1,354,370 research outputs found
DNA damage response in adult stem cells
No full textThis review discusses the processes of DNA-damage-response and DNA-damage repair in stem and progenitor cells of several tissues. The long life-span of stem cells suggests that they may respond differently to DNA damage than their downstream progeny and, indeed, studies have begun to elucidate the unique stem cell response mechanisms to DNA damage. Because the DNA damage responses in stem cells and progenitor cells are distinctly different, stem and progenitor cells should be considered as two different entities from this point of view. Hematopoietic and mammary stem cells display a unique DNA-damage response, which involves active inhibition of apoptosis, entry into the cell-cycle, symmetric division, partial DNA repair and maintenance of self-renewal. Each of these biological events depends on the up-regulation of the cell-cycle inhibitor p21. Moreover, inhibition of apoptosis and symmetric stem cell division are the consequence of the down-regulation of the tumor suppressor p53, as a direct result of p21 up-regulation. A deeper understanding of these processes is required before these findings can be translated into human anti-aging and anti-cancer therapies. One needs to clarify and dissect the pathways that control p21 regulation in normal and cancer stem cells and define (a) how p21 blocks p53 functions in stem cells and (b) how p21 promotes DNA repair in stem cells. Is this effect dependent on p21s ability to inhibit p53? Such molecular knowledge may pave the way to methods for maintaining short-term tissue reconstitution while retaining long-term cellular and genomic integrity
Leukemia-associated fusion proteins : multiple mechanisms of action to drive cell transformation
No full textLeukemic cells are defined by two main biological features: arrest of differentiation at a specific stage compatible with continued proliferation, and enhanced resistance to stress. Recent work shows that the leukemia-associated fusion protein PML-RAR can mediate both biological effects targeting independent pathways, through a unifying mechanism. Differentiation block is achieved through transcriptional silencing of genes physiologically regulated by RAR, which are involved in hematopoietic differentiation. In contrast, enhanced resistance to stress is due to the capacity of the fusion protein to cause degradation of the tumor suppressor p53, thus explaining the puzzling observation that mutations of p53 are remarkably rare in acute myeloid leukemias (AMLs). Interestingly, this latter phenomenon depends on expression of wild-type PML, acting as a molecular bridge between p53 and the fusion protein. Strikingly, both effects require a unifying molecular mechanism: aberrant recruitment of histone deacetylases (HDACs). Therefore, the study of this form of leukemia appears also of interest for a better understanding of the action of HDAC inhibitors, potential antitumor drugs that are at the early stages of clinical studies
Mechanisms of selective anticancer action of histone deacetylase inhibitors
No full textHistone deacetylases (HDACs) regulate transcription and specific functions, such as tumor suppression by p53, and are frequently altered in cancer. Inhibitors of HDACs (HDACl) possess anti-tumor activity and are well tolerated, suggesting that they might develop into a specific strategy for cancer treatment. Indeed, HDACls have successfully entered clinical trials, but the molecular basis for their selective anti-tumor activities is not clear. Recent work on leukemias expressing the PML-RAR or AML1-ETO oncogenes, known to initiate leukemogenesis through deregulation of HDACs, shows that HDACls induce massive blast cell apoptosis. Interestingly, the pro-apoptotic activity of the drug is not due to the relief of oncogene-mediated inhibition of the p53 tumor-suppressor pathway but, instead, relies on the selective upregulation of the death receptors DR5 and Fas and their cognate ligands TRAIL and FasL. Significantly, normal myeloid progenitors are not sensitive to HDACl-induced apoptosis and oncogene expression is not sufficient to confer HDACl-sensitivity to normal cells, demonstrating that sensitivity to HDACl is a property of the fully transformed phenotype. In principle, our findings could thus apply to other cancers, where the contribution of HDACs to tumorigenesis is not yet defined. (copyright)2005 Landes Bioscience
The emerging role of p53 in stem cells
No full textAmong the hundreds of oncogenes and tumor suppressors that have been identified in the past 50 years, p53 is probably the best characterized; nevertheless, new functions are constantly being discovered. As a tumor suppressor, p53 regulates cellular responses to different stress stimuli by inducing reversible cell cycle arrest and DNA repair, or triggering senescence or apoptosis. Recent findings on the regulation of stem cell (SC) division and reprogramming suggest the intriguing possibility that p53 also carries out its tumor suppression function by regulating SC homeostasis. Specifically, p53 activation may counteract SC expansion by several emerging mechanisms including restriction of self-renewing divisions, inhibition of symmetric division and block of reprogramming of somatic/progenitor cells into SCs
Links between tumor suppressors: p53 is required for TGF-beta gene responses by cooperating with Smads
No full textThe p53 tumor suppressor belongs to a family of proteins that sense multiple cellular inputs to regulate cell proliferation, apoptosis, and differentiation. Whether and how these functions of p53 intersect with the activity of extracellular growth factors is not understood. Here, we report that key cellular responses to TGF-beta signals rely on p53 family members. During Xenopus embryonic development, p53 promotes the activation of multiple TGF-beta target genes. Moreover, mesoderm differentiation is inhibited in p53-depleted embryos. In mammalian cells, the full transcriptional activation of the CDK inhibitor p21(WAF1) by TGF-beta requires p53. p53-deficient cells display an impaired cytostatic response to TGF-beta signals. Smad and p53 protein complexes converge on separate cis binding elements on a target promoter and synergistically activate TGF-beta induced transcription. p53 can physically interact in vivo with Smad2 in a TGF-beta-dependent fashion. The results unveil a previously unrecognized link between two primary tumor suppressor pathways in vertebrates
A 6-bit Low-Area Hybrid ADC Design For System-on-Chip Measurements
No full textIn recent years, with the declining dimensions of transistors, the system-on-chips (SoCs) have had more physical defects. These physical defects ultimately result in failures that cannot be tolerated in functional safety applications such as electric cars, aerospace, etc. For the digital peripherals of the SoCs, there are well-known methods such as scan chains, whereas there are methods for analog circuits such as analog scan chains or Analog Test Bus (ATB).
