic framework. Integrated tephrostratigraphy,40Ar/39Ar dating and diatom biostratigraphy permitted an accurate chronostratigraphy to be established. Both biostratigraphic and radiometric ages converge to indicate a late Miocene age for the two sites, amending previous attribution of Cerro Colorado and Cerro Los Quesos to the middle Miocene. Age models for the site of Cerro Los Quesos reveal that sedimentation rates are high but in line with those of high-productivity environments, thus invalidating the hypothesis of exceptional sedimentation rates as the main cause for the formation of the Lagerstätte. These results are extremely important also in the perspective of building a complete stratigraphic framework for the Pisco Fm.

Dynamics of epithelial monolayers has recently been interpreted in terms of a jamming or rigidity transition. How cells control such phase transitions is, however, unknown. Here we show that RAB5A, a key endocytic protein, is sufficient to induce large-scale, coordinated motility over tens of cells, and ballistic motion in otherwise kinetically arrested monolayers. This is linked to increased traction forces and to the extension of cell protrusions, which align with local velocity. Molecularly, impairing endocytosis, macropinocytosis or increasing fluid efflux abrogates RAB5A-induced collective motility. A simple model based on mechanical junctional tension and an active cell reorientation mechanism for the velocity of self-propelled cells identifies regimes of monolayer dynamics that explain endocytic reawakening of locomotion in terms of a combination of large-scale directed migration and local unjamming. These changes in multicellular dynamics enable collectives to migrate under physical constraints and may be exploited by tumours for interstitial dissemination.

Vascular associated endothelial cell (ECs) progenitors are still poorly studied and their role in the newly forming vasculature at embryonic or postnatal stage remains elusive. In the present work, we first defined a set of genes highly expressed during embryo development and strongly downregulated in the adult mouse. In this group, we then concentrated on the progenitor cell marker Peg3/PW1. By in vivo staining of the vasculature we found that only a subset of cells coexpressed endothelial markers and PW1. These cells were quite abundant in the embryo vasculature but declined in number at postnatal and adult stages. Using a reporter mouse for PW1 expression, we have been able to isolate PW1‐positive (PW1posECs) and negative endothelial cells (PW1negECs). PW1‐positive cells were highly proliferative in comparison to PW1negECs and were able to form colonies when seeded at clonal dilution. Furthermore, by RNAseq analysis, PW1posECs expressed endothelial cell markers together with mesenchymal and stem cell markers. When challenged by endothelial growth factors in vitro, PW1posECs were able to proliferate more than PW1negECs and to efficiently form new vessels in vivo. Taken together these data identify a subset of vessel associated endothelial cells with characteristics of progenitor cells. Considering their high proliferative potential these cells may be of particular importance to design therapies to improve the perfusion of ischemic tissues or to promote vascular repair. StemCells2017;35:1328–1340 (1): We identified a subpopulation of Endothelial Cells that specifically express the transcription factor PW1. These cells have a salt and pepper distribution along developing blood vessels. Scale bar = 20 μm. (2): Tacking advantage of the PW1nLacZ reporter mouse, we sorted out PW1 positive endothelial cells and characterized them. (2.1): RNAseq performed on PW1 positive ad PW1 negative endothelial cells revealed different gene expression profiles. (3.1): Isolated PW1 positive Endothelial cells seeded at clonal density were able to form endothelial cell colonies. Scale bar = 20 μm. (3.2): Isolated PW1 positive endothelial cells reimplanted in a Matrigel plug generated new blood vessels. Scale bar = 20 μm.

