Conserved and unique transcriptional features of pharyngeal arches in the skate (Leucoraja erinacea) and evolution of the jaw

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Hirschberger, C., Sleight, V. A., Criswell, K. E., Clark, S. J., & Gillis, J. A. Conserved and unique transcriptional features of pharyngeal arches in the skate (Leucoraja erinacea) and evolution of the jaw. Molecular Biology and Evolution, (2021): msab123, https://doi.org/10.1093/molbev/msab123The origin of the jaw is a long-standing problem in vertebrate evolutionary biology. Classical hypotheses of serial homology propose that the upper and lower jaw evolved through modifications of dorsal and ventral gill arch skeletal elements, respectively. If the jaw and gill arches are derived members of a primitive branchial series, we predict that they would share common developmental patterning mechanisms. Using candidate and RNAseq/differential gene expression analyses, we find broad conservation of dorsoventral patterning mechanisms within the developing mandibular, hyoid and gill arches of a cartilaginous fish, the skate (Leucoraja erinacea). Shared features include expression of genes encoding members of the ventralising BMP and endothelin signalling pathways and their effectors, the joint markers nkx3.2 and gdf5 and pro-chondrogenic transcription factor barx1, and the dorsal territory marker pou3f3. Additionally, we find that mesenchymal expression of eya1/six1 is an ancestral feature of the mandibular arch of jawed vertebrates, while differences in notch signalling distinguish the mandibular and gill arches in skate. Comparative transcriptomic analyses of mandibular and gill arch tissues reveal additional genes differentially expressed along the dorsoventral axis of the pharyngeal arches, including scamp5 as a novel marker of the dorsal mandibular arch, as well as distinct transcriptional features of mandibular and gill arch muscle progenitors and developing gill buds. Taken together, our findings reveal conserved patterning mechanisms in the pharyngeal arches of jawed vertebrates, consistent with serial homology of their skeletal derivatives, as well as unique transcriptional features that may underpin distinct jaw and gill arch morphologies.This work was supported by a Biotechnology and Biological Sciences Research Council Doctoral Training Partnership studentship to CH, by a Wolfson College Junior Research Fellowship and MBL Whitman Early Career Fellowship to VAS, and by a Royal Society University Research Fellowship (UF130182 and URF\R\191007), Royal Society Research Grant (RG140377) and University of Cambridge Sir Isaac Newton Trust Grant (14.23z) to JAG

Duplex DNA from Sites of Helicase-Polymerase Uncoupling Links Non-B DNA Structure Formation to Replicative Stress

BACKGROUND: Replication impediments can produce helicase-polymerase uncoupling allowing lagging strand synthesis to continue for as much as 6 kb from the site of the impediment. MATERIALS AND METHODS: We developed a cloning procedure designed to recover fragments from lagging strand near the helicase halt site. RESULTS: A total of 62% of clones from a p53-deficient tumor cell line (PC3) and 33% of the clones from a primary cell line (HPS-19I) were within 5 kb of a G-quadruplex forming sequence. Analyses of a RACK7 gene sequence, that was cloned multiple times from the PC3 line, revealed multiple deletions in region about 1 kb from the cloned region that was present in a non-B conformation. Sequences from the region formed G-quadruplex and i-motif structures under physiological conditions. CONCLUSION: Defects in components of non-B structure suppression systems (e.g. p53 helicase targeting) promote replication-linked damage selectively targeted to sequences prone to G-quadruplex and i-motif formation

Evidence-Based Multifactorial Assessment of Preschool-Age Children Who Stutter.

This review summarizes extant findings supporting multifactorial models of stuttering within the context of preschool-age stuttering assessment. Evidence is given for a number of speech-language and associated factors/domains to consider when evaluating young children who stutter. Selected factors are presented in two parts: (1) Caregiver Interview and (2) Direct Child Assessment. Factors addressed during caregiver interviews include: gender, time since and age at stuttering onset, family history of stuttering, caregivers’ perception/concerns about stuttering, and temperament. Factors addressed during direct child assessments include: stuttering behaviors, speech-associated attitudes/awareness, speech rate, as well as speech sound and language development. Interactions/relations among factors are noted, showing their combined effects and contributions to childhood stuttering. Additionally, suggested clinical applications are provided wherever appropriate. Such evidence and practical applications bridge the gap between theory and clinical practice, thus advancing the abilities of speech-language pathologists to conduct well-informed, comprehensive stuttering evaluations

