Inhibitors against poly (ADP-ribose) polymerase (PARP) are promising targeted agents currently used to treat BRCA-mutant ovarian cancer and are in clinical trials for other cancer types, including ...BRCA-mutant breast cancer. To enhance the clinical response to PARP inhibitors (PARPis), understanding the mechanisms underlying PARPi sensitivity is urgently needed. Here, we show enhancer of zeste homolog 2 (EZH2), an enzyme that catalyzes H3 lysine trimethylation and associates with oncogenic function, contributes to PARPi sensitivity in breast cancer cells. Mechanistically, upon oxidative stress or alkylating DNA damage, PARP1 interacts with and attaches poly-ADP-ribose (PAR) chains to EZH2. PARylation of EZH2 by PARP1 then induces PRC2 complex dissociation and EZH2 downregulation, which in turn reduces EZH2-mediated H3 trimethylation. In contrast, inhibition of PARP by PARPi attenuates alkylating DNA damage-induced EZH2 downregulation, thereby promoting EZH2-mediated gene silencing and cancer stem cell property compared with PARPi-untreated cells. Moreover, the addition of an EZH2 inhibitor sensitizes the BRCA-mutant breast cells to PARPi. Thus, these results may provide a rationale for combining PARP and EZH2 inhibition as a therapeutic strategy for BRCA-mutated breast and ovarian cancers.
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•A mechanistic model of wire arc additive manufacturing is validated experimentally.•3D transient model considers mass addition, heat transfer, fluid flow and free surface.•New ...results on cooling rates, solidification parameters, droplet impact & finger penetration.•Effects of power, welding speed, wire diameter and feed rate are evaluated.
Structure, properties and serviceability of components made by wire arc additive manufacturing (WAAM) depend on the process parameters such as arc power, travel speed, wire diameter and wire feed rate. However, the selection of appropriate processing conditions to fabricate defect free and structurally sound components by trial and error is expensive and time consuming. Here we develop, test and utilize a three-dimensional heat transfer and fluid flow model of WAAM to calculate temperature and velocity fields, deposit shape and size, cooling rates and solidification parameters. The calculated fusion zone geometries and cooling rates for various arc power and travel speed and thermal cycles considering convective flow of molten metal agreed well with the corresponding experimental data for H13 tool steel deposits. It was found that convection is the main mechanism of heat transfer inside the molten pool. Faster travel speed enhanced the cooling rate but reduced the ratio of temperature gradient to solidification growth rate indicating increased instability of plane front solidification of components. Higher deposition rates could be achieved by increasing the heat input, using thicker wires and rapid wire feeding.
The caspase family is well characterized as playing a crucial role in modulation of programmed cell death (PCD), which is a genetically regulated, evolutionarily conserved process with numerous links ...to many human diseases, most notably cancer. In this review, we focus on summarizing the intricate relationships between some members of the caspase family and their key apoptotic mediators, involving tumour necrosis factor receptors, the Bcl‐2 family, cytochrome c, Apaf‐1 and IAPs in cancer initiation and progression. We elucidate new emerging types of cross‐talk between several caspases and autophagy‐related genes (Atgs) in cancer. Moreover, we focus on presenting several PCD‐modulating agents that may target caspases‐3, ‐8 and ‐9, and their substrates PARP‐1 and Beclin‐1, which may help us harness caspase‐modulated PCD pathways for future drug discovery.
A
bstract
We probe the multipartite entanglement structure of the vacuum state of a CFT in 1+1 dimensions, using recovery operations that attempt to reconstruct the density matrix in some region from ...its reduced density matrices on smaller subregions. We use an explicit recovery channel known as the twirled Petz map, and study distance measures such as the fidelity, relative entropy, and trace distance between the original state and the recovered state. One setup we study in detail involves three contiguous intervals
A
,
B
and
C
on a spatial slice, where we can view these quantities as measuring correlations between
A
and
C
that are not mediated by the region
B
that lies between them. We show that each of the distance measures is both UV finite and independent of the operator content of the CFT, and hence depends only on the central charge and the cross-ratio of the intervals. We evaluate these universal quantities numerically using lattice simulations in critical spin chain models, and derive their analytic forms in the limit where
A
and
C
are close using the OPE expansion. In the case where
A
and
C
are far apart, we find a surprising non-commutativity of the replica trick with the OPE limit. For all values of the cross-ratio, the fidelity is strictly better than a general information-theoretic lower bound in terms of the conditional mutual information. We also compare the mutual information between various subsystems in the original and recovered states, which leads to a more qualitative understanding of the differences between them. Further, we introduce generalizations of the recovery operation to more than three adjacent intervals, for which the fidelity is again universal with respect to the operator content.
