Thirty years after oxygen isotope records from microfossils deposited in ocean sediments confirmed the hypothesis that variations in the Earth's orbital geometry control the ice ages, fundamental ...questions remain over the response of the Antarctic ice sheets to orbital cycles. Furthermore, an understanding of the behaviour of the marine-based West Antarctic ice sheet (WAIS) during the 'warmer-than-present' early-Pliocene epoch (∼5-3 Myr ago) is needed to better constrain the possible range of ice-sheet behaviour in the context of future global warming. Here we present a marine glacial record from the upper 600 m of the AND-1B sediment core recovered from beneath the northwest part of the Ross ice shelf by the ANDRILL programme and demonstrate well-dated, ∼40-kyr cyclic variations in ice-sheet extent linked to cycles in insolation influenced by changes in the Earth's axial tilt (obliquity) during the Pliocene. Our data provide direct evidence for orbitally induced oscillations in the WAIS, which periodically collapsed, resulting in a switch from grounded ice, or ice shelves, to open waters in the Ross embayment when planetary temperatures were up to ∼3 °C warmer than today and atmospheric CO2 concentration was as high as ∼400 p.p.m.v. (refs 5, 6). The evidence is consistent with a new ice-sheet/ice-shelf model that simulates fluctuations in Antarctic ice volume of up to +7 m in equivalent sea level associated with the loss of the WAIS and up to +3 m in equivalent sea level from the East Antarctic ice sheet, in response to ocean-induced melting paced by obliquity. During interglacial times, diatomaceous sediments indicate high surface-water productivity, minimal summer sea ice and air temperatures above freezing, suggesting an additional influence of surface melt under conditions of elevated CO2.
We present a high-resolution paleoclimatic and paleoenvironmental reconstruction of the last five millennia from a shallow water marine sedimentary record from the central Tyrrhenian Sea (Gulf of ...Gaeta) using planktonic foraminifera, pollen, oxygen stable isotope, tephrostratigrapy and magnetostratigrapy. This multiproxy approach allows to evidence and characterize nine time intervals associated with archaeological/cultural periods: Eneolithic (base of the core–ca. 2410BCE), Early Bronze Age (ca. 2410BCE–ca. 1900BCE), Middle Bronze Age–Iron Age (ca. 1900BCE–ca. 500BCE), Roman Period (ca. 500BCE–ca. 550CE), Dark Age (ca. 550CE–ca. 860CE), Medieval Climate Anomaly (ca. 860CE–ca. 1250CE), Little Ice Age (ca. 1250CE–ca. 1850CE), Industrial Period (ca. 1850CE–ca. 1950CE), Modern Warm Period (ca. 1950CE–present day). The reconstructed climatic evolution in the investigated sedimentary succession is coherent with the short-term climate variability documented at the Mediterranean scale.
By integrating the planktonic foraminiferal turnover from carnivorous to herbivorous–opportunistic species, the oxygen isotope record and the pollen distribution, we document important modification from the onset of the Roman Period to the present-day. From ca. 500CE upwards the documentation of the cooling trend punctuated by climate variability at secular scale evidenced by the short-term δ18O is very detailed. We hypothesise that the present day warm conditions started from the end of cold Maunder event. Additionally, we provide that the North Atlantic Oscillation (NAO) directly affected the central Mediterranean region during the investigated time interval.
•A high-resolution paleoclimate reconstruction for the last five millennia is proposed.•Planktonic foraminifera and pollen records combined with oxygen stable isotope allow us to characterize climate phases.•Oxygen isotopic record performed on Globigerinoides ruber results in phase with the North Atlantic Oscillation (NAO).