The detailed study of diatom laminations conducted by means of backscattered electron imaging serves as tool to unravel details of past ocean dynamics. In this paper we apply this method to the analysis of the diatomites of Cerro Los Quesos, Upper Miocene Pisco Fm, Peru. Numerous studies have been conducted on the Pisco Fm; however, a focus on its paleoceanographic significance is still lacking. In this work, we provide information on the oceanographic setting in the area at the time of diatomites deposition. The high abundance of deep‐living Coscinodiscuslaminae, proceeded by either a mixed lamina or a terrigenous one, let us hypothesize a deep position of the thermocline during the deposition of the Pisco diatomites; together with the scarcity of Chaetoceros Hyalochaetespp. resting spores, this evidence confutes the belief that equals high biogenic silica content in marine sediments with enhanced upwelling. Conversely, the depositional setting of the Pisco Fm diatomites is more similar to what is known as “permanent El Niño” (or “El Padre”) state, meaning a constant weakened upwelling (or upwelling of nutrients‐poor waters). Climate modeling warns that an increase in atmospheric CO2may lead to this mean state in the near future. Thanks to this study we also obtained refined information on the diatomites sedimentations rates. The comparison of the Pisco diatomites sedimentation rates with those of Quaternary diatomites gave strength to the hypothesis that the formation of the vertebrate Lagerstätte may have been enhanced, among others, by the so‐called “impact‐burial” mechanism. Some sedimentary rocks are formed by the remains of small organisms. This is the case of diatoms, microscopic algae with a siliceous exoskeleton. As we know the ecological conditions of the modern oceans in which different diatom species live, when we found them in sedimentary rocks, we can infer the ecological conditions of the oceans millions of years ago. Here, we present the species that we found in some Peruvian rocks, the so‐called Pisco Formation, which dates back to 7/6 Million of years ago. Different species are preserved in these rocks in the same order in which they bloomed, so that we can identify small “laminae” (horizontal strips in the rock with thicknesses smaller than 1 mm) for each blooming season. The species that we recognize are those that today bloom during “El‐Niño,” a climatic warm condition that causes loss of large fishery stocks, inundations and droughts. This small finding helps us hypothesize how climate may evolve if the Earth's temperatures keep on rising. Also, the Pisco formation is famous because of their huge content of fossil whales and dolphins, thus the study of this rock helps us understand how these large mammals got preserved trough millions of years. Laminae of the Upper Miocene diatomaceous Pisco Formation reveal that the fall dump mechanism regulated marine export productionThe predominance of fall dump over upwelling implies a drop of the temperature gradient between the Western and Eastern PacificEvidences highlight a need of caution when using biogenic silica as a proxy for paleo upwelling Laminae of the Upper Miocene diatomaceous Pisco Formation reveal that the fall dump mechanism regulated marine export production The predominance of fall dump over upwelling implies a drop of the temperature gradient between the Western and Eastern Pacific Evidences highlight a need of caution when using biogenic silica as a proxy for paleo upwelling

Two methane migration mechanisms have been proposed for coarse‐grained gas hydrate reservoirs: short‐range diffusive gas migration and long‐range advective fluid transport from depth. Herein, we demonstrate that short‐range fluid flow due to overpressure in marine sediments is a significant additional methane transport mechanism that allows hydrate to precipitate in large quantities in thick, coarse‐grained hydrate reservoirs. Two‐dimensional simulations demonstrate that this migration mechanism, short‐range advective transport, can supply significant amounts of dissolved gas and is unencumbered by limitations of the other two end‐member mechanisms. Short‐range advective migration can increase the amount of methane delivered to sands as compared to the slow process of diffusion, yet it is not necessarily limited by effective porosity reduction as is typical of updip advection from a deep source. Short‐range advection is proposed as a methane migration mechanism in marine hydrate‐bearing sandsHydrate distributions in overpressured coarse‐grained sands are hypothesized as functions of sand dip angleTwo‐dimensional basin‐scale simulations show overpressured flow focusing as a significant means of methane transport in sands

Supplemental Digital Content is available in the text.

An increasing number of innovative technologies are fostering Intelligent Transportation Systems (ITS), thus setting the milestones of future paradigms in vehicular mobility. Among these technologies, Positioning Navigation and Timing (PNT) systems and low-latency communication networks play a fundamental role. This synergy can enable cooperative approaches leading to innovative, advanced services. Research contributions proposing these approaches rely on hypothetical protocols not being yet in place. An extension of current protocols is advisable to push forward the state-of-the-art solutions in PNT collaborative applications. To this aim, this work proposes a new type of vehicular message, namely Cooperative Enhancement Message (CEM), along with a related open protocol to permit the use of Global Navigation Satellite Systems (GNSS) raw measurements in vehicular networks. CEM aims at enabling information sharing beyond what is currently allowed by Cooperative Awareness Messages (CAM) and Collective Perception Messages (CPM). It complements such paradigms supporting the enhancement of localization accuracy, precision, and integrity guaranteed by state-of-the-art cooperative algorithms. Furthermore, a validation of the proposed study is accomplished through a novel network simulation framework. Contextually, the paper presents an analysis assessing network performance when concurrent CEM and CAM transmissions are intended to supply cooperative vehicle applications in IEEE 802.11p and Cellular-V2X.