Abstract
The dramatic changes in the magnetic field at the dipolarization front (DF) provide a suitable environment for electron acceleration, which usually can cause the flux enhancement of ...energetic electrons behind the front. However, it is unknown whether energetic electrons observed at the DF are energized locally, and which mechanism accelerates the electrons at the DF is unclear. Our study performs a direct quantitative analysis to reveal the acceleration process of energetic electrons at the DF using the high-time-resolution data from NASA's Magnetospheric Multiscale mission. The fluxes of energetic electrons at 90° are enhanced at the front. Under adiabatic conditions, our quantitative analysis indicates that these electrons at the front could be locally accelerated to over 100 keV by betatron acceleration. Eventually, the electron temperature anisotropy formed via the betatron mechanism could provide the free energy to excite whistler waves at the DF. Our quantitative study provides, for the first time, strong direct evidence for the local electron acceleration at the DF.
A
bstract
Within the colour dipole picture for deep inelastic scattering at small Bjorken
x
, we study the production of a pair of relatively hard jets via coherent diffraction. By “relatively hard” ...we mean that the transverse momenta of the two jets — the quark (
q
) and the antiquark (
q
¯
) generated by the decay of the virtual photon — are much larger than the target saturation momentum
Q
s
(
Y
ℙ
) evaluated at the rapidity gap
Y
ℙ
. We argue that the typical final-state configurations are such that the hard
q
q
¯
dijets are accompanied by a semi-hard gluon jet, with a transverse momentum of the order of
Q
s
(
Y
ℙ
). The presence of this third jet ensures that the scattering is strong and thus avoids the strong suppression of exclusive (hard) dijet production due to colour transparency. For such “2+1” jet configurations, we demonstrate that both the emission of the semi-hard gluon and its scattering with the hadronic target can be factorised in terms of an effective gluon-gluon dipole. This effective description, originally proposed in
1
–
7
, builds a bridge between the colour dipole picture and the transverse-momentum dependent (TMD) version of the collinear factorisation: the cross-section for diffractive 2+1 jets can be written as the product between a hard factor describing the
q
q
¯
dijets and a semi-hard factor expressing the unintegrated gluon distribution of the Pomeron. The latter is controlled by gluon dipole scattering in the black disk limit and hence is strongly sensitive to gluon saturation. By integrating out the kinematics of the 3 jets, we obtain the
q
q
¯
g
contribution to the diffractive structure function in collinearly-factorised form.
Abstract
Assisted by the Magnetospheric Multiscale mission capturing unprecedented high-resolution data in the terrestrial magnetotail, we apply a local streamline-topology classification methodology ...to investigate the categorization of the magnetic field topological structures at kinetic scales in the turbulent reconnection outflow. It is found that strong correlations exist between the straining and rotational part of the velocity gradient tensor as well as the magnetic field gradient tensor. Strong energy dissipation prefers to occur at regions with high magnetic stress or current density, which is contributed mainly by O-type topologies. These results indicate that the kinetic structures with O-type topology play a more important role in energy dissipation in turbulent reconnection outflow.
In the current work an investigation of the microstructures of EBM built Ti-6Al-4V test bars has been performed using OM, SEM, TEM and XRD. It has been found that the prior β phase, that formed ...during the initial solidification, possesses a column shaped morphology with growing direction parallel to built direction. Typical (α+β) structures namely Widmanstätten α platelets with rod-like β phase formed on the interfaces of the fine α grains, have been observed in the columnar prior β grains. Grain boundary α phase was found to be formed around the boundaries of the columnar prior β grains. Different phases present in the parts, especially the BCC β phases have been characterized. The TEM/EDX results indicate very high V composition in the β phase. Results of TEM/SAED and XRD also revealed that a superlattice structure could be present in the β phase. Phase transformation sequence is discussed according to the processing history and the microstructures observed.
► α+β and individual β phase is observed and characterized by SEM, TEM and XRD. ► β-phase is identified as rod-like structure embedded in α matrix and platelets. ► Phase transformation sequence is discussed as per thermal history and microstructures.
Observation of Interchange Reconnection on Mars Lin, R. T.; Huang, S. Y.; Yuan, Z. G. ...
Astrophysical journal/The Astrophysical journal,
01/2024, Letnik:
960, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract
Without a global dipole magnetic field, Mars has magnetic anomalies, i.e., crustal fields, in the southern hemisphere and interesting flexible magnetic fields in the magnetotail. The ...magnetic field topology is complex and flexible in the Martian magnetotail, especially over regions of strong crustal fields. However, the answer to how the magnetic field topology within crustal field regions transitions is elusive. Here we report the first case of interchange reconnection between open and closed crustal fields in the near-Mars magnetotail, using Mars Atmosphere and Volatile Evolution (MAVEN) observations. While MAVEN crossed from a region of closed crustal field to one of open crustal field, several characteristics of reconnection, such as the Hall magnetic field and plasma outflow, were observed. And plasmas are exchanged in the reconnection region. Our observations demonstrate that interchange reconnection can occur between open and closed crustal fields in the Martian near-magnetotail. Interchange reconnection occurring on the nightside changes the magnetic field topology within the crustal field regions and contributes to the escape of heavy ions.
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