Background
Despite differences in how it is defined, there is a general consensus amongst clinicians and researchers that the sexual abuse of children and adolescents ('child sexual abuse') is a ...substantial social problem worldwide. The effects of sexual abuse manifest in a wide range of symptoms, including fear, anxiety, post‐traumatic stress disorder and various externalising and internalising behaviour problems, such as inappropriate sexual behaviours. Child sexual abuse is associated with increased risk of psychological problems in adulthood. Cognitive‐behavioural approaches are used to help children and their non‐offending or 'safe' parent to manage the sequelae of childhood sexual abuse. This review updates the first Cochrane review of cognitive‐behavioural approaches interventions for children who have been sexually abused, which was first published in 2006.
Objectives
To assess the efficacy of cognitive‐behavioural approaches (CBT) in addressing the immediate and longer‐term sequelae of sexual abuse on children and young people up to 18 years of age.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2011 Issue 4); MEDLINE (1950 to November Week 3 2011); EMBASE (1980 to Week 47 2011); CINAHL (1937 to 2 December 2011); PsycINFO (1887 to November Week 5 2011); LILACS (1982 to 2 December 2011) and OpenGrey, previously OpenSIGLE (1980 to 2 December 2011). For this update we also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP).
Selection criteria
We included randomised or quasi‐randomised controlled trials of CBT used with children and adolescents up to age 18 years who had experienced being sexually abused, compared with treatment as usual, with or without placebo control.
Data collection and analysis
At least two review authors independently assessed the eligibility of titles and s identified in the search. Two review authors independently extracted data from included studies and entered these into Review Manager 5 software. We synthesised and presented data in both written and graphical form (forest plots).
Main results
We included 10 trials, involving 847 participants. All studies examined CBT programmes provided to children or children and a non‐offending parent. Control groups included wait list controls (n = 1) or treatment as usual (n = 9). Treatment as usual was, for the most part, supportive, unstructured psychotherapy. Generally the reporting of studies was poor. Only four studies were judged 'low risk of bias' with regards to sequence generation and only one study was judged 'low risk of bias' in relation to allocation concealment. All studies were judged 'high risk of bias' in relation to the blinding of outcome assessors or personnel; most studies did not report on these, or other issues of bias. Most studies reported results for study completers rather than for those recruited.
Depression, post‐traumatic stress disorder (PTSD), anxiety and child behaviour problems were the primary outcomes. Data suggest that CBT may have a positive impact on the sequelae of child sexual abuse, but most results were not statistically significant. Strongest evidence for positive effects of CBT appears to be in reducing PTSD and anxiety symptoms, but even in these areas effects tend to be 'moderate' at best. Meta‐analysis of data from five studies suggested an average decrease of 1.9 points on the Child Depression Inventory immediately after intervention (95% confidence interval (CI) decrease of 4.0 to increase of 0.4; I2 = 53%; P value for heterogeneity = 0.08), representing a small to moderate effect size. Data from six studies yielded an average decrease of 0.44 standard deviations on a variety of child post‐traumatic stress disorder scales (95% CI 0.16 to 0.73; I2 = 46%; P value for heterogeneity = 0.10). Combined data from five studies yielded an average decrease of 0.23 standard deviations on various child anxiety scales (95% CI 0.3 to 0.4; I2 = 0%; P value for heterogeneity = 0.84). No study reported adverse effects.
Authors' conclusions
The conclusions of this updated review remain the same as those when it was first published. The review confirms the potential of CBT to address the adverse consequences of child sexual abuse, but highlights the limitations of the evidence base and the need for more carefully conducted and better reported trials.
The act of position measurement alters the motion of an object being measured. This quantum measurement backaction is typically much smaller than the thermal motion of a room-temperature object and ...thus difficult to observe. By shining laser light through a nanomechanical beam, we measure the beam’s thermally driven vibrations and perturb its motion with optical force fluctuations at a level dictated by the Heisenberg measurement-disturbance uncertainty relation. We demonstrate a cross-correlation technique to distinguish optically driven motion from thermally driven motion, observing this quantum backaction signature up to room temperature. We use the scale of the quantum correlations, which is determined by fundamental constants, to gauge the size of thermal motion, demonstrating a path toward absolute thermometry with quantum mechanically calibrated ticks.
Abstract
We investigate the ionizing effect of low-energy cosmic rays (CRs) from a young star on its protoplanetary disc (PPD). We consider specifically the effect of ∼3 GeV protons injected at the ...inner edge of the PPD. An increase in the ionization fraction as a result of these CRs could allow the magnetorotational instability to operate in otherwise magnetically dead regions of the disc. For the typical values assumed we find an ionization rate of ζCR ∼ 10−17 s−1 at 1 au. The transport equation is solved by treating the propagation of the CRs as diffusive. We find for increasing diffusion coefficients the CRs penetrate further in the PPD, while varying the mass density profile of the disc is found to have little effect. We investigate the effect of an energy spectrum of CRs. The influence of a disc wind is examined by including an advective term. For advective wind speeds between 1 and 100 km s−1 diffusion dominates at all radii considered here (out to 10 au) for reasonable diffusion coefficients. Overall, we find that low-energy CRs can significantly ionize the mid-plane of PPDs out to ∼1 au. By increasing the luminosity or energy of the CRs, within plausible limits, their radial influence could increase to ∼2 au at the mid-plane but it remains challenging to significantly ionize the mid-plane further out.
