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"Taylor, Linda"
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Hyperplastic Growth of Pulmonary Artery Smooth Muscle Cells from Subjects with Pulmonary Arterial Hypertension Is Activated through JNK and p38 MAPK
Smooth muscle in the pulmonary artery of PAH subjects, both idiopathic and hereditary, is characterized by hyperplasia. Smooth muscle cells (HPASMC) isolated from subjects with or without PAH retain their in vivo phenotype as illustrated by their expression of alpha-smooth muscle actin and expression of H-caldesmon. Both non PAH and PAH HPASMC display a lengthy, approximately 94h, cell cycle. The HPASMC from both idiopathic and hereditary PAH display an abnormal proliferation characterized by continued growth under non-proliferative, non-growth stimulated conditions. This effector independent proliferation is JNK and p38 MAP kinase dependent. Blocking the activation of either abrogates the HPASMC growth. HPASMC from non PAH donors under quiescent conditions display negligible proliferation but divide upon exposure to growth factors such as PDGF-BB or FGF2 but not EGF. This growth does not involve the MAP kinases. Instead it routes via the tyrosine kinase receptor through mTOR and then 6SK. In the PAH cells PDGF-BB and FGF2 augment the dysregulated cell proliferation, also through mTOR/6SK. Additionally, blocking the activation of mTOR also modulates the MAP kinase promoted dysregulated growth. These results highlight key alterations in the growth of HPASMC from subjects with PAH which contribute to the etiology of the disease and can clearly be targeted at various regulatory points for future therapies.
Journal Article
Unraveling endothelin-1 induced hypercontractility of human pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension
Contraction of human pulmonary artery smooth muscle cells (HPASMC) isolated from pulmonary arterial hypertensive (PAH) and normal (non-PAH) subject lungs was determined and measured with real-time electrical impedance. Treatment of HPASMC with vasoactive peptides, endothelin-1 (ET-1) and bradykinin (BK) but not angiotensin II, induced a temporal decrease in the electrical impedance profile mirroring constrictive morphological change of the cells which typically was more robust in PAH as opposed to non-PAH cells. Inhibition with LIMKi3 and a cofilin targeted motif mimicking cell permeable peptide (MMCPP) had no effect on ET-1 induced HPASMC contraction indicating a negligible role for these actin regulatory proteins. On the other hand, a MMCPP blocking the activity of caldesmon reduced ET-1 promoted contraction pointing to a regulatory role of this protein and its activation pathway in HPASMC contraction. Inhibition of this MEK/ERK/p90RSK pathway, which is an upstream regulator of caldesmon phosphorylation, reduced ET-1 induced cell contraction. While the regulation of ET-1 induced cell contraction was found to be similar in PAH and non-PAH cells, a key difference was the response to pharmacological inhibitors and to siRNA knockdown of Rho kinases (ROCK1/ROCK2). The PAH cells required much higher concentrations of inhibitors to abrogate ET-1 induced contractions and their contraction was not affected by siRNA against either ROCK1 or ROCK2. Lastly, blocking of L-type and T-type Ca2+ channels had no effect on ET-1 or BK induced contraction. However, inhibiting the activity of the sarcoplasmic reticulum Ca2+ ATPase blunted ET-1 and BK induced HPASMC contraction in both PAH and non-PAH derived HPASMC. In summary, our findings here together with previous communications illustrate similarities and differences in the regulation PAH and non-PAH smooth muscle cell contraction relating to calcium translocation, RhoA/ROCK signaling and the activity of caldesmon. These findings may provide useful tools in achieving the regulation of the vascular hypercontractility taking place in PAH.
Journal Article
Immigrant Children and Youth in the USA: Facilitating Equity of Opportunity at School
A great deal has been written about immigrant children and youth. Drawing on work done in the USA, this paper focuses on implications for school improvement policy and practice. Discussed are (1) the increasing influx of immigrants into schools; (2) different reasons families migrate; (3) concerns that arise related to immigrant students; (4) prevailing school practices for addressing immigrant concerns; (5) a framework for broadening what schools and communities do; and (6) policy implications, cautions, and recommendations for embedding immigrant concerns into a unified, comprehensive, and equitable system of student and learning supports.
