A Profile of Working Memory Ability in Poor Readers

Objective: This study aimed to provide a comprehensive working memory profile of a group of children with established poor reading ability. Methods: Participants included a group of established “poor readers” and a group of age- and gender-matched controls with typically developing reading ability. The participants completed a comprehensive battery of assessments examining four components of working memory—the central executive, phonological loop, visuospatial sketchpad, and episodic buffer. Results: As predicted, the poor reading group scored significantly lower than the typically developing reading group on measures of the phonological loop and central executive. There were no significant differences between the two groups on measures of the visuospatial sketchpad or episodic buffer. Contrary to predictions, a subgroup of poor readers with poor visuospatial working memory was not found, further highlighting the inconsistent findings in this area of working memory. Conclusions: The results provide support for past research findings of deficits in the phonological loop and central executive of poor readers. The finding of typical episodic buffer functioning demonstrates the potential to draw on this relative strength in implementing interventions with poor readers. This implicates the importance of increasing awareness of specific working memory deficits in poor readers, and may guide future research into more effective teaching strategies and interventions for this population

Variable levels of drift in tunicate cardiopharyngeal gene regulatory elements.

Background: Mutations in gene regulatory networks often lead to genetic divergence without impacting gene expression or developmental patterning. The rules governing this process of developmental systems drift, including the variable impact of selective constraints on different nodes in a gene regulatory network, remain poorly delineated. Results: Here we examine developmental systems drift within the cardiopharyngeal gene regulatory networks of two tunicate species, Corella inflata and Ciona robusta. Cross-species analysis of regulatory elements suggests that trans-regulatory architecture is largely conserved between these highly divergent species. In contrast, cis-regulatory elements within this network exhibit distinct levels of conservation. In particular, while most of the regulatory elements we analyzed showed extensive rearrangements of functional binding sites, the enhancer for the cardiopharyngeal transcription factor FoxF is remarkably well-conserved. Even minor alterations in spacing between binding sites lead to loss of FoxF enhancer function, suggesting that bound trans-factors form position-dependent complexes. Conclusions: Our findings reveal heterogeneous levels of divergence across cardiopharyngeal cis-regulatory elements. These distinct levels of divergence presumably reflect constraints that are not clearly associated with gene function or position within the regulatory network. Thus, levels of cis-regulatory divergence or drift appear to be governed by distinct structural constraints that will be difficult to predict based on network architectur

Table_1_The unified protocol for transdiagnostic treatment of emotional disorders for misophonia: a pilot trial exploring acceptability and efficacy.docx

IntroductionMisophonia is a recently defined disorder characterized by distressing responses to everyday sounds, such as chewing or sniffling. Individuals with misophonia experience significant functional impairment but have limited options for evidenced-based behavioral treatment. To address this gap in the literature, the current pilot trial explored the acceptability and efficacy of a transdiagnostic cognitive-behavioral approach to treating symptoms of misophonia.MethodsThis trial was conducted in two studies: In Study 1, the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) was delivered to eight patients in order to receive feedback to guide revisions to the treatment to suit this population. In Study 2, ten patients received the revised UP treatment to explore its acceptability and preliminary efficacy. This study used a single-case experimental design with multiple baselines, randomizing patients to either a 2-week baseline or 4-week baseline prior to the 16 weeks of treatment, followed by four weeks of follow-up.ResultsThe findings from these studies suggested that patients found both the original and adapted versions of the UP to be acceptable and taught them skills for how to manage their misophonia symptoms. Importantly, the findings also suggested that the UP can help remediate symptoms of misophonia, particularly the emotional and behavioral responses.DiscussionThese findings provide preliminary evidence that this transdiagnostic treatment for emotional disorders can improve symptoms of misophonia in adults.</p

Cambiarenes: Single-Step Synthesis and Anion Binding of a Clip- Shaped Macrocycle with a Redox-Active Core

We report the synthesis of a novel macrocyclic host molecule that forms in a single step from commercially available starting materials. The core of the macrocycle backbone possesses two quinone rings and, thus, is redox-active. Host-guest binding involving the clip-shaped cavity indicates selective binding of pyridine N-oxides based of the electron density of and steric bulk of the anionic oxygen.</div

Identification And Characterization Of A B-Raf Kinase Alpha Helix Critical For The Activity Of MEK Kinase In MAPK Signaling

In the mitogen-activated protein kinase (MAPK) pathway, an oncogenic V600E mutation in B-Raf kinase causes the enzyme to be constitutively active, leading to aberrantly high phosphorylation levels of its downstream effectors, MEK and ERK kinases. The V600E mutation in B-Raf accounts for more than half of all melanomas and ~3% of all cancers and many drugs target the ATP-binding site of the enzyme for its inhibition. Since B-Raf can develop resistance against these drugs and such drugs can induce paradoxical activation, drugs that target allosteric sites are needed. To identify other potential drug targets, we used information from the available B-Raf-MEK crystal structure to generate an active form of B-RafV600E that can be expressed using a bacterial expression system. In doing so, we identified an alpha helix on B-Raf, found at the B-Raf-MEK interface, that is critical for their interaction and the oncogenic activity of B-RafV600E. We introduced mutations along this alpha helix to pinpoint regions that are important for the B-Raf-MEK interaction and tested their effects on binding and phosphorylation. We performed binding experiments between B-Raf mutants and MEK using pull downs and biolayer interferometry. We also assessed phosphorylation levels of MEK, as well as its downstream target ERK, in vitro and in cells. These studies showed that mutating certain residues on this alpha helix is detrimental to binding and downstream activity. This result suggests that this B-Raf alpha helix binding site on MEK could be a site to target for drug development to treat B-RafV600E-induced melanomas. Our cell-based data with a point mutation in B-Raf further suggests that combination therapies with ATP-competitive inhibitors would be useful to further reduce B-Raf activity and prevent the development of resistanc

Identification And Characterization Of A B-Raf Kinase α-Helix Critical For The Activity Of MEK Kinase In MAPK Signaling

In the MAPK pathway, an oncogenic V600E mutation in B-Raf kinase causes the enzyme to be constitutively active, leading to aberrantly high phosphorylation levels of its downstream effectors, MEK and ERK kinases. The V600E mutation in B-Raf accounts for more than half of all melanomas and ∼3% of all cancers, and many drugs target the ATP binding site of the enzyme for its inhibition. Because B-Raf can develop resistance against these drugs and such drugs can induce paradoxical activation, drugs that target allosteric sites are needed. To identify other potential drug targets, we generated and kinetically characterized an active form of B-RafV600E expressed using a bacterial expression system. In doing so, we identified an α-helix on B-Raf, found at the B-Raf–MEK interface, that is critical for their interaction and the oncogenic activity of B-RafV600E. We assessed the binding between B-Raf mutants and MEK using pull downs and biolayer interferometry and assessed phosphorylation levels of MEK in vitro and in cells as well as its downstream target ERK to show that mutating certain residues on this α-helix is detrimental to binding and downstream activity. Our results suggest that this B-Raf α-helix binding site on MEK could be a site to target for drug development to treat B-RafV600E-induced melanomas