The replisome must overcome DNA damage to ensure complete chromosome replication. Here, we describe the earliest events in this process by reconstituting collisions between a eukaryotic replisome, ...assembled with purified proteins, and DNA damage. Lagging-strand lesions are bypassed without delay, leaving daughter-strand gaps roughly the size of an Okazaki fragment. In contrast, leading-strand polymerase stalling significantly impacts replication fork progression. We reveal that the core replisome itself can bypass leading-strand damage by re-priming synthesis beyond it. Surprisingly, this restart activity is rare, mainly due to inefficient leading-strand re-priming, rather than single-stranded DNA exposure or primer extension. We find several unanticipated mechanistic distinctions between leading- and lagging-strand priming that we propose control the replisome’s initial response to DNA damage. Notably, leading-strand restart was specifically stimulated by RPA depletion, which can occur under conditions of replication stress. Our results have implications for pathway choice at stalled forks and priming at DNA replication origins.
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•Reconstitution of collisions between a eukaryotic replisome and DNA damage•Leading-strand damage specifically causes fork stalling and uncoupling•The eukaryotic replisome can re-initiate leading-strands downstream of DNA damage•Multiple mechanistic differences exist between leading- and lagging-strand priming
To study the earliest events following DNA polymerase stalling during replication, Taylor and Yeeles reconstituted collisions between a yeast replisome assembled with purified proteins and template DNA damage. Surprisingly, re-priming of leading-strand synthesis beyond damage is inefficient but is promoted by RPA depletion, whereas lagging-strand priming occurs robustly after damage.
Abstract
We assess the ionising effect of low energy protostellar cosmic rays in protoplanetary disks around a young solar mass star for a wide range of disk parameters. We assume a source of low ...energy cosmic rays located close to the young star which travel diffusively through the protoplanetary disk. We use observationally inferred values from nearby star-forming regions for the total disk mass and the radial density profile. We investigate the influence of varying the disk mass within the observed scatter for a solar mass star. We find that for a large range of disk masses and density profiles that protoplanetary disks are “optically thin” to low energy (∼3 GeV) cosmic rays. At R ∼ 10 au, for all of the disks that we consider (Mdisk = 6.0 × 10−4 − 2.4 × 10−2M⊙), the ionisation rate due to low energy stellar cosmic rays is larger than that expected from unmodulated galactic cosmic rays. This is in contrast to our previous results which assumed a much denser disk which may be appropriate for a more embedded source. At R ∼ 70 au, the ionisation rate due to stellar cosmic rays dominates in ∼50% of the disks. These are the less massive disks with less steep density profiles. At this radius there is at least an order of magnitude difference in the ionisation rate between the least and most massive disk that we consider. Our results indicate, for a wide range of disk masses, that low energy stellar cosmic rays provide an important source of ionisation at the disk midplane at large radii (∼70 au).
Chromosome replication is performed by a complex and intricate ensemble of proteins termed the replisome, where the DNA polymerases Polδ and Polε, DNA polymerase α-primase (Polα) and accessory ...proteins including AND-1, CLASPIN and TIMELESS-TIPIN (respectively known as Ctf4, Mrc1 and Tof1-Csm3 in Saccharomyces cerevisiae) are organized around the CDC45-MCM-GINS (CMG) replicative helicase
. Because a functional human replisome has not been reconstituted from purified proteins, how these factors contribute to human DNA replication and whether additional proteins are required for optimal DNA synthesis are poorly understood. Here we report the biochemical reconstitution of human replisomes that perform fast and efficient DNA replication using 11 purified human replication factors made from 43 polypeptides. Polε, but not Polδ, is crucial for optimal leading-strand synthesis. Unexpectedly, Polε-mediated leading-strand replication is highly dependent on the sliding-clamp processivity factor PCNA and the alternative clamp loader complex CTF18-RFC. We show how CLASPIN and TIMELESS-TIPIN contribute to replisome progression and demonstrate that, in contrast to the budding yeast replisome
, AND-1 directly augments leading-strand replication. Moreover, although AND-1 binds to Polα
, the interaction is dispensable for lagging-strand replication, indicating that Polα is functionally recruited via an AND-1-independent mechanism for priming in the human replisome. Collectively, our work reveals how the human replisome achieves fast and efficient leading-strand and lagging-strand DNA replication, and provides a powerful system for future studies of the human replisome and its interactions with other DNA metabolic processes.
