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The rough guide to Sri Lanka
The Rough Guide to Sri Lanka is the most comprehensive and user-friendly guide to exploring this fascinating island country. Each chapter includes thoroughly researched travel information, hotel and restaurant listings, and thoughtful background on the environment, politics, culture, music and history, and a practical language guide ensures you can interact with locals. The full-color design combines glorious images to whet your appetite with a practical layout and dozens of accessible and accurate maps to guide you from the urban centers to the jungle, beaches and mountains.
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Methotrexate Is a JAK/STAT Pathway Inhibitor
The JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains.
We used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin.
Aminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential.
Journal Article
Operational psychology : a new field to support national security and public safety
Operational psychology plays a unique role in supporting issues of nationa security, national defense, and public safety. In this book, authors Mark A. Staal and Sally C. Harvey, both operational psychologists and retired military colonels, lead a team of experts explaining the field, its many roles, and how it is expanding--back cover.
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Professional Learning Communities: A Review of the Literature
International evidence suggests that educational reform's progress depends on teachers' individual and collective capacity and its link with school-wide capacity for promoting pupils' learning. Building capacity is therefore critical. Capacity is a complex blend of motivation, skill, positive learning, organisational conditions and culture, and infrastructure of support. Put together, it gives individuals, groups, whole school communities and school systems the power to get involved in and sustain learning over time. Developing professional learning communities appears to hold considerable promise for capacity building for sustainable improvement. As such, it has become a 'hot topic' in many countries.
Journal Article
تعجيز العقبات وتمكين البيئات
إنه حقا كتاب جيد البناء حظي بشهرة واسعة ويستخدمه الطلاب على نطاق واسع... بسبب خصائصه العظيمة وسهولة فهمه وتنوع مشارب المشاركين فى إعداده. يشتمل على أحدث النصوص المتاحة في مجال دراسة الإعاقة ؛ فبالإضافة إلى تحليل العوائق والعقبات التي يواجهها الأشخاص المعوقون في مجالات التعليم والسكن والترفيه والعمل، تضمنت هذه النسخة المنقحة فصولا جديدة حول القضايا الدولية، التنوع والاختلاف بين الأشخاص المعوقين، النشاط الجنسي، أخلاقيات علم الأحياء.
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