JQ1 suppresses tumor growth via PTEN/PI3K/AKT pathway in endometrial cancer

Overexpression of c-Myc is associated with worse outcomes in endometrial cancer, indicating that c-Myc may be a promising target for endometrial cancer therapy. A novel small molecule, JQ1, has been shown to block BRD4 resulting in inhibition of c-Myc expression and tumor growth. Thus, we investigated whether JQ1 can inhibit endometrial cancer growth in cell culture and xenograft models. In PTEN-positive endometrial cancer cells, JQ1 significantly suppressed cell proliferation via induction of G1 phase arrest and apoptosis in a dose-dependent manner, accompanied by a sharp decline in cyclin D1 and CDK4 protein expression. However, PTEN-negative endometrial cancer cells exhibited intrinsic resistance to JQ1, despite significant c-Myc inhibition. Moreover, we found that PTEN and its downstream PI3K/AKT signaling targets were modulated by JQ1, as evidenced by microarray analysis. Silencing of PTEN in PTEN-positive endometrial cancer cells resulted in resistance to JQ1, while upregulation of PTEN in PTEN-negative endometrial cancer cells increased sensitivity to JQ1. In xenografts models of PTEN-positive and PTEN-knock-in endometrial cancer, JQ1 significantly upregulated the expression of PTEN, blocked the PI3K/AKT signaling pathway and suppressed tumor growth. These effects were attenuated in PTEN-negative and PTEN-knockdown xenograft models. Thus, JQ1 resistance appears to be highly associated with the status of PTEN expression in endometrial cancer. Our findings suggest that targeting BRD4 using JQ1 might serve as a novel therapeutic strategy in PTEN-positive endometrial cancers

Beta interferon production is regulated by P38 mitogen-activated protein kinase in macrophages via both MSK1/2-and tristetraprolin-dependent pathways

Autocrine or paracrine signaling by beta interferon (IFN-β) is essential for many of the responses of macrophages to pathogen-associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents and is therefore tightly regulated. We demonstrate here that macrophage expression of IFN-β is negatively regulated by mitogen- and stress-activated kinases 1 and 2 (MSK1/2). Lipopolysaccharide (LPS)-induced expression of IFN-β was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and -2 promote the expression of the anti-inflammatory cytokine interleukin 10, it did not strongly contribute to the ability of MSKs to regulate IFN-β expression. Instead, MSK1 and -2 inhibit IFN-β expression via the induction of dual-specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and Jun N-terminal protein kinase (JNK). Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and overexpression of IFN-β mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFN-β: first, JNKmediated activation of c-jun, which binds to the IFN-β promoter, and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFN-β mRNA

Adopting Immunization Recommendations: A New Dissemination Model

Objective: This paper presents a new approach for understanding factors related to physician adoption of clinical guidelines, using children's vaccine recommendations as a case study. Methods: The model traces sequential steps, from awareness to agreement to adoption and, finally, adherence to the guideline. Movement through these stages can be catalyzed or retarded by many influences, grouped into two major categories: environmental characteristics of the physician's practice, and information characteristics of the guideline. Environmental characteristics include sociocultural factors, professional characteristics, and practice organization factors. Information characteristics include the guideline's relative advantage, complexity, and compatibility with existing guidelines and protocols, as well as mechanisms of guideline dissemination. Implications: This model can be used to identify characteristics that will likely impede or facilitate guideline adoption, and to focus dissemination efforts on key issues.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45322/1/10995_2004_Article_412802.pd

Young children’s family history of stuttering and their articulation, language and attentional abilities: An exploratory study

Purpose—The purpose of this study was to determine whether young children who do (CWS) and do not stutter (CWNS) with a positive versus negative family history of stuttering differ in articulation, language and attentional abilities and family histories of articulation, language and attention related disorders. Method—Participants were 25 young CWS and 50 young CWNS. All 75 participants’ caregivers consistently reported a positive or negative family history of stuttering across three consecutive time points that were about 8 months apart for a total of approximately 16 months. Each participant’s family history focused on the same, relatively limited number of generations (i.e., participants’ parents & siblings). Children’s family history of stuttering as well as articulation, language, and attention related disorders was obtained from one or two caregivers during an extensive interview. Children’s speech and language abilities were measured using four standardized articulation and language tests and their attentional abilities were measured using caregiver reports of temperament. Results—Findings indicated that (1) most caregivers (81.5% or 75 out 92) were consistent in their reporting of positive or negative history of stuttering; (2) CWNS with a positive family history of stuttering, compared to those with a negative family history of stuttering, were more likely to have reported a positive family history of attention deficit/hyperactivity disorder (ADHD), and (3) CWNS with a positive family history of stuttering had lower language scores than those with a negative family history of stuttering. However, there were no such significant differences in family histories of ADHD and language scores for CWS with a positive versus negative family history of stuttering. In addition, although 24% of CWS versus 12% of CWNS’s caregivers reported a positive family history of stuttering, inferential analyses indicated no significant differences between CWS and CWNS in relative proportions of family histories of stuttering. Conclusions—Finding that a relatively high proportion (i.e., 81.5%) of caregivers consistently reported a positive or negative family history of stuttering across three consecutive time points should provide some degree of assurance to those who collect such caregiver reports. Based on such consistent caregiver reports, linguistic as well as attentional vulnerabilities appear associated with a positive family history of stuttering, a finding that must await further empirical study for confirmation or refutation

Do UK universities communicate their brands effectively through their websites?

This paper attempts to explore the effectiveness of UK universities’ websites. The area of branding in higher education has received increasing academic investigation, but little work has researched how universities demonstrate their brand promises through their websites. The quest to differentiate through branding can be challenging in the university context, however. It is argued that those institutions that have a strong distinctive image will be in a better position to face a changing future. Employing a multistage methodology, the web pages of twenty UK universities were investigated by using a combination of content and multivariable analysis. Results indicated ‘traditional values’ such as teaching and research were often well communicated in terms of online brand but ‘emotional values’ like social responsibility and the universities’ environments were less consistently communicated, despite their increased topicality. It is therefore suggested that emotional values may offer a basis for possible future online differentiation