The appropriate execution of DNA double-strand break (DSB) repair is critical for genome stability and tumor avoidance. 53BP1 and BRCA1 directly influence DSB repair pathway choice by regulating 5′ ...end resection, but how this is achieved remains uncertain. Here we report that Rif1−/− mice are severely compromised for 53BP1-dependent class switch recombination (CSR) and fusion of dysfunctional telomeres. The inappropriate accumulation of RIF1 at DSBs in S phase is antagonized by BRCA1, and deletion of Rif1 suppresses toxic nonhomologous end joining (NHEJ) induced by PARP inhibition in Brca1-deficient cells. Mechanistically, RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination.
Display omitted
► RIF1 is essential for 53BP1-dependent CSR and fusion of dysfunctional telomeres ► BRCA1 antagonizes RIF1 in S phase to prevent error-prone repair by toxic NHEJ ► N-terminal phospho-SQ/TQ domain of 53BP1 interacts with and recruits RIF1 to DSBs ► RIF1 and 53BP1 promote NHEJ in G1 by blocking 5′ end resection of DSBs
To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or ...retinal vein occlusion (RVO).
Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab (0.5 mg for AMD/RVO, 0.3 mg for DME). The main outcome measures were serum PKs and plasma free-VEGF concentrations after the first and third injections.
A total of 151 patients were included. In AMD/DME/RVO, systemic exposure to each drug was highest with bevacizumab, then aflibercept, and lowest with ranibizumab. Ranibizumab cleared from the bloodstream more quickly than bevacizumab or aflibercept. Aflibercept treatment resulted in the greatest reductions in plasma free-VEGF relative to baseline levels, whereas ranibizumab treatment resulted in the smallest decreases in plasma free-VEGF.
The three anti-VEGF treatments examined in this analysis demonstrated notable differences in systemic PKs. Generally, the reduction in plasma free-VEGF levels correlated with elevated levels of circulating anti-VEGF agents, with the reduction in free-VEGF levels greatest with aflibercept and least with ranibizumab.
The total red shift
z
might be recast as a combination of the expansion red shift and a static shift due to the energy–momentum tensor non-conservation of a photon propagating through ...Electro-Magnetic (EM) fields. If massive, the photon may be described by the de Broglie–Proca (dBP) theory which satisfies the Lorentz(-Poincaré) Symmetry (LoSy) but not gauge-invariance. The latter is regained in the Standard-Model Extension (SME), associated with LoSy Violation (LSV) that naturally dresses photons of a mass. The non-conservation stems from the vacuum expectation value of the vector and tensor LSV fields. The final colour (red or blue) and size of the static shift depend on the orientations and strength of the LSV and EM multiple fields encountered along the path of the photon. Turning to cosmology, for a zero
Ω
Λ
energy density, the discrepancy between luminosity and red shift distances of SNeIa disappears thanks to the recasting of
z
. Massive photons induce an effective dark energy acting ‘optically’ but not dynamically.
In the presence of Lorentz Symmetry Violation (LSV) associated with the Standard-Model Extension (SME), we have recently shown the non-conservation of the energy-momentum tensor of a light-wave ...crossing an Electro-Magnetic (EM) background field even when the latter and the LSV are constant. Incidentally, for a space-time dependent LSV, the presence of an EM field is not necessary. Herein, we infer that in a particle description, the energy non-conservation for a photon implies violation of frequency invariance
in vacuo
, giving rise to a red or blue shift. We discuss the potential consequences on cosmology.
To investigate the impact of the 2 major DNA repair machineries on cellular survival in response to irradiation with the 2 types of ionizing radiation.
The DNA repair and cell survival endpoints in ...wild-type, homologous recombination (HR)-deficient, and nonhomologous end-joining-deficient cells were analyzed after irradiation with clinically relevant, low-linear energy transfer (LET) protons and 200-keV photons.
All cell lines were more sensitive to proton irradiation compared with photon irradiation, despite no differences in the induction of DNA breaks. Interestingly, HR-deficient cells and wild-type cells with small interfering RNA-down-regulated Rad51 were markedly hypersensitive to proton irradiation, resulting in an increased relative biological effectiveness in comparison with the relative biological effectiveness determined in wild-type cells. In contrast, lack of nonhomologous end-joining did not result in hypersensitivity toward proton irradiation. Repair kinetics of DNA damage in wild-type cells were equal after both types of irradiation, although proton irradiation resulted in more lethal chromosomal aberrations. Finally, repair kinetics in HR-deficient cells were significantly delayed after proton irradiation, with elevated amounts of residual γH2AX foci after irradiation.
