Past strategies and future directions for identifying AMP-activated protein kinase (AMPK) modulators

AMP-activated protein kinase (AMPK) is a promising therapeutic target for cancer, type II diabetes, and other illnesses characterized by abnormal energy utilization. During the last decade, numerous labs have published a range of methods for identifying novel AMPK modulators. The current understanding of AMPK structure and regulation, however, has propelled a paradigm shift in which many researchers now consider ADP to be an additional regulatory nucleotide of AMPK. How can the AMPK community apply this new understanding of AMPK signaling to translational research? Recent insights into AMPK structure, regulation, and holoenzyme-sensitive signaling may provide the hindsight needed to clearly evaluate the strengths and weaknesses of past AMPK drug discovery efforts. Improving future strategies for AMPK drug discovery will require pairing the current understanding of AMPK signaling with improved experimental designs

Challenges of mainstreaming green infrastructure in built environment professions

© 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Green infrastructure (GI) has been identified as a promising approach to help cities adapt to climate change through the provision of multiple ecosystem services. However, GI contributions to urban resilience will not be realized until it is more fully mainstreamed in the built environment and design professions. Here, we interrogate five key challenges for the effective implementation of GI: (1) design standards; (2) regulatory pathways; (3) socio-economic considerations; (4) financeability; and (5) innovation. Methods include a literature review, case studies, and interviews with resilience managers. We propose a people-centred and context-dependent approach to advance effective implementation of GI in urban planning. We highlight two underlying currents that run across all of the challenges–(1) the role of political will as a pre-condition for tackling all challenges holistically; and (2) the role of stakeholder engagement in achieving public support, harnessing funding, and maintaining and monitoring GI in the long term. Highlights: • The effective implementation of GI is context-specific and should adhere to the basic principles of appropriate technology. • Continuous community engagement is needed to ensure the inclusivity and multi-functionality of GI. • Challenges to successful GI are intersectional and therefore cannot be addressed singly in isolation

Improved MECP2 gene therapy extends the survival of MeCP2-null mice without apparent toxicity after intracisternal delivery

Intravenous administration of AAV9/hMECP2 has been shown to extend the lifespan of Mecp2-/y mice, but this delivery route induces liver toxicity in wild-type (WT) mice. To reduce peripheral transgene expression, we explored the safety and efficacy of AAV9/hMECP2 injected into the cisterna magna (ICM). AAV9/hMECP2 (1 x 1012 vg; ICM) extended Mecp2-/y survival, but aggravated hindlimb clasping and abnormal gait phenotypes. In WT mice, 1 x 1012 vg of AAV9/hMECP2 induced clasping and abnormal gait. A lower dose mitigated these adverse phenotypes but failed to extend survival of Mecp2-/y mice. Thus, ICM delivery of this vector is impractical as a treatment for Rett syndrome (RTT). To improve the safety of MeCP2 gene therapy, the gene expression cassette was modified to include more endogenous regulatory elements believed to modulate MeCP2 expression in vivo. In Mecp2-/y mice, ICM injection of the modified vector extended lifespan and was well tolerated by the liver, but did not rescue RTT behavioral phenotypes. In WT mice, these same doses of the modified vector had no adverse effects on survival or neurological phenotypes. In summary, we identified limitations of the original vector and demonstrated that an improved vector design extends Mecp2-/y survival without apparent toxicity

Achieving Flow: An Exploratory Investigation of Elite College Athletes and Musicians

While studies on the characteristics of flow states and their relation to peak performance exist, little is known about the dynamics by which flow states emerge and develop over time. The current paper qualitatively explores the necessary pre-conditions to enter flow, and the development of flow over time until its termination. Using an elicitation interview, participants (10 athletes and 12 musicians) were asked to recall their flow experiences in sports or music performances. The analysis resulted in the identification of the following three phases that athletes and musicians experience during flow: (1) Preparation to enter flow; (2) Entry into the flow state and; (3) Exit from the flow state. These three phases are characterized by several sub-themes contributing to the experience of flow. The function of emotions is crucial, as they play a core role across all three phases and regulate flow over time. The findings provide insights into the phenomenological characteristics of the transition and maintenance of the three proposed phases and the temporal dynamics of flow

Past strategies and future directions for identifying AMP-activated protein kinase (AMPK) modulators

AMP-activated protein kinase (AMPK) is a promising therapeutic target for cancer, type II diabetes, and other illnesses characterized by abnormal energy utilization. During the last decade, numerous labs have published a range of methods for identifying novel AMPK modulators. The current understanding of AMPK structure and regulation, however, has propelled a paradigm shift in which many researchers now consider ADP to be an additional regulatory nucleotide of AMPK. How can the AMPK community apply this new understanding of AMPK signaling to translational research? Recent insights into AMPK structure, regulation, and holoenzyme-sensitive signaling may provide the hindsight needed to clearly evaluate the strengths and weaknesses of past AMPK drug discovery efforts. Improving future strategies for AMPK drug discovery will require pairing the current understanding of AMPK signaling with improved experimental designs