Interaction takes two: typical adults exhibit mind-blindness towards those with Autism Spectrum Disorder

Recent work suggests that we are better at interpreting the movements of others who move like us, and that individuals with Autism Spectrum Disorder (ASD) move in a quantifiably different way from typical individuals. Therefore, ‘social impairments’ exhibited by individuals with ASD may, at least in part, represent a failure by typical individuals to infer the correct mental states from the movements of those with ASD. To examine this possibility, individuals with ASD and typical adults manually directed two triangles to generate animations depicting mental state interactions. Kinematic analysis of the generated animations demonstrated that the participants with ASD moved atypically, specifically with increased jerk compared to the typical participants. In confirmation of our primary hypothesis, typical individuals were better able to identify the mental state portrayed in the animations produced by typical, relative to autistic individuals. The participants with ASD did not show this ‘same group’ advantage, demonstrating comparable performance for the two sets of animations. These findings have significant implications for clinical assessment and intervention in ASD, and potentially other populations with atypical movement

Epithelial cell-directed efferocytosis in the post-partum mammary gland is necessary for tissue homeostasis and future lactation

<p>Abstract</p> <p>Background</p> <p>Mammary glands harbor a profound burden of apoptotic cells (ACs) during post-lactational involution, but little is known regarding mechanisms by which ACs are cleared from the mammary gland, or consequences if this process is interrupted. We investigated AC clearance, also termed efferocytosis, during post-lactational remodeling, using mice deficient for MerTK, Axl, and Tyro3, three related receptor tyrosine kinases (RTKs) regulating macrophage-mediated efferocytosis in monocytes. MerTK expression, apoptosis and the accumulation of apoptotic debris were examined in histological sections of MerTK-deficient, Axl/Tyro3-deficient, and wild-type mammary glands harvested at specific time points during lactation and synchronized involution. The ability of primary mammary epithelial cells (MECs) to engulf ACs was assessed in culture. Transplant of MerTK-deficient mammary epithelium into cleared WT mammary fat pads was used to assess the contribution of WT mammary macrophages to post-lactational efferocytosis.</p> <p>Results</p> <p>ACs induced MerTK expression in MECs, resulting in elevated MerTK levels at the earliest stages of involution. Loss of MerTK resulted in AC accumulation in post-lactational MerTK-deficient mammary glands, but not in Axl and Tyro3-deficient mammary glands. Increased vascularization, fibrosis, and epithelial hyperproliferation were observed in MerTK-deficient mammary glands through at least 60 days post-weaning, due to failed efferocytosis after lactation, but did not manifest in nulliparous mice. WT host-derived macrophages failed to rescue efferocytosis in transplanted MerTK-deficient mammary epithelium.</p> <p>Conclusion</p> <p>Efferocytosis by MECs through MerTK is crucial for mammary gland homeostasis and function during the post-lactational period. Efferocytosis by MECs thus limits pathologic consequences associated with the apoptotic load following lactation.</p

ErbB4/HER4: Role in Mammary Gland Development, Differentiation and Growth Inhibition

The ErbB receptor tyrosine kinase family has often been associated with increased growth of breast epithelial cells, as well as malignant transformation and progression. In contrast, ErbB4/HER4 exhibits unique attributes from a two step proteolytic cleavage which releases an 80 kilodalton, nuclear localizing, tyrosine kinase to a signal transduction mechanism that slows growth and stimulates differentiation of breast cells. This review provides an overview of ErbB4/HER4 in growth and differentiation of the mammary epithelium, including its physiologic role in development, the contrasting growth inhibition/tumor suppression and growth acceleration of distinct ErbB4/HER4 isoforms and a description of the unique cell cycle regulated pattern of nuclear HER4 ubiquitination and destruction

"It's not just about walking.....it's the practice nurse that makes it work": a qualitative exploration of the views of practice nurses delivering complex physical activity interventions in primary care

Background: Physical activity (PA) is important for physical and mental health in adults and older adults. Interventions incorporating theory-based behaviour change techniques (BCTs) can be useful in helping people to increase their PA levels and can be delivered by practice nurses in primary care. We undertook two primary care based complex walking interventions among adults and older adults. Both interventions were underpinned by BCTs and delivered by practice nurses and we sought their views and experiences of delivering over 1400 complex PA consultations.&nbsp; Methods: Semi structured interviews with two practice nurse groups (n = 4 and n = 5) and two individual interviews (total n = 11) were conducted by independent facilitators; audio-recorded, transcribed verbatim and analysed using thematic analysis.&nbsp; Results: Five key themes emerged as enablers and/or barriers to delivering the intervention: preparation and training; initial and ongoing support; adherence to the protocol; the use of materials and equipment; and engagement of participants. The themes were organised into a framework of 'pre-trial' and 'delivery of the intervention'. Two additional 'post-trial' themes were identified; changed practice and the future feasibility of the intervention. Nurses believed that taking part in the trial, especially the BCT training, enhanced the quality and delivery of advice and support they provided within routine consultations, although the lack of time available routinely makes this challenging.&nbsp; Conclusion: Delivering an effective behaviour change intervention in primary care requires adequate training and support for practice nurses both initially and throughout the trial as well as adequate consultation time. Enhanced skills from participating in such trials can lead to long-term changes, including more patient-centred consulting.&nbsp; Trial registration: PACE-Lift ISRCTN 42122561, PACE-UP ISRCTN 98538934