Our data indicate a differential quality of DNA damage by proton versus photon irradiation, with a specific requirement for homologous recombination for DNA repair and enhanced cell survival. This has potential relevance for clinical stratification of patients carrying mutations in the DNA damage response pathways.
Within the standard model extension (SME), we expand our previous findings on four classes of violations of Super-Symmetry (SuSy) and Lorentz Symmetry (LoSy), differing in the handedness of the ...Charge conjugation-Parity-Time reversal (CPT) symmetry and in whether considering the impact of photinos on photon propagation. The violations, occurring at the early universe high energies, show visible traces at present in the Dispersion Relations (DRs). For the CPT-odd classes (
V
μ
breaking vector) associated with the Carroll–Field–Jackiw (CFJ) model, the DRs and the Lagrangian show for the photon an effective mass, gauge invariant, proportional to
|
V
|
. The group velocity exhibits a classic dependency on the inverse of the frequency squared. For the CPT-even classes (
k
F
breaking tensor), when the photino is considered, the DRs display also a massive behaviour inversely proportional to a coefficient in the Lagrangian and to a term linearly dependent on
k
F
. All DRs display an angular dependence and lack LoSy invariance. In describing our results, we also point out the following properties: (i) the appearance of complex or simply imaginary frequencies and super-luminal speeds and (ii) the emergence of bi-refringence. Finally, we point out the circumstances for which SuSy and LoSy breakings, possibly in presence of an external field, lead to the non-conservation of the photon energy-momentum tensor. We do so for both CPT sectors.
Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking.
Fifty-six ...patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5 mg), bevacizumab (1.25 mg), or aflibercept (2.0 mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections.
Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10 pg/mL) as early as 3 h postdose until ≥7 days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4 pg/mL compared with baseline of 17 pg/mL.
There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF.
NCT02118831.
Protecting stalled DNA replication forks from degradation by promiscuous nucleases is essential to prevent genomic instability, a major driving force of tumorigenesis. Several proteins commonly ...associated with the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) have been implicated in the stabilization of stalled forks. Human CtIP, in conjunction with the MRE11 nuclease complex, plays an important role in HR by promoting DSB resection. Here, we report an unanticipated function for CtIP in protecting reversed forks from degradation. Unlike BRCA proteins, which defend nascent DNA strands from nucleolytic attack by MRE11, we find that CtIP protects perturbed forks from erroneous over-resection by DNA2. Finally, we uncover functionally synergistic effects between CtIP and BRCA1 in mitigating replication-stress-induced genomic instability. Collectively, our findings reveal a DSB-resection- and MRE11-independent role for CtIP in preserving fork integrity that contributes to the survival of BRCA1-deficient cells.
Display omitted
•CtIP protects reversed forks from nucleolytic degradation•CtIP prevents DNA2-dependent over-resection of nascent strands•CtIP nuclease mutants are defective in fork protection•CtIP-mediated fork protection synergizes with BRCA1, not BRCA2
Przetocka et al. identify a function of CtIP in maintaining replication fork stability that is distinct from its role in DSB resection. CtIP keeps DNA2 nuclease in check to limit the degradation of stalled forks. Loss of CtIP in BRCA1-deficient cells aggravates replication-stress-induced genomic instability, causing synthetic lethality.
An idealized "test" object in general relativity moves along a geodesic. However, if the object has a finite mass, this will create additional curvature in the spacetime, causing it to deviate from ...geodesic motion. If the mass is nonetheless sufficiently small, such an effect is usually treated perturbatively and is known as the gravitational self-force due to the object. This issue is still an open problem in gravitational physics today, motivated not only by basic foundational interest, but also by the need for its direct application in gravitational wave astronomy. In particular, the observation of extreme-mass-ratio inspirals by the future space-based detector LISA will rely crucially on an accurate modeling of the self-force driving the orbital evolution and gravitational wave emission of such systems. In this paper, we present a novel derivation, based on conservation laws, of the basic equations of motion for this problem. They are formulated with the use of a quasilocal (rather than matter) stress-energy-momentum tensor-in particular, the Brown-York tensor-so as to capture gravitational effects in the momentum flux of the object, including the self-force. Our formulation and resulting equations of motion are independent of the choice of the perturbative gauge. We show that, in addition to the usual gravitational self-force term, they also lead to an additional "self-pressure" force not found in previous analyses, and also that our results correctly recover known formulas under appropriate conditions. Our approach thus offers a fresh geometrical picture from which to understand the self-force fundamentally, and potentially useful new avenues for computing it practically.
PDF