Here, we report on the Quaternary Volsci Volcanic Field (VVF, central Italy). In light of new
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Ar/
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Ar geochronological data and compositional characterization of juvenile eruptive products, we ...refine the history of VVF activity, and outline the implications on the pre-eruptive magma system and the continental subduction processes involved. Different from the nearby volcanic districts of the Roman and Campanian Provinces, the VVF was characterized by small-volume (0.01–0.1 km
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) eruptions from a network of monogenetic centers (mostly tuff rings and scoria cones, with subordinate lava occurrences), clustered along high-angle faults of lithospheric depth. Leucite-bearing, high-K (HKS) magmas (for which we report for the first time the phlogopite phenocryst compositions) mostly fed the early phase of activity (∼761–539 ka), then primitive, plagioclase-bearing (KS) magmas appeared during the climactic phase (∼424–349 ka), partially overlapping with HKS ones, and then prevailed during the late phase of activity (∼300–231 ka). The fast ascent of primitive magma batches is typical of a tectonically controlled volcanic field, where the very low magma flux is a passive byproduct of regional tectonic strain. We suggest that the dominant compressive stress field acting at depth was accompanied by an extensional regime in the upper crust, associated with the gravity spreading of the Apennine chain, allowing the fast ascent of magma from the mantle source with limited stationing in shallow reservoirs.
Geomorphological investigations in Rome’s river valley are revealing the dynamism of the prehistoric landscape. It is becoming increasingly apparent that paleogeographic conditions that defined Rome ...in the historical era are the product of changes since the Bronze Age, which may be the result of local fault activity in addition to fluvial dynamism. Through a dedicated borehole chronostratigraphic study, integrated by
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C and archaeological dates, and paleomagnetic investigations, we offer here new evidence for fault displacement since ca. 4500 years/BP. We present the failure of the sedimentary fabric of a clay horizon caused by liquefaction processes commonly linked with seismic shaking, interpreting an (ca. 4 m) offset to signify the existence of a fault line located at the foot of the Capitoline Hill. In addition, we show evidence for another (ca. 1 m) offset affecting a stratigraphic horizon in the river channel, occurring along another hypothesized fault line crossing through the Tiber Valley. Movement along this fault may have contributed to a documented phase of fast overflooding dated to the sixth century BCE which eventually led to the birth of the Tiber Island. The most plausible scenario implies progressive deformation, with an average tectonic rate of 2 mm/year, along these inferred fault lines. This process was likely punctuated with moderate earthquakes, but no large event necessarily occurred. Together, the available evidence suggests that during the early centuries of sedentary habitation at the site of Rome, active fault lines contributed to significant changes to the Tiber River valley, capable of challenging lowland activities.
Development of RNA interference-based therapies with appropriate therapeutic window remains a challenge for advanced cancers. Because cancer stem cells (CSC) are responsible of sustaining the ...metastatic spread of the disease to distal organs and the progressive gain of resistance of advanced cancers, new anticancer therapies should be validated specifically for this subpopulation of cells. A new amphihilic-based gene delivery system that combines Pluronic
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F127 micelles with polyplexes spontaneously formed by electrostatic interaction between anionic siRNA and cationic polyethylenimine (PEI) 10K, was designed (PM). Resultant PM gather the requirements for an efficient and safe transport of siRNA in terms of its physicochemical characteristics, internalization capacity, toxicity profile and silencing efficacy. PM were loaded with a siRNA against AKT2, an important oncogene involved in breast cancer tumorigenesis, with a special role in CSC malignancy. Efficacy of siAKT2-PM was validated in CSC isolated from two breast cancer cell lines: MCF-7 and Triple Negative MDA-MB-231 corresponding to an aggressive subtype of breast cancer. In both cases, we observed significant reduction on cell invasion capacity and strong inhibition of mammosphere formation after treatment. These results prompt AKT2 inhibition as a powerful therapeutic target against CSC and pave the way to the appearance of more effective nanomedicine-based gene therapies aimed to prevent CSC-related tumor recurrence.
Uplift and subsidence alternate throughout the life cycle of a volcano mirroring magma accumulation, migration and/or gas pressurization, and magma cooling or depressurization, respectively. The ...unusual occurrence of coeval inflation and deflation is difficult to reconcile with the recharging or cooling of a single magma chamber, or hydrological processes. Here we show a persistent flank uplift and central subsidence at Colli Albani volcano near Rome (Italy), by mapping about 20 years of deformation by InSAR data. The magmatic helium signature increases in correspondence with N‐S faults along the western slope of Colli Albani, which are therefore interpreted as deep‐seated structures directly or indirectly connected with an underlying magma reservoir. Deformation modeling shows that these faults are pathways for fresh magma intrusion, whereas a residual magma is cooling below the deflating caldera. Therefore, magma recharge at depth is controlled by major faults along which the vents of the most recent activity (<200 ka ago) concentrate in the western side of the volcano and not by the caldera structures. We demonstrate that the Colli Albani magmatic system is slowly rejuvenating, posing a volcanic threat for Rome.