This paper presents a 6-bit, low-area Analog-to-Digital Converter (ADC) for SoC analog voltage measurements. The advantage of the proposed ADC design is the low additional area cost to the design of the SoC and increasing the testability of the analog peripherals. This ADC design converts the analog signals, which are difficult to observe, to the digital domain, which is easy to route and observe. This architecture comprises two small ADCs for doing coarse and fine conversions. The ADC for the coarse conversion is a 3-bit SAR ADC, and the ADC for the fine conversion is a 3-bit flash ADC. The suggested ADC is implemented using the 130 nm technology of the Infineon, and it has a total area of 0.007 mm^2. The fine ADC of the proposed ADC can be shared between the peripherals nearby inside the SoC, and the additional area per peripheral would be only 0.0015 mm^2. The Signal-to-Noise Distortion Ratio (SNDR) of the design is 37dB, and the Figure of Merit (FoM) is 2.15 pJ/conv
Application of paleomagnetic methods on two variably welded peralkaline fallout deposits from Pantelleria Island (Sicily Strait): inferences on emplacement temperature and welding
No full textOne of the major volcanological issues is to outline the eruptive and depositional mechanisms of explosive eruptions and to constrain the emplacement temperature (Temp) of the associated pyroclastic deposits for the inferences on the thermal evolution, welding and rheomorphism, before cooling to the glass transition temperature (Tg).
Emplacement temperature of pyroclastic deposits, in particular ignimbrites, can be constrained using paleomagnetic methods on lithic clasts entrained during eruptive climax. At Pantelleria island, a paleomagnetic study was carried out on the Green Tuff welded and rheomorphic ignimbrite [Scarani et al., 2023], but there is limited understanding of less explosive inter-ignimbritic eruptions.
Here we provide paleomagnetic data of two variably welded fallout deposits belonging to the old local centres of Cala dell’Altura (pantelleritic) and Cala delle Giache (comenditic), in the attempt to ascertain any possible relationship of welding degree of peralkaline airfalls with the emplacement temperature recorded by lithic clasts.
Thermal demagnetization of lithic clasts does not show evident relationships with welding in the Cala dell’Altura fallout, indicating that unwelded and welded layers were emplaced at the same temperature range between the TCurie of magnetite (580 °C) and T pre-eruptive (700°C for pantelleritic magma, 800 °C for comenditic), thus suggesting poorly efficient cooling (low column height or high deposition rate). On the contrary the Cala Giache fallout, characterized by some initial phreatomagmatic episodes, shows an evident bimodality, with lithics in the welded layers emplaced at high temperature (580-800°C) and those in the unwelded layers at lower temperature, pointing out to a more efficient cooling, possibly due to early magma-water interaction and/or lower deposition rate.
Post-depositional magnetic disturbance occurred in proximity of some large (30 cm in length) lithics, deforming very local (cm-scale) geomagnetic field and affecting the magnetic orientation of smaller lithics nearby. Secondarily, we detected post-depositional tilting of few lithics due to sliding along the unconsolidated matrix of the unwelded fallouts
Large earthquakes along slow converging plate margins: Calabrian Arc paleoseismicity based on the submarine turbidite record
No full textThe Calabrian Arc subduction-rollback system hosts seismogenic faults capable of generating earth-
quakes exceeding magnitude 7. Since earthquakes are the result of long-term geodynamic processes, doc-
umenting seismic activity during a sufficiently long time interval is of fundamental importance for
hazard scenarios. Instrumental and historical data provide critical information on seismogenesis, but they
cover time periods shorter than the recurrence times of large earthquakes, especially in areas with low
deformation rates such as Calabria. If onshore paleoseismological studies are fundamental to compile
earthquake catalogs, they are sometime affected by the relatively poor continuity of sedimentation in
the subaerial environment.
In this study we applied the paleoseismological approach to the submarine environment to reconstruct
the record of high-energy sedimentary events triggered by seismic activity. We analyzed three gravity
cores collected in disconnected sedimentary basins to reconstruct resedimentation processes during
the Holocene, integrating inland information for a better assessment of tectonic activity and seismogen-
esis. Multiproxy analyses of the sedimentary record constrained by radiometric dating allowed recon-
structing event stratigraphy and linking resedimented deposits to specific earthquakes.