The human replisome is an elaborate arrangement of molecular machines responsible for accurate chromosome replication. At its heart is the CDC45‐MCM‐GINS (CMG) helicase, which, in addition to ...unwinding the parental DNA duplex, arranges many proteins including the leading‐strand polymerase Pol ε, together with TIMELESS‐TIPIN, CLASPIN and AND‐1 that have key and varied roles in maintaining smooth replisome progression. How these proteins are coordinated in the human replisome is poorly understood. We have determined a 3.2 Å cryo‐EM structure of a human replisome comprising CMG, Pol ε, TIMELESS‐TIPIN, CLASPIN and AND‐1 bound to replication fork DNA. The structure permits a detailed understanding of how AND‐1, TIMELESS‐TIPIN and Pol ε engage CMG, reveals how CLASPIN binds to multiple replisome components and identifies the position of the Pol ε catalytic domain. Furthermore, the intricate network of contacts contributed by MCM subunits and TIMELESS‐TIPIN with replication fork DNA suggests a mechanism for strand separation.
SYNOPSIS
Cryo‐EM structures of the core human replisome reveal its complex architecture and show how TIMELESS‐TIPIN, AND‐1, Pol ε and CLASPIN engage the CMG helicase. Contacts between MCM subunits and DNA suggest a mechanism for strand separation.
High‐resolution structure of a reconstituted human replisome comprising the CMG helicase, AND‐1, TIMELESS‐TIPIN, Pol ε, CLASPIN and fork DNA.
Detailed description of the protein‐protein and protein‐DNA contacts that underpin the organisation of the human replisome.
Atomic model for three regions of CLASPIN showing how the protein extends across one side of the replisome contacting TIMELESS, MCM2 and MCM6.
Identification of a specific conformation for the catalytic domain of Pol ε, demonstrating that Pol ε can adopt a “linear” configuration in the human replisome.
Cryo‐EM structures of reconstituted human core replisomes show how TIMELESS‐TIPIN, AND‐1, Pol ε and CLASPIN engage the CMG helicase, and suggest a mechanism for DNA strand separation.
Leading-strand polymerase stalling at DNA damage impairs replication fork progression. Using biochemical approaches, we show this arises due to both slower template unwinding following ...helicase–polymerase uncoupling and establishment of prolonged stalled fork structures. Fork slowing and stalling occur at structurally distinct lesions, are always associated with continued lagging-strand synthesis, are observed when either Pol ε or Pol δ stalls at leading-strand damage, and do not require specific helicase–polymerase coupling factors. Hence, the key trigger for these replisome-intrinsic responses is cessation of leading-strand polymerization, revealing this as a crucial driver of normal replication fork rates. We propose that this helps balance the need for sufficient uncoupling to activate the DNA replication checkpoint with excessive destabilizing single-stranded DNA exposure in eukaryotes.
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•The replisome displays indistinguishable responses to structurally distinct lesions.•Cessation of leading-strand synthesis triggers an inbuilt brake in the replisome.•Fork slowing occurs even with the minimal proteins needed for replication in vitro.•Either Pol ε or Pol δ stalling on the leading-strand impedes fork progression.•Lagging-strand synthesis always occurs efficiently beyond leading-strand damage.
ABSTRACT
Cosmic rays may have contributed to the start of life on the Earth. Here, we investigate the evolution of the Galactic cosmic ray spectrum at the Earth from ages t = 0.6−6.0 Gyr. We use a 1D ...cosmic ray transport model and a 1.5D stellar wind model to derive the evolving wind properties of a solar-type star. At $t=1\,$ Gyr, approximately when life is thought to have begun on the Earth, we find that the intensity of ∼GeV Galactic cosmic rays would have been ∼10 times smaller than the present-day value. At lower kinetic energies, Galactic cosmic ray modulation would have been even more severe. More generally, we find that the differential intensity of low-energy Galactic cosmic rays decreases at younger ages and is well described by a broken power law in solar rotation rate. We provide an analytic formula of our Galactic cosmic ray spectra at the Earth’s orbit for different ages. Our model is also applicable to other solar-type stars with exoplanets orbiting at different radii. Specifically, we use our Galactic cosmic ray spectrum at 20 au for $t=600\,$ Myr to estimate the penetration of cosmic rays in the atmosphere of HR 2562b, a directly imaged exoplanet orbiting a young solar-type star. We find that the majority of particles <0.1 GeV are attenuated at pressures ≳10−5 bar and thus do not reach altitudes below ∼100 km. Observationally constraining the Galactic cosmic ray spectrum in the atmosphere of a warm Jupiter would in turn help constrain the flux of cosmic rays reaching young Earth-like exoplanets.
Rorschach inkblots have had a striking impact on the worlds of art and science because of the remarkable variety of associations with recognizable and namable objects they induce. Originally adopted ...as a projective psychological tool to probe mental health, psychologists and artists have more recently interpreted the variety of induced images simply as a signature of the observers' creativity. Here we analyze the relationship between the spatial scaling parameters of the inkblot patterns and the number of induced associations, and suggest that the perceived images are induced by the fractal characteristics of the blot edges. We discuss how this relationship explains the frequent observation of images in natural scenery.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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