Ack1 Mediated AKT/PKB Tyrosine 176 Phosphorylation Regulates Its Activation

The AKT/PKB kinase is a key signaling component of one of the most frequently activated pathways in cancer and is a major target of cancer drug development. Most studies have focused on its activation by Receptor Tyrosine Kinase (RTK) mediated Phosphatidylinositol-3-OH kinase (PI3K) activation or loss of Phosphatase and Tensin homolog (PTEN). We have uncovered that growth factors binding to RTKs lead to activation of a non-receptor tyrosine kinase, Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. Mice expressing activated Ack1 specifically in the prostate exhibit AKT Tyr176-phosphorylation and develop murine prostatic intraepithelial neoplasia (mPINs). Further, expression levels of Tyr176-phosphorylated-AKT and Tyr284-phosphorylated-Ack1 were positively correlated with the severity of disease progression, and inversely correlated with the survival of breast cancer patients. Thus, RTK/Ack1/AKT pathway provides a novel target for drug discovery

Consumers as tutors – legitimate teachers?

BACKGROUND: The aim of this study was to research the feasibility of training mental health consumers as tutors for 4(th )year medical students in psychiatry. METHODS: A partnership between a consumer network and an academic unit in Psychological Medicine was formed to jointly develop a training package for consumer tutors and a curriculum in interviewing skills for medical students. Student attitudes to mental health consumers were measured pre and post the program. All tutorial evaluation data was analysed using univariate statistics. Both tutors and students evaluated the teaching program using a 4 point rating scale. The mean scores for teaching and content for both students and tutors were compared using an independent samples t-test. RESULTS: Consumer tutors were successfully trained and accredited as tutors and able to sustain delivery of tutorials over a 4 year period. The study found that whilst the medical students started with positive attitudes towards consumers prior to the program, there was a general trend towards improved attitude across all measures. Other outcomes for tutors and students (both positive and negative) are described. CONCLUSIONS: Consumer tutors along with professional tutors have a place in the education of medical students, are an untapped resource and deliver largely positive outcomes for students and themselves. Further possible developments are described

The HER4 Cytoplasmic Domain, But Not Its C Terminus, Inhibits Mammary Cell Proliferation

Unlike the proliferative action of other EGF receptor family members, HER4/ErbB4 is often associated with growth inhibitory and differentiation signaling. These actions may involve HER4 two-step proteolytic processing by intra-membraneous γ-secretase, releasing the soluble, intracellular 80kDa HER4 cytoplasmic domain, s80HER4. We demonstrate that pharmacologic inhibition of either γ-secretase activity or HER4 tyrosine kinase activity blocked heregulin-dependent growth inhibition of SUM44 breast cancer cells. We next generated breast cell lines stably expressing GFP-s80HER4 (GFP fused to the N-terminus of the HER4 cytoplasmic domain, residues 676–1308), GFP-CTHER4 (GFP fused to N-terminus of the HER4 C-terminus distal to the tyrosine kinase domain, residues 989–1308) or GFP alone. Both GFP-s80HER4 and GFP-CTHER4 were found in the nucleus, but GFP-s80HER4 accumulated to a greater extent and sustained its nuclear localization. s80HER4 was constitutively tyrosine phosphorylated and treatment of cells with a specific HER family tyrosine kinase inhibitor i) blocked tyrosine phosphorylation; ii) markedly diminished GFP-s80HER4 nuclear localization, and iii) reduced STAT5A tyrosine phosphorylation and nuclear localization as well as GFP-s80HER4:STAT5A interaction. Multiple normal mammary and breast cancer cell lines, stably expressing GFP-s80HER4 (SUM44, MDA-MB-453, MCF10A, SUM102, and HC11) were growth inhibited compared to the same cell line expressing GFP-CTHER4, or GFP alone. The s80HER4-induced cell number reduction was due to slower growth, as rates of apoptosis were equivalent in GFP, GFP-CTHER4, and GFP-s80HER4 expressing cells. Lastly, GFP-s80HER4 enhanced differentiation signaling as indicated by increased basal and prolactin-dependent β–casein expression. These results indicate that surface HER4 tyrosine phosphorylation and ligand-dependent release of s80HER4 are necessary, and s80HER4 signaling is sufficient for HER4-dependent growth inhibition

HER4 D-Box Sequences Regulate Mitotic Progression and Degradation of the Nuclear HER4 Cleavage Product s80HER4

Heregulin-mediated activation of HER4 initiates receptor cleavage (releasing an 80-kDa HER4 intracellular domain, s80HER4, containing nuclear localization sequences) and results in G2/M delay by unknown signaling mechanisms. We report herein that s80HER4 contains a functional cyclin B-like sequence known as a D-box, which targets proteins for degradation by APC/C, a multisubunit ubiquitin ligase. s80HER4 ubiquitination and ptoteosomal degradation occurred during mitosis but not during S-phase. Inhibition of an APC subunit (APC2) using siRNA knock-down impaired s80HER4 degradation. Mutation of the s80HER4 D-box sequence stabilized s80HER4 during mitosis, and s80HER4-dependent growth inhibition via G2/M delay was significantly greater with the D-box mutant. Polyomvirus middle-T antigen-transformed HC11 cells expressing s80HER4 resulted in smaller, less proliferative, more differentiated tumors in vivo than those expressing kinase-dead s80HER4 or the empty vector. Cells expressing s80HER4 with a disrupted D-box did not form tumors, instead forming differentiated ductal structures. These results suggest that cell cycle-dependent degradation of s80HER4 limits its growth inhibitory action, and stabilization of s80HER4 enhances tumor suppression, thus providing a link between HER4-mediated growth inhibition and cell cycle control