Deficiency of RecA-dependent RecFOR and RecBCD pathways causes increased instability of the (GAA·TTC)n sequence when GAA is the lagging strand template

The most common mutation in Friedreich ataxia is an expanded (GAA·TTC)n sequence, which is highly unstable in human somatic cells and in the germline. The mechanisms responsible for this genetic instability are poorly understood. We previously showed that cloned (GAA·TTC)n sequences replicated in Escherichia coli are more unstable when GAA is the lagging strand template, suggesting erroneous lagging strand synthesis as the likely mechanism for the genetic instability. Here we show that the increase in genetic instability when GAA serves as the lagging strand template is seen in RecA-deficient but not RecA-proficient strains. We also found the same orientation-dependent increase in instability in a RecA+ temperature-sensitive E. coli SSB mutant strain (ssb-1). Since stalling of replication is known to occur within the (GAA·TTC)n sequence when GAA is the lagging strand template, we hypothesized that genetic stability of the (GAA·TTC)n sequence may require efficient RecA-dependent recombinational restart of stalled replication forks. Consistent with this hypothesis, we noted significantly increased instability when GAA was the lagging strand template in strains that were deficient in components of the RecFOR and RecBCD pathways. Our data implicate defective processing of stalled replication forks as a mechanism for genetic instability of the (GAA·TTC)n sequence

On the Core-Halo Mass Relation in Scalar Field Dark Matter Models and its Consequences for the Formation of Supermassive Black Holes

Scalar-field dark matter (SFDM) halos exhibit a core-envelope structure with soliton-like cores and CDM-like envelopes. Simulations without self-interaction (free-field case) report a core-halo mass relation $M_c\propto M_{h}^{\beta}$, with either $\beta=1/3$ or $\beta=5/9$, which can be understood if core and halo obey certain energy or velocity scalings. We extend the core-halo mass relations to include SFDM with self-interaction (SI), either repulsive or attractive, and investigate its implications for the gravitational instability and collapse of solitonic cores, leading to supermassive black hole (SMBH) formation. For SFDM parameters that make $\sim$ Kpc-sized cores and CDM-like structure formation on large scales but suppressed on small scales, cores are stable for all galactic halos of interest, from the free-field to the repulsive SI limit. For attractive SI, however, halos masses $M_h\sim (10^{10}-10^{12}) M_\odot$ have cores that collapse to SMBHs with $M_{SMBH}\sim 10^{6}-10^8 M_\odot$, as observations seem to require, while smaller-mass halos have stable cores, for particle masses $m\simeq (2.14\times 10^{-22}-9.9\times 10^{-20})\rm{eV}/c^2$, if the free-field has $\beta=1/3$, or $m = 2.23\times 10^{-21}-1.7\times 10^{-18}\rm{eV}/c^2$, if $\beta=5/9$. For free-field and repulsive cases, however, if previous constraints on particle parameters are relaxed to allow much smaller (sub-galactic scale) cores, then halos can also form SMBHs, for the same range of halo and BH masses, as long as $\beta = 5/9$ is correct for the free-field. In that case, structure formation in SFDM would be largely indistinguishable from Cold Dark Matter (CDM). Such SFDM models might not resolve the small-scale structure problems of CDM, but they would explain the formation of SMBHs quite naturally. Since CDM, itself, has not yet been ruled out, such SFDM models must also be viable (Abbreviated).Comment: 27 pages, 7 figures. Accepted by PR

Epigenetic Silencing in Friedreich Ataxia Is Associated with Depletion of CTCF (CCCTC-Binding Factor) and Antisense Transcription

Background: Over 15 inherited diseases are caused by expansion of triplet-repeats. Friedreich ataxia (FRDA) patients are homozygous for an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene. The expanded GAA triplet-repeat results in deficiency of FXN gene transcription, which is reversed via administration of histone deacetylase inhibitors indicating that transcriptional silencing is at least partially due to an epigenetic abnormality. Methodology/Principal Findings: We found a severe depletion of the chromatin insulator protein CTCF (CCCTC-binding factor) in the 59UTR of the FXN gene in FRDA, and coincident heterochromatin formation involving the +1 nucleosome via enrichment of H3K9me3 and recruitment of heterochromatin protein 1. We identified FAST-1 (FXN Antisense Transcript – 1), a novel antisense transcript that overlaps the CTCF binding site in the 59UTR, which was expressed at higher levels in FRDA. The reciprocal relationship of deficient FXN transcript and higher levels of FAST-1 seen in FRDA was reproduced in normal cells via knockdown of CTCF. Conclusions/Significance: CTCF depletion constitutes an epigenetic switch that results in increased antisense transcription, heterochromatin formation and transcriptional deficiency in FRDA. These findings provide a mechanistic basis for the transcriptional silencing of the FXN gene in FRDA, and broaden our understanding of disease pathogenesis in triplet-repea

Quasilocal Conservation Laws: Why We Need Them

We argue that conservation laws based on the local matter-only stress-energy-momentum tensor (characterized by energy and momentum per unit volume) cannot adequately explain a wide variety of even very simple physical phenomena because they fail to properly account for gravitational effects. We construct a general quasi}local conservation law based on the Brown and York total (matter plus gravity) stress-energy-momentum tensor (characterized by energy and momentum per unit area), and argue that it does properly account for gravitational effects. As a simple example of the explanatory power of this quasilocal approach, consider that, when we accelerate toward a freely-floating massive object, the kinetic energy of that object increases (relative to our frame). But how, exactly, does the object acquire this increasing kinetic energy? Using the energy form of our quasilocal conservation law, we can see precisely the actual mechanism by which the kinetic energy increases: It is due to a bona fide gravitational energy flux that is exactly analogous to the electromagnetic Poynting flux, and involves the general relativistic effect of frame dragging caused by the object's motion relative to us.Comment: 20 pages, 1 figur

Wave Mechanics and General Relativity: A Rapprochement

Using exact solutions, we show that it is in principle possible to regard waves and particles as representations of the same underlying geometry, thereby resolving the problem of wave-particle duality