Onshore and offshore data allow to identify large-magnitude earthquakes in the central Calabrian Arc
subduction system during the Holocene, with inferred epicenters located either along normal faults
onshore and/or related to the slab dynamics. The turbidite record reveals 20 major events during the last
10 ka, with sources including crustal faults in Calabria (i.e. Lakes, Rossano and Cittanova faults). Analyses
of sediment samples and high-resolution seismic reflection images allowed identification of different
types of resedimented deposits during the last 30–50 ka. The basin-wide occurrence of three megatur-
bidites/homogenites suggests they are related to megatsunamis sourced by far field earthquakes along
the Hellenic Arc. Megaturbidites with a more limited spatial extent are interpreted as subduction-type
events in the Calabrian Arc, while thinner seismo-turbidites record the activity of crustal structures
including faults onshore. Results suggest a recurrence time of 2–3 ka for major Calabrian Arc events that
needs to be considered for a reliable hazard assessment in the Mediterranean region
40Ar/39Ar dating of tuff vents in the Campi Flegrei caldera (southern Italy): toward a new chronostratigraphic reconstruction of the Holocene volcanic activity
No full textAbstract. The Campi Flegrei hosts numerous monogenetic
vents inferred to be younger than the 15 ka Neapolitan Yellow Tuff. Sanidine crystals from the three young Campi Flegrei vents of Fondi di Baia, Bacoli and Nisida were dated using 40Ar/39Ar geochronology. These vents, together with several other young edifices, occur roughly along the inner border of the Campi Flegrei caldera, suggesting that the volcanic conduits are controlled by caldera-bounding faults. Plateau ages of ∼9.6 ka (Fondi di Baia), ∼8.6 ka (Bacoli) and ∼3.9 ka (Nisida) indicate eruptive activity during intervals previously interpreted as quiescent. A critical revision, involving calendar age correction of
literature 14C data and available 40Ar/39Ar age data, is presented. A new reference chronostratigraphic framework for Holocene Phlegrean activity, which significantly differs from the previously adopted ones, is proposed. This has important implications for understanding the Campi Flegrei eruptive history and, ultimately, for the evaluation of related volcanic risk and hazard, for which the inferred history of its recent activity is generally taken into account
The submerged structure and stratal architecture of the Neapolitan Yellow Tuff (NYT) caldera, offshore the Campi Flegrei, (Eastern Tyrrhenian Margin): new insights from high resolution seismics and gravity core data
No full textThe Campi Flegrei is an active volcanic area defined by a
quasi-circular depression that covers some 200 km2 of the coastal
zone of SW Italy, a large part of which develops off the Naples
(Pozzuoli) Bay (Fig. 1). The area has been active at least since 60
ka BP ( Pappalardo et al., 1999), and is structurally dominated by a
caldera, 6 km in diameter, associated with the eruption of the
Neapolitan Yellow Tuff (NYT), a 40 km3 Dense Rock Equivalent
(DRE) ignimbrite (Scarpati et al., 1993) dated at ca 15 ka BP
(Deino et al., 2004), that covered the district now occupied by the
city of Naples, the Campi Flegrei and a large area of the
continental shelf off the Pozzuoli Bay.
The volcanological evolution of the NYT caldera as been long
described on the basis of outcrop and subsurface studies onland
(Rosi & Sbrana, 1987; Orsi et al., 1996, 2004 and references
therein; Di Vito et al., 1999; Perrotta et al., 2006; Fedele et al.,
2011), but its offshore morphology, detailed structure and recent
stratigraphic setting are still poorly understood.
In this study we integrate geological and geophysical data of
different resolution/penetration obtained from high-resolution
reflection seismic profiles (Sparker and Chirp source) with gravity
core and swath bathymetry to better constrain the shallow
structure, stratigraphic architecture and latest Quaternary to
Holocene evolution of the submerged sector of the NYT caldera
off the Pozzuoli Bay.
Our data clearly image, for the first time, the offshore geometry
of the NYT caldera ring-fault zone, as well as the style and timing
of volcano-tectonic deformation associated with the late stage
evolution of the NYT inner caldera resurgence. Our interpretation
suggests that since 15 ka the offshore sector of NYT inner caldera
underwent significant deformation and uplift (with minor
subsidence episodes) that occurred at almost the same rate as the
post-glacial sea-level rise. Particularly, the inner Pozzuoli Bay
started to deform soon after 15 ka BP, when sea-level rise was
initially faster than uplift. This caused a general increase of the
accommodation space that was progressively filled up by
volcaniclastic sediments. Since ca. 8 ka BP, along with the mid
Holocene decrease in the rate of the sea-level rise, the early NYT
resurgent structure was then uplifted up to the sea-level or even to
partial subaerial exposure. From ca. 8 to 5 ka BP two distinct
layers of volcaniclastic resediments, mostly represented by gravity
flow deposits, formed throughout the Bay. A significant post-
Roman (post 2 ka BP) subsidence phase of ca 10 m is then
recorded offshore Pozzuoli by the drowning of the infralittoral
prograding wedge below the present-day fair-weather wave base.
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