SALL2- a member of the Spalt gene family- is a poorly characterized transcription factor found deregulated in various cancers, which suggests it plays a role in the disease. We previously identified ...SALL2 as a novel interacting protein of neurotrophin receptors and showed that it plays a role in neuronal function, which does not necessarily explain why or how SALL2 is deregulated in cancer. Previous evidences indicate that SALL2 gene is regulated by the WT1 and AP4 transcription factors. Here, we identified SALL2 as a novel downstream target of the p53 tumor suppressor protein. Bioinformatic analysis of the SALL2 gene revealed several putative p53 half sites along the promoter region. Either overexpression of wild-type p53 or induction of the endogenous p53 by the genotoxic agent doxorubicin repressed SALL2 promoter activity in various cell lines. However R175H, R249S, and R248W p53 mutants, frequently found in the tumors of cancer patients, were unable to repress SALL2 promoter activity, suggesting that p53 specific binding to DNA is important for the regulation of SALL2. Electrophoretic mobility shift assay demonstrated binding of p53 to one of the identified p53 half sites in the Sall2 promoter, and chromatin immunoprecipitation analysis confirmed in vivo interaction of p53 with the promoter region of Sall2 containing this half site. Importantly, by using a p53ERTAM knockin model expressing a variant of p53 that is completely dependent on 4-hydroxy-tamoxifen for its activity, we show that p53 activation diminished SALL2 RNA and protein levels during genotoxic cellular stress in primary mouse embryo fibroblasts (MEFs) and radiosensitive tissues in vivo. Thus, our finding indicates that p53 represses SALL2 expression in a context-specific manner, adding knowledge to the understanding of SALL2 gene regulation, and to a potential mechanism for its deregulation in cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The interaction between agricultural production and wildlife can shape, and even condition, the functioning of both systems. In this study, we i) explored the degree to which a widespread European ...bat, namely the common bent‐wing bat Miniopterus schreibersii, consumes crop‐damaging insects at a continental scale, and ii) tested whether its dietary niche is shaped by the extension and type of agricultural fields. We employed a dual‐primer DNA metabarcoding approach to characterize arthropod 16S and COI DNA sequences within bat faecal pellets collected across 16 Southern European localities, to first characterize the bat species’ dietary niche, second measure the incidence of agricultural pests across their ranges and third assess whether geographical dietary variation responds to climatic, landscape diversity, agriculture type and vegetation productivity factors. We detected 12 arthropod orders, among which lepidopterans were predominant. We identified >200 species, 44 of which are known to cause agricultural damage. Pest species were detected at all but one sampling site and in 94% of the analysed samples. Furthermore, the dietary diversity of M. schreibersii exhibited a negative linear relation with the area of intensive agricultural fields, thus suggesting crops restrict the dietary niche of bats to prey taxa associated with agricultural production within their foraging range. Overall, our results imply that M. schreibersii might be a valuable asset for biological pest suppression in a variety of agricultural productions and highlight the dynamic interplay between wildlife and agricultural systems.
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•A quinary interatomic potential and the corresponding average atom (AA) potential are used for simulating nanoindentation in HEAs.•Local compositional fluctuations lead to higher ...hardness in the HEA compared to the AA material.•Plasticity is dominated by dislocation activity, with twinning appearing as a complementary deformation mechanism.•Comparison with an AA model provides more meaningful results than the ones obtained after studying a single component, such as Ni.•Local chemical fluctuations do result in increased hardness and quantitative differences in plasticity.
The nanoindentation response of a FeNiCrCoCu high-entropy alloy is explored by means of atomistic simulations. In order to study the role of compositional complexity, we compare the behavior of the quinary FeNiCrCoCu alloy with that of an average atom potential fitted to the same overall properties of the alloy. In this way, we reveal the influence of compositional randomness of the multicomponent alloys on the onset of plasticity, deformation mechanisms and residual microstructure. Plasticity is dominated by dislocation activity, with twinning appearing as a complementary deformation mechanism in both models. While the HEA alloy substrate yields for a similar indenter penetration, indentation hardness is higher in the HEA alloy. After mitigation of strain rate effects, major differences are observed, influenced by the more difficult movement of dislocations in the compositionally complex HEA alloy. The results are in agreement with previous studies of plasticity in high entropy alloys and highlight the importance of using average atom models over comparison with single element studies for understanding complex multi principal element alloys.
This paper reports atomistic simulation studies of tensile and compressive behavior of nanowires of a model quinary high entropy face-centered cubic (FCC) alloy. The simulations employ empirical ...interatomic potentials and use massively parallel molecular dynamics techniques at the atomistic level to study the deformation mechanisms. The studies consider pristine cylindrical nanowires oriented along various crystallographic directions. The focus is the role that local composition fluctuations in the random alloy plays in the deformation response. The deformation behavior observed for the complex random alloy is compared with a corresponding “average atom” material that has the same average properties but no local compositional fluctuations. In all cases, deformation is governed by dislocations emitted from the free surface. Twinning was also found, depending on the crystallographic orientation and loading mode. We show that for all orientations, the high entropy alloy (HEA) wires show the onset of plasticity at lower stress levels than the average atom material. However, after the onset of plasticity, the HEA presents a higher strength, mostly driven by the fact that the dislocations emitted from the surface do not glide as easily in the random alloy as they do in the average atom material.
We report the results of compressive tests for a model bi-continuous nanoporous gold structure using atomistic simulations focusing on the densification regime and the plasticity mechanisms taking ...place. The stress – strain response follows a logarithmic evolution proportional to the inverse of strain and we provide a simple scaling law for this behavior. Hardening is correlated to the dislocation density and an exponential dependence is revealed. The plasticity mechanisms were inspected revealing the presence of Hirth and Frank partials contributing to the hardening of the sample. Lomer–Cottrel locks, perfect dislocations, and twinning were also found.