Journal Article
The Effects of Habitat Disturbance on Lemurs at Ranomafana National Park, Madagascar
The alarming rate of deforestation in Madagascar is driving some endemic primates to extinction. Surprisingly, anthropogenic habitat disturbance is not always deleterious. The effect of disturbance on lemur abundance may be related to diet, with frugivorous species more prone to population declines than folivores or insectivores. To test the effects of disturbance on lemur abundance and group size, we surveyed 2 sites within contiguous forest at Ranomafana National Park, 1 lightly disturbed primary forest (Vato) and 1 heavily logged forest (Tala). We quantified forest structure variables along 6 survey routes and conducted 68 diurnal and 42 nocturnal lemur surveys. Canopy closure, canopy height, and understory visibility were greater in Vato than in Tala. We encountered 2 frugivorous lemurs (
Eulemur rufifrons
,
Varecia variegata
) and 1 folivore (
Avahi peyrierasi
) significantly more frequently in Vato than in Tala, whereas the opposite was true for the insectivorous
Microcebus rufus
. Rates did not differ statistically for 1 frugivore (
Eulemur rubriventer
) and 2 folivores (
Propithecus edwardsi
,
Hapalemur griseus
). Comparisons across the 6 survey routes suggest that the abundance was heterogeneous within as well as between sites. Neither group size nor composition differed between sites. Encounter rates for
Varecia variegata
were positively related to canopy closure, and encounter rates for
Avahi peyrierasi
were positively related to canopy height. Encounter rates for
Microcebus rufus
were negatively related to canopy closure, height, and understory visibility. Similar to other studies, the results suggest that some lemurs, including folivores, may cope with anthropogenic disturbance better than others, including some frugivores. Lemur abundance is heterogeneous, though, even on small spatial scales.
Journal Article
The Role of Teacher Efficacy in Strengthening Classroom Support for Preschool Children with Disabilities Who Exhibit Challenging Behaviors
Challenging student behaviors are a prominent factor in the development of teacher stress and burnout. When classroom-based teachers of preschool children with disabilities were surveyed to identify their training needs in one North Carolina county, the most frequent request was how to address behavior challenges of preschool children with disabilities. This study examined how instructional support to teachers of preschool children with disabilities and challenging behaviors affected three teachers’ classroom practices. The teachers received training and mentoring in classroom behavior management strategies and engaged in an online community of learners discussion group. Interviews and interactions from an online learning community were used to disclose whether the participants had implemented effective intervention strategies in their classrooms following the training. Teachers felt more competent in managing challenging behaviors after the online interaction with their colleagues. Teachers’ online interactions were a highly effective way to impact teacher efficacy. Therefore, special education preschool programs should consider providing more opportunities for the teachers to build their own learning communities to interact and support one another.
Journal Article
Mental health in schools
'This resource gives the reader everything needed to design and implement a successful mental health program to benefit a diverse student population. The authors present a strong case for planning and delivering comprehensive integrated services. I commend the authors for their willingness to tackle the tough issues surrounding mental health services for all students' - Marian White-Hood, Director of Academics, Accountability, and Principal Support See Forever Foundation Necessary reading for anyone concerned with student wellness and effective schools! For many children, schools are the main or only providers of mental health services. In this visionary and comprehensive book, two nationally known experts describe a new approach to school-based mental health-one that better serves students, maximizes resources, and promotes academic performance. The authors describe how educators can effectively coordinate internal and external resources to support a healthy school environment and help at-risk students overcome barriers to learning. School leaders, psychologists, counsellors, and policy makers will find essential guidance, including: - An overview of the history and current state of school mental health programmes, discussing major issues confronting the field - Strategies for effective school-based initiatives, including addressing behaviour issues, introducing classroom-based activities, and coordinating with community resources - A call to action for higher-quality mental health programming across public schools-including how collaboration, research, and advocacy can make a difference Gain the knowledge you need to develop or improve your school's mental health programme to better serve both the academic and mental health needs of your students!
eBook
A Cell Permeable Peptide Targeting the Intracellular Loop 2 of Endothelin B Receptor Reduces Pulmonary Hypertension in a Hypoxic Rat Model
Cell permeable peptides (CPP) aid cellular uptake of targeted cargo across the hydrophobic plasma membrane. CPP-mediated cargo delivery of receptor signaling motifs provides an opportunity to regulate specific receptor initiated signaling cascades. Both endothelin-1 receptors, ETA and ETB, have been targets of antagonist therapies for individuals with pulmonary arterial hypertension (PAH). These therapies have had success but have been accompanied by adverse reactions. Also, unlike the CPP which target specific signaling cascades, the antagonists target the entire function of the receptor. Using the CPP strategy of biased antagonism of the ETB receptor's intracellular loop 2 (ICB2), we demonstrate blunting of hypoxic pulmonary hypertension (HPH) in the rat, including indices of pulmonary arterial pressure, right ventricular hypertrophy and pulmonary vascular remodeling. Further, ex vivo analysis of the pulmonary artery treated with the IC2B peptide upon injection manifests marked reductions in Akt and ERK activation. Both kinases have been intimately related to cell proliferation and vascular contraction, the hallmarks of PAH. These observations in sum illustrate an involvement of the ETB receptor in HPH and furthermore provide a basis for a novel, CPP-based, strategy in the treatment of PAH, ultimately able to target not only ET-1, but also other factors involved in the development of PAH.
Journal Article
