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The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is an essential lipid A biosynthetic enzyme that is conserved in the majority of gram-negative bacteria. It has emerged as an attractive novel antibiotic target due to the recent discovery of an LpxH-targeting sulfonyl piperazine compound (referred to as AZ1) by AstraZeneca. However, the molecular details of AZ1 inhibition have remained unresolved, stymieing further development of this class of antibiotics. Here we report the crystal structure of Klebsiella pneumoniae LpxH in complex with AZ1. We show that AZ1 fits snugly into the L-shaped acyl chain-binding chamber of LpxH with its indoline ring situating adjacent to the active site, its sulfonyl group adopting a sharp kink, and its N-CF₃–phenyl substituted piperazine group reaching out to the far side of the LpxH acyl chain-binding chamber. Intriguingly, despite the observation of a single AZ1 conformation in the crystal structure, our solution NMR investigation has revealed the presence of a second ligand conformation invisible in the crystalline state. Together, these distinct ligand conformations delineate a cryptic inhibitor envelope that expands the observed footprint of AZ1 in the LpxH-bound crystal structure and enables the design of AZ1 analogs with enhanced potency in enzymatic assays. These designed compounds display striking improvement in antibiotic activity over AZ1 against wild-type K. pneumoniae, and coadministration with outer membrane permeability enhancers profoundly sensitizes Escherichia coli to designed LpxH inhibitors. Remarkably, none of the sulfonyl piperazine compounds occupies the active site of LpxH, foretelling a straightforward path for rapid optimization of this class of antibiotics.

A proven framework for whole-school improvement The School Leadership Playbook is a practical guide for education leaders looking to push their school's and students' achievement to the next level. Developed by renowned leadership preparation program New Leaders, the Transformational Leadership Framework focuses on the five categories that drive a school's success: Learning and Teaching, School Culture, Talent Management, Operations and Systems, and Personal Leadership. This book illustrates how each of these factors contributes to breakthrough gains, and outlines a plan for implementing changes in your own school. You'll learn how to accurately diagnose the current state of your school's academics and culture and create an action plan for the year ahead. The TLF is grounded in the latest research and case studies of the highest-gaining turnaround schools, and shows you the specific actions you can take to attract, retain, and support high-performing teachers; improve school culture; successfully involve parents and the community; and ultimately drive student success. New Leaders developed the UEF to pinpoint what schools achieving significant student academic gains were doing, and how they were doing it. This book provides a practical breakdown of the framework to help you begin leading these changes in your own school. * Ensure rigorous goal- and data-driven teaching and learning * Build and manage a high-performance faculty aligned to the school's vision * Implement effective and efficient operations and systems * Model the tone you would like to see from students and teachers school-wide By matching the needs of the school to effective principal actions and school practices, leaders can create a plan for transformational change.

Chronic obstructive pulmonary disease (COPD) and lung cancer are both detrimental diseases that present great burdens on society. Years of life lost (YLL), premature years of life lost (PYLL), working years lost (WYL), and productivity loss are all effective measures in identifying economic burden of disease. We propose a population-based study to analyze comprehensive provincial cohorts of Saskatchewan residents with COPD, lung cancer, and combined COPD and lung cancer in order to identify the burden these diseases present. Saskatchewan residents over the age of 35 years who had COPD, lung cancer, or both, between January 1, 2000, and December 31, 2015, will be identified and used in this study. Data for analysis including age, gender, and date of death, alongside Statistics Canada income estimates, will be used to estimate productivity loss and WYL. Statistics Canada life tables will be used to calculate YLL and PYLL by subtracting the patients' ages at death by their life expectancies, adjusted using sex and age at death. We will link the Saskatchewan cancer registry with Saskatchewan health administrative databases to create three cohorts: (1) COPD; (2) lung cancer; and (3) COPD and lung cancer. Individuals with lung cancer will be identified using ICDO-T (International Classification of Diseases for Oncology-Topography) codes, and those with COPD will be defined and identified as individuals who had at least 1 visit to a physician with a diagnosis of COPD or 1 hospital separation with a diagnosis of COPD. Those without a valid health care coverage for a consecutive 12 months prior to the first diagnostic code will be excluded from the study. Those with a combined diagnosis of COPD and lung cancer will be identified as individuals who were diagnosed with COPD in the 12 months following their lung cancer diagnosis or anytime preceding their lung cancer diagnosis. As of April 2021, we have had access to all relevant data for this study, have received funding (January 2020), and have begun the preliminary analysis of our data set. It is well documented that COPD and lung cancer are both destructive diseases in terms of YLL, PYLL, WYL, and productivity loss; however, no studies have been conducted to analyze a cohort with combined COPD and lung cancer. Understanding the economic burden associated with each of our 3 cohorts is necessary in understanding and thus reducing the societal impact of COPD and lung cancer. RR1-10.2196/31350.

