CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition.

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in aberrant cytokine receptor and kinase signaling. In particular, chromosomal rearrangements resulting in the overexpression of cytokine receptor-like factor 2 (CRLF2) occur in 50% of Ph-like ALL cases. CRLF2 overexpression is associated with particularly poor clinical outcomes, though the molecular basis for this is currently unknown. Glucocorticoids (GCs) are integral to the treatment of ALL and GC resistance at diagnosis is an important negative prognostic factor. Given the importance of GCs in ALL therapy and the poor outcomes for patients with CRLF2 overexpression, we hypothesized that the aberrant signal transduction associated with CRLF2 overexpression might mediate intrinsic GC insensitivity. To test this hypothesis, we exposed Ph-like ALL cells from patient-derived xenografts to GCs and found that CRLF2 rearranged (CRLF2R) leukemias uniformly demonstrated reduced GC sensitivity in vitro. Furthermore, targeted inhibition of signal transduction with the MEK inhibitor trametinib and the Akt inhibitor MK2206, but not the JAK inhibitor ruxolitinib, was sufficient to augment GC sensitivity. These data suggest that suboptimal GC responses may in part underlie the poor clinical outcomes for patients with CRLF2 overexpression and provide rationale for combination therapy involving GCs and signal transduction inhibitors as a means of enhancing GC efficacy

Complete RNA inverse folding: computational design of functional hammerhead ribozymes

Nanotechnology and synthetic biology currently constitute one of the most innovative, interdisciplinary fields of research, poised to radically transform society in the 21st century. This paper concerns the synthetic design of ribonucleic acid molecules, using our recent algorithm, RNAiFold, which can determine all RNA sequences whose minimum free energy secondary structure is a user-specified target structure. Using RNAiFold, we design ten cis-cleaving hammerhead ribozymes, all of which are shown to be functional by a cleavage assay. We additionally use RNAiFold to design a functional cis-cleaving hammerhead as a modular unit of a synthetic larger RNA. Analysis of kinetics on this small set of hammerheads suggests that cleavage rate of computationally designed ribozymes may be correlated with positional entropy, ensemble defect, structural flexibility/rigidity and related measures. Artificial ribozymes have been designed in the past either manually or by SELEX (Systematic Evolution of Ligands by Exponential Enrichment); however, this appears to be the first purely computational design and experimental validation of novel functional ribozymes. RNAiFold is available at http://bioinformatics.bc.edu/clotelab/RNAiFold/.Comment: 17 pages, 2 tables, 7 figures, final version to appear in Nucleic Acids Researc

Sustainability science graduate students as boundary spanners

Graduate training in sustainability science (SS) focuses on interdisciplinary research, stakeholder-researcher partnerships, and creating solutions from knowledge. But becoming a sustainability scientist also requires specialized training that addresses the complex boundaries implicit in sustainability science approaches to solving social-ecological system challenges. Using boundary spanning as a framework, we use a case study of the Sustainability Solutions Initiative (SSI) at the University of Maine to explicate key elements for graduate education training in SS. We used a mixed-methods approach, including a quantitative survey and autoethnographic reflection, to analyze our experiences as SSI doctoral students. Through this research, we identified four essential SS boundaries that build on core sustainability competencies which need to be addressed in SS graduate programs, including: disciplines within academia, students and their advisors, researchers and stakeholders, and place-based and generalizable research. We identified key elements of training necessary to help students understand and navigate these boundaries using core competencies. We then offer six best practice recommendations to provide a basis for a SS education framework. Our reflections are intended for academic leaders in SS who are training new scientists to solve complex sustainability challenges. Our experiences as a cohort of doctoral students with diverse academic and professional backgrounds provide a unique opportunity to reflect not only on the challenges of SS but also on the specific needs of students and programs striving to provide solutions

Land Conservation in the Northeastern United States: An Assessment of Historic Trends and Current Conditions

This article discusses the evolution of land conservation efforts and outcomes in the Northeast, examine major drivers of landscape change, and review key conservation tools that have been used to protect public values at the local and landscape levels. We then assess the current status of land conservation, and draw lessons for other regions facing conservation challenges across mixed ownership landscapes under varying development and land-use pressures. Finally, we explore new and emerging trends in the factors driving land development and conservation activities in an effort to assess the challenges that lie ahead

Correlates of Segmental Pulse Wave Velocity in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study

Carotid-femoral PWV (cfPWV) is a well-established measure of central arterial stiffness, while brachial-ankle PWV (baPWV) is being used more frequently in East Asian countries. Few studies have simultaneously characterized the distributions and correlates of segment-specific PWV measures and their associations with cardiovascular risk factors

Smoking Behaviors and Arterial Stiffness Measured by Pulse Wave Velocity in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study

Though smoking is strongly associated with peripheral vascular disease and arteriosclerosis, smoking’s association with arterial stiffness has been inconsistent and mostly limited to a single arterial segment. We examined the relationship between smoking behaviors with arterial stiffness in multiple arterial segments among community dwelling older adults

Association of Central Arterial Stiffness and Pressure Pulsatility with Mild Cognitive Impairment and Dementia: The Atherosclerosis Risk in Communities Study-Neurocognitive Study (ARIC-NCS)

The association of central arterial stiffness and pressure pulsatility with mild cognitive impairment and dementia is not well characterized in the population-based setting

Repeatability of Central and Peripheral Pulse Wave Velocity Measures: The Atherosclerosis Risk in Communities (ARIC) Study

Arterial stiffness measures are emerging tools for risk assessment and stratification for hypertension and cardiovascular disease (CVD). Carotid-femoral pulse wave velocity (cfPWV) is an established measure of central arterial stiffness. Other measures of PWV include femoral-ankle (faPWV), a measure of peripheral stiffness, and brachial-ankle PWV (baPWV), a composite measure of central and peripheral stiffness. Repeatability of central, peripheral, and composite PWV measures has not been adequately examined or compared

Carotid artery intima-media thickness in polycystic ovary syndrome: a systematic review and meta-analysis

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder associated with cardiovascular disease (CVD) risk factors and metabolic disturbances. This systematic review and meta-analysis was conducted to determine whether carotid intima-media thickness (CIMT), a marker of subclinical atherosclerosis, is higher in women with PCOS compared with women without PCOS