Despite the relevant therapeutic progresses made in these last 2 decades, the prognosis of acute myeloid leukemia (AML) remains poor. Phorbol esters are used at very low concentrations as differentiating agents in the therapy of myeloid leukemias. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), in turn, is a death ligand that spares normal cells and is therefore currently under clinical trials for cancer therapy. Emerging evidence, however, suggests that TRAIL is also involved in nonapoptotic functions, like cell differentiation. PKCϵ is differentially modulated along normal hematopoiesis, and its levels modulate the response of hematopoietic precursors to TRAIL. Here, we investigated the effects of the combination of phorbol esters (phorbol ester 4-β-phorbol-12,13-dibutyrate [PDBu]) and TRAIL in the survival/differentiation of AML cells. We demonstrate here that PDBu sensitizes primary AML cells to both the apoptogenic and the differentiative effects of TRAIL via PKCϵ down-modulation, without affecting TRAIL receptor surface expression. We believe that the use of TRAIL in combination with phorbol esters (or possibly more specific PKCϵ down-modulators) might represent a significative improvement of our therapeutic arsenal against AML.

Despite the relevant therapeutic progresses made in these last 2 decades, the prognosis of acute myeloid leukemia (AML) remains poor. Phorbol esters are used at very low concentrations as differentiating agents in the therapy of myeloid leukemias. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), in turn, is a death ligand that spares normal cells and is therefore currently under clinical trials for cancer therapy. Emerging evidence, however, suggests that TRAIL is also involved in nonapoptotic functions, like cell differentiation. PKCϵ is differentially modulated along normal hematopoiesis, and its levels modulate the response of hematopoietic precursors to TRAIL. Here, we investigated the effects of the combination of phorbol esters (phorbol ester 4-β-phorbol-12,13-dibutyrate [PDBu]) and TRAIL in the survival/differentiation of AML cells. We demonstrate here that PDBu sensitizes primary AML cells to both the apoptogenic and the differentiative effects of TRAIL via PKCϵ down-modulation, without affecting TRAIL receptor surface expression. We believe that the use of TRAIL in combination with phorbol esters (or possibly more specific PKCϵ down-modulators) might represent a significative improvement of our therapeutic arsenal against AML.

In CSF, extended (55 kDa) and truncated (33 kDa) tau forms have been previously recognized, and the tau 33 kDa/55 kDa ratio has been found significantly reduced in progressive supranuclear palsy (PSP) vs in other neurodegenerative disorders. The aim of this study was to evaluate the diagnostic value of the CSF tau form ratio as a biomarker of PSP and to correlate the structural anatomic changes as measured by means of voxel-based morphometry (VBM) to CSF tau form ratio decrease.

We analyzed soluble vascular adhesion molecules (sVCAM-1), reactive oxygen metabolites (ROMs) level, total antioxidant status (TAS) and telediastolic left ventricular volume (TLW) in patients with myocardial infarction undergoing reperfusion therapy and treated with antioxidant vitamins (AT) or placebo (P) before and for 1 month after reperfusion. After reperfusion, sVCAM-1 serum concentration, reactive oxygen metabolites level, and TLW were significantly higher in patients treated with placebo than in those treated with antioxidant vitamins, while TAS was significantly higher in patients treated with antioxidant supplementation. We observed that 48 hours after reperfusion sVCAM-1 (P) vs sVCAM −1(AT) was 2.03±0.5 vs 1.63±0.7 μg/ml with p<0.01; ROMs (P) vs ROMs (AT) were 335.60±35.80 vs 307.50±47.10 U.CARR with p<0.05; TAS (P) vs TAS (AT) was 526.47±44.24 vs 737.65±51.15 μmol/l with p<0.01; 1 week after reperfusion TLW (P) vs TLW (AT) was 125.12±29.80 vs 119.40±29.40 ml with p<0.05; 1 month after reperfusion TLW (P) vs TLW (AV) was 132.00±33.50 vs 123.40±21.60 ml with p<0.05. In the first period after infarction, vitamin treatment improves the antioxidant system and reduces oxidative stress, inflammatory process and left ventricular remodeling.

Abstract Prosperous deep coral mounds including living colonies of Lophelia pertusa together with Madrepora oculata and Desmophyllum dianthus (= D. cristagalli) have been discovered in 2000, by fishery operations on the eastern side of the Ionian Sea. The living coral mounds are located between ca. 300 and 1,100 m on a gently dipping shelf off Apulia at Santa Maria di Leuca (SML), and characterized by a complex seabed topography. Side scan sonar, shallow high-resolution seismics and sampling indicate that these Lophelia-bearing coral mounds colonize quasi-indurate (firmground) Pleistocene sediment. At places live corals were found on Pleistocene coral-hardgrounds. The fauna associated with these Ionian modern coral mounds is less diversified than modern Eastern Atlantic counterparts. The core of living coral mounds colonies is at present located in 500–700 m and is tentatively suggested that their survival is mostly controlled by oceanographic factors. The SML coral banks represent so far a unique example of living Lophelia-bearing coral mounds in the Mediterranean basin.