The Nrf2 transcription factor governs the expression of hundreds genes involved in cell defense against oxidative stress, the hallmark of numerous diseases such as neurodegenerative, cardiovascular, ...some viral pathologies, diabetes and others. The main route for Nrf2 activity regulation is via interactions with the Keap1 protein. Under the normoxia the Keap1 binds the Nrf2 and targets it to the proteasomal degradation, while the Keap1 is regenerated. Upon oxidative stress the interactions between Nrf2 and Keap1 are interrupted and the Nrf2 activates the transcription of the protective genes. Currently, the Nrf2 system activation is considered as a powerful cytoprotective strategy for treatment of different pathologies, which pathogenesis relies on oxidative stress including viral diseases of pivotal importance such as COVID-19. The implementation of this strategy is accomplished mainly through the inactivation of the Keap1 “guardian” function. Two approaches are now developing: the Keap1 modification via electrophilic agents, which leads to the Nrf2 release, and direct interruption of the Nrf2:Keap1 protein-protein interactions (PPI). Because of theirs chemical structure, the Nrf2 electrophilic inducers could non-specifically interact with others cellular proteins leading to undesired effects. Whereas the non-electrophilic inhibitors of the Nrf2:Keap1 PPI could be more specific, thereby widening the therapeutic window.
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•Nrf2/Keap1 pathway is a key system, regulating expression of antioxidant and cytoprotective genes.•Modulation of the Nrf2/Keap1 system has been proven beneficial in controlling different diseases.•Electrophilic Nrf2 inducers are more advanced, but lack specificity.•Direct Nrf2:Keap1 inhibitors are more specific, but face delivery concerns.
This paper considers a set of equations describing the static isotropic gravitational field of a macroscopic body within the framework of the theory of gravity with a constraint. It is shown that for ...any static solid body, the energy of the gravitational field created by it is equal in magnitude to its rest energy, and the energy density defined in this theory is positive everywhere. A general approximate solution of the gravitational field equations is obtained. A nonsingular solution exists only at certain values for the three integration constants. The out-of-body metric coincides with the Schwarzschild metric, but unlike the general relativity theory (GR), the curvature tensor invariants have a certain finite value everywhere. It is claimed that a generally covariant theory of gravity, constructed on the basis of GR, is not physical since it violates the principle of material unity of the world.
We consider the ideal Fermi gas of indistinguishable particles without spin but with electric charge, confined to a Euclidean plane
R
2
perpendicular to an external constant magnetic field of ...strength
B
>
0
. We assume this (infinite) quantum gas to be in thermal equilibrium at zero temperature, that is, in its ground state with chemical potential
μ
≥
B
(in suitable physical units). For this (pure) state we define its local entropy
S
(
Λ
)
associated with a bounded (sub)region
Λ
⊂
R
2
as the von Neumann entropy of the (mixed) local substate obtained by reducing the infinite-area ground state to this region
Λ
of finite area
|
Λ
|
. In this setting we prove that the leading asymptotic growth of
S
(
L
Λ
)
, as the dimensionless scaling parameter
L
>
0
tends to infinity, has the form
L
B
|
∂
Λ
|
up to a precisely given (positive multiplicative) coefficient which is independent of
Λ
and dependent on
B
and
μ
only through the integer part of
(
μ
/
B
-
1
)
/
2
. Here we have assumed the boundary curve
∂
Λ
of
Λ
to be sufficiently smooth which, in particular, ensures that its arc length
|
∂
Λ
|
is well-defined. This result is in agreement with a so-called area-law scaling (for two spatial dimensions). It contrasts the zero-field case
B
=
0
, where an additional logarithmic factor
ln
(
L
)
is known to be present. We also have a similar result, with a slightly more explicit coefficient, for the simpler situation where the underlying single-particle Hamiltonian, known as the Landau Hamiltonian, is restricted from its natural Hilbert space
L
2
(
R
2
)
to the eigenspace of a single but arbitrary Landau level. Both results extend to the whole one-parameter family of quantum Rényi entropies. As opposed to the case
B
=
0
, the corresponding asymptotic coefficients depend on the Rényi index in a non-trivial way.
Olivine compositions provide critical information on the composition and origin of primary mantle-derived melts and their sources. The minor and trace elements (Ni, Mn, Ca, Al, Cr, Co, Ti, Zn, P, ...Na), which are present at concentrations over 10ppm, are especially informative and can be determined by electron probe microanalysis (EPMA). Here we report a new analytical method to analyse these elements with unprecedented precision for an electron microprobe.
The method was developed using the new JEOL JXA 8230 EPMA at ISTerre, UJF, Grenoble, France. The facility has a tungsten source gun and is equipped with five wavelength-dispersive spectrometers (WDS) and one silicon drift detector energy-dispersive spectrometer (SDD, EDS). It is placed in an environment with closely controlled temperature (+/−0.5°C) and humidity (+/−4%).