Key Points
The Colli Albani volcano is characterized by lateral uplift and central subsidence
Magmatic helium signature sharply increases in correspondence with N‐S faults on the western flank
Deformation modeling suggests that the N‐S faults, not the caldera structures, control magma recharge at depth
The concept of therapeutic cancer vaccines is based on the activation of the immune system against tumor cells after the presentation of tumor antigens. Nanoparticles (NPs) have shown great potential ...as delivery systems for cancer vaccines as they potentiate the co-delivery of tumor-associated antigens and adjuvants to dendritic cells (DCs), insuring effective activation of the immune system against tumor cells. In this review, the immunological mechanisms behind cancer vaccines, including the role of DCs in the stimulation of T lymphocytes and the use of Toll-like receptor (TLR) ligands as adjuvants will be discussed. An overview of each of the three essential components of a therapeutic cancer vaccine – antigen, adjuvant and delivery system – will be provided with special emphasis on the potential of particulate delivery systems for cancer vaccines, in particular those made of biodegradable aliphatic polyesters, such as poly(lactic-co-glycolic acid) (PLGA) and poly-ε-caprolactone (PCL). Some of the factors that can influence NP uptake by DCs, including size, surface charge, surface functionalization and route of administration, will also be considered.
Biodegradable polymeric nanoparticles (NPs) with entrapped tumor antigens as well as adjuvants can be targeted to specific receptors expressed on dendritic cells (DCs). Display omitted
BackgroundInhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as ...PD-1/PD-L1 inhibitors. While significant clinical outcomes are observed on patients who respond to these therapeutics, a large proportion of the patients do not benefit from the currently available immune checkpoint inhibitors, which strongly emphasize the importance of developing new immunotherapeutic agents.MethodsIn this study, we followed a transdisciplinary approach to discover novel small molecules that can modulate PD-1/PD-L1 interaction. To that end, we employed in silico analyses combined with in vitro, ex vivo, and in vivo experimental studies to assess the ability of novel compounds to modulate PD-1/PD-L1 interaction and enhance T-cell function.ResultsAccordingly, in this study we report the identification of novel small molecules, which like anti-PD-L1/PD-1 antibodies, can stimulate human adaptive immune responses. Unlike these biological compounds, our newly-identified small molecules enabled an extensive infiltration of T lymphocytes into three-dimensional solid tumor models, and the recruitment of cytotoxic T lymphocytes to the tumor microenvironment in vivo, unveiling a unique potential to transform cancer immunotherapy.ConclusionsWe identified a new promising family of small-molecule candidates that regulate the PD-L1/PD-1 signaling pathway, promoting an extensive infiltration of effector CD8 T cells to the tumor microenvironment.
The coronavirus disease-19 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The long incubation period of this new virus, which is mostly asymptomatic yet ...contagious, is a key reason for its rapid spread across the world. Currently, there is no worldwide-approved treatment for COVID-19. Therefore, the clinical and scientific communities have joint efforts to reduce the severe impact of the outbreak. Research on previous emerging infectious diseases have created valuable knowledge that is being exploited for drug repurposing and accelerated vaccine development. Nevertheless, it is important to generate knowledge on SARS-CoV-2 mechanisms of infection and its impact on host immunity, to guide the design of COVID-19 specific therapeutics and vaccines suitable for mass immunization. Nanoscale delivery systems are expected to play a paramount role in the success of these prophylactic and therapeutic approaches. This Review provides an overview of SARS-CoV-2 pathogenesis and examines immune-mediated approaches currently explored for COVID-19 treatments, with an emphasis on nanotechnological tools.
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