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OBJECTIVE:The aim of the Advanced Approach to Arterial Stiffness study was to compare arterial stiffness measured simultaneously with two different methods in different age groups of middle-aged and ...older adults with or without metabolic syndrome (MetS). The specific effects of the different MetS components on arterial stiffness were also studied.
METHODS:This prospective, multicentre, international study included 2224 patients aged 40 years and older, 1664 with and 560 without MetS. Patients were enrolled in 32 centres from 18 European countries affiliated to the International Society of Vascular Health & Aging. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) and the carotid–femoral pulse wave velocity (CF-PWV) in four prespecified age groups40–49, 50–59, 60–74, 75–90 years. In this report, we present the baseline data of this study.
RESULTS:Both CF-PWV and CAVI increased with age, with a higher correlation coefficient for CAVI (comparison of coefficients P < 0.001). Age-adjusted and sex-adjusted values of CF-PWV and CAVI were weakly intercorrelated (r = 0.06, P < 0.001). Age-adjusted and sex-adjusted values for CF-PWV but not CAVI were higher in presence of MetS (CF-PWV9.57 ± 0.06 vs. 8.65 ± 0.10, P < 0.001; CAVI8.34 ± 0.03 vs. 8.29 ± 0.04, P = 0.40; mean ± SEM; MetS vs. no MetS). The absence of an overall effect of MetS on CAVI was related to the heterogeneous effects of the components of MetS on this parameterCAVI was positively associated with the high glycaemia and high blood pressure components, whereas lacked significant associations with the HDL and triglycerides components while exhibiting a negative association with the overweight component. In contrast, all five MetS components showed positive associations with CF-PWV.
CONCLUSION:This large European multicentre study reveals a differential impact of MetS and age on CAVI and CF-PWV and suggests that age may have a more pronounced effect on CAVI, whereas MetS increases CF-PWV but not CAVI. This important finding may be due to heterogeneous effects of MetS components on CAVI. The clinical significance of these original results will be assessed during the longitudinal phase of the study.
The Emirates Mars Mission Emirates Mars Infrared Spectrometer (EMIRS) will provide remote measurements of the martian surface and lower atmosphere in order to better characterize the geographic and ...diurnal variability of key constituents (water ice, water vapor, and dust) along with temperature profiles on sub-seasonal timescales. EMIRS is a FTIR spectrometer covering the range from 6.0-100+ μm (1666-100 cm
−1
) with a spectral sampling as high as 5 cm
−1
and a 5.4-mrad IFOV and a 32.5×32.5 mrad FOV. The EMIRS optical path includes a flat 45° pointing mirror to enable one degree of freedom and has a +/- 60° clear aperture around the nadir position which is fed to a 17.78-cm diameter Cassegrain telescope. The collected light is then fed to a flat-plate based Michelson moving mirror mounted on a dual linear voice-coil motor assembly. An array of deuterated L-alanine doped triglycine sulfate (DLaTGS) pyroelectric detectors are used to sample the interferogram every 2 or 4 seconds (depending on the spectral sampling selected). A single 0.846 μm laser diode is used in a metrology interferometer to provide interferometer positional control, sampled at 40 kHz (controlled at 5 kHz) and infrared signal sampled at 625 Hz. The EMIRS beamsplitter is a 60-mm diameter, 1-mm thick 1-arcsecond wedged chemical vapor deposited diamond with an antireflection microstructure to minimize first surface reflection. EMIRS relies on an instrumented internal v-groove blackbody target for a full-aperture radiometric calibration. The radiometric precision of a single spectrum (in 5 cm
−1
mode) is <3.0×10
−8
W cm
−2
sr
−1
/cm
−1
between 300 and 1350 cm
−1
over instrument operational temperatures (<∼0.5 K NE
Δ
T @ 250 K). The absolute integrated radiance error is < 2% for scene temperatures ranging from 200-340 K. The overall EMIRS envelope size is 52.9×37.5×34.6 cm and the mass is 14.72 kg including the interface adapter plate. The average operational power consumption is 22.2 W, and the standby power consumption is 18.6 W with a 5.7 W thermostatically limited, always-on operational heater. EMIRS was developed by Arizona State University and Northern Arizona University in collaboration with the Mohammed bin Rashid Space Centre with Arizona Space Technologies developing the electronics. EMIRS was integrated, tested and radiometrically calibrated at Arizona State University, Tempe, AZ.
Two structurally constrained chelators based on a fused bicyclic scaffold, 4‐amino‐4‐methylperhydro‐pyrido1,2‐a1,4diazepin‐N,N′,N′‐triacetic acids (4R*,10aS*)‐PIDAZTA (L1) and (4R*,10aR*)‐PIDAZTA ...(L2), were designed for the preparation of GaIII‐based radiopharmaceuticals. The stereochemistry of the ligand scaffold has a deep impact on the properties of the complexes, with unexpected Ga(L2)OH species being superior in terms of both thermodynamic stability and inertness. This peculiar behavior was rationalized on the basis of molecular modeling and appears to be related to a better fit in size of GaIII into the cavity of L2. Fast and efficient formation of the GaIII chelates at room temperature was observed at pH values between 7 and 8, which enables 68Ga radiolabeling under truly physiological conditions (pH 7.4).
Getting into stride: Bicyclic ligands, namely 4‐amino‐4‐methylperhydro‐pyrido1,2‐a1,4diazepin‐N,N′,N′‐triacetic acids (PIDAZTAs), have been synthesized as building blocks for the development of 68Ga‐based radiopharmaceuticals (see graphic). Quantitative radiolabeling was achieved under mild conditions in minutes. The chelators show stereochemistry‐driven thermodynamic and kinetic stability
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