The analytical conditions are as follows: acceleration voltage 25kV, 900nA beam current; WDS detection for trace elements (Ni, Mn, Ca, Al, Cr, Co, Ti, Zn, P, Na) and EDS detection for Si, Mg and Fe; total counting time 12min; ZAF correction. The analysed volume is a half-sphere with a diameter of approximately 7μm for most elements or a cylinder with a diameter of 7μm and depth of approximately 2μm for Al and Na. Instrumental drift during analytical sessions was monitored by repeated measurements of olivine standards. For trace elements, the method yields detection limits from 4 to 10ppm and similar precision of individual analyses (2 standard errors). The detectable amount of an element is down to 2∗10−15 g and the precision for Fo in olivine is 200–300ppm (2 standard errors).
Comparison of data obtained using the EPMA with laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) for a large range of olivine compositions confirms the accuracy of the EPMA which is similar to the precision noted above.
Electron probe microanalysis of Ni, Mn, Ca, Al, Cr, Co, Ti, Zn, P, Na in olivine by WDS, precision better than 10ppm (2σ).•Simultaneous with trace elements, analysis of Fe, Mg and Si in olivine by EDS, precision for Fo better than 300ppm (2σ).•Analytical volume is a half-sphere with a diameter of approximately 7μm for most elements.
It is proved that the one-particle density matrix
γ
(
x
,
y
)
for multi-particle Coulombic systems is real analytic away from the nuclei and from the diagonal
x
=
y
.
Archaean komatiites (ultramafic lavas) result from melting under extreme conditions of the Earth's mantle. Their chemical compositions evoke very high eruption temperatures, up to 1,600 degrees ...Celsius, which suggests even higher temperatures in their mantle source. This message is clouded, however, by uncertainty about the water content in komatiite magmas. One school of thought holds that komatiites were essentially dry and originated in mantle plumes while another argues that these magmas contained several per cent water, which drastically reduced their eruption temperature and links them to subduction processes. Here we report measurements of the content of water and other volatile components, and of major and trace elements in melt inclusions in exceptionally magnesian olivine (up to 94.5 mole per cent forsterite). This information provides direct estimates of the composition and crystallization temperature of the parental melts of Archaean komatiites. We show that the parental melt for 2.7-billion-year-old komatiites from the Abitibi greenstone belt in Canada contained 30 per cent magnesium oxide and 0.6 per cent water by weight, and was depleted in highly incompatible elements. This melt began to crystallize at around 1,530 degrees Celsius at shallow depth and under reducing conditions, and it evolved via fractional crystallization of olivine, accompanied by minor crustal assimilation. As its major- and trace-element composition and low oxygen fugacities are inconsistent with a subduction setting, we propose that its high H2O/Ce ratio (over 6,000) resulted from entrainment into the komatiite source of hydrous material from the mantle transition zone. These results confirm a plume origin for komatiites and high Archaean mantle temperatures, and evoke a hydrous reservoir in the deep mantle early in Earth's history.
This review describes artificial modular nanotransporters (MNTs) delivering their cargos into target cells and then into the nuclei - the most vulnerable cell compartment for most anticancer agents ...and especially for radionuclides emitting short-range particles. The MNT strategy uses natural subcellular transport processes inherent in practically all cells including cancer cells. The MNTs use these processes just as a passenger who purchased tickets for a multiple-transfer trip making use of different kinds of public transport to reach the desired destination. The MNTs are fusion polypeptides consisting of several parts, replaceable modules, accomplishing binding to a specific receptor on the cell and subsequent internalization, endosomal escape and transport into the cell nucleus. Radionuclides emitting short-range particles, like Auger electron emitters, acquire cell specificity and significantly higher cytotoxicity both
and
when delivered by the MNTs into the nuclei of cancer cells. MNT modules are interchangeable, allowing replacement of receptor recognition modules, which permits their use for different types of cancer cells and, as a cocktail of several MNTs, for targeting several tumor-specific molecules for personalized medicine.
More than 50 per cent of the Earth's upper mantle consists of olivine and it is generally thought that mantle-derived melts are generated in equilibrium with this mineral. Here, however, we show that ...the unusually high nickel and silicon contents of most parental Hawaiian magmas are inconsistent with a deep olivine-bearing source, because this mineral together with pyroxene buffers both nickel and silicon at lower levels. This can be resolved if the olivine of the mantle peridotite is consumed by reaction with melts derived from recycled oceanic crust, to form a secondary pyroxenitic source. Our modelling shows that more than half of Hawaiian magmas formed during the past 1 Myr came from this source. In addition, we estimate that the proportion of recycled (oceanic) crust varies from 30 per cent near the plume centre to insignificant levels at the plume edge. These results are also consistent with volcano volumes, magma volume flux and seismological observations.
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