Bridge the achievement gap with proven strategies for student success Breakthrough Principals debunk s the myth of the 'superhero' principal by detailing the common actions and practices of leaders at our nation's fastest-gaining public schools. Based on the authors' Transformational Leadership Framework, which they developed through in-depth study of more than 100 high-gaining, high-poverty schools, the book distills findings into a practical, action-focused plan for diagnosing school needs and implementing structures, systems and practices that accelerate student achievement. Brought to life by case studies of principals who have led dramatic gains in student achievement, the book is a how-to guide for increasing the quality of teaching and learning; improving school culture; attracting and supporting high-performing teachers; and involving parents and community to help students achieve. You'll learn how breakthrough principals make the school's mission a real part of both strategy and practice, and set up sustainable systems that support consistent, ongoing improvement. High-impact practices are organized into five broad categories: learning and teaching, school-wide culture, aligned staff, operations and systems, and personal leadership. The primary job of school leadership is to help students succeed. It begins with first recognizing and prioritizing areas of need, then finding and implementing the most effective solutions. Whether you work in a turn around environment, or want to make a good school better, this book will give you a set of concrete practices—illustrated through examples of real principals in real schools—that have been proven to work. * Discover the primary drivers of student achievement * Work toward the school's vision in staffing, operations, and systems * Set the tone for all relationships and practices with good leadership Closing the achievement gap is a major goal of educational leadership, and principals are forever searching for viable methods that help them better serve their students. Breakthrough Principals unveils the details behind the success stories from across the nation to provide a roadmap to transformative gains.

Bridge the achievement gap with proven strategies for student success Breakthrough Principals debunk s the myth of the 'superhero' principal by detailing the common actions and practices of leaders at our nation's fastest-gaining public schools. Based on the authors' Transformational Leadership Framework, which they developed through in-depth study of more than 100 high-gaining, high-poverty schools, the book distills findings into a practical, action-focused plan for diagnosing school needs and implementing structures, systems and practices that accelerate student achievement. Brought to life by case studies of principals who have led dramatic gains in student achievement, the book is a how-to guide for increasing the quality of teaching and learning; improving school culture; attracting and supporting high-performing teachers; and involving parents and community to help students achieve. You'll learn how breakthrough principals make the school's mission a real part of both strategy and practice, and set up sustainable systems that support consistent, ongoing improvement. High-impact practices are organized into five broad categories: learning and teaching, school-wide culture, aligned staff, operations and systems, and personal leadership. The primary job of school leadership is to help students succeed. It begins with first recognizing and prioritizing areas of need, then finding and implementing the most effective solutions. Whether you work in a turn around environment, or want to make a good school better, this book will give you a set of concrete practices—illustrated through examples of real principals in real schools—that have been proven to work. * Discover the primary drivers of student achievement * Work toward the school's vision in staffing, operations, and systems * Set the tone for all relationships and practices with good leadership Closing the achievement gap is a major goal of educational leadership, and principals are forever searching for viable methods that help them better serve their students. Breakthrough Principals unveils the details behind the success stories from across the nation to provide a roadmap to transformative gains.

This article describes the experience of a teacher-leader at a New York City high school who successfully coached a team of ninth-grade English teachers to improve students’ reading and writing achievement over the course of one year.

Biomolecules such as proteins are highly dynamic, and undergo a wide variety of motions at different timescales. Movements as small as a bond vibration or as large as a domain rearrangement can be critical for the function of a protein, making consideration and investigation of protein dynamics necessary for understanding biological systems and developing therapeutics. In this work, we describe the development and implementation of novel techniques to study dynamics in proteins and protein-bound ligands, and discuss our investigation of the crucial role of dynamics in two disease-relevant systems.First, we have expanded the utility of Chemical Exchange Saturation Transfer (CEST) NMR techniques to aid in the characterization of dynamics for nitrogen- and carbon-attached protons, as well as fluorine nuclei. Protons and fluorine nuclei can be exceptionally sensitive to their chemical environment, allowing detection and measurement of protein motions which may not be readily identified by conventional heteronuclear experiments. Additionally, we discovered the motion of a protein-bound ligand and utilized such information to improve the potency of an antibiotic molecule.Next, we undertook the investigation and optimization of an inhibitor targeting translesion synthesis, a process that cancer cells can employ to resist the killing action of chemotherapeutics. Early work on this project demonstrated that inhibition of Rev1, an important scaffold in the translesion synthesis process, by the compound JH-RE-06 sensitizes cancer cells to cisplatin chemotherapy and prevents drug resistance. Surprisingly, we found that this inhibition occurs through inhibitor-induced dimerization of Rev1, which masks the protein-protein interface required for assembly of the translesion machinery. We further investigated a transient conformational change in the C-terminal tail of Rev1 and validated dimerization in solution using NMR. Our structure- activity relationship investigation of JH-RE-06 yielded a number of insights into how to develop more potent inhibitors. Most significantly, we found that small changes in the chemical structure of the inhibitor resulted in improved inhibitory activity and also led to a novel dimer arrangement. Our combination of Rev1 crystal structures and dynamics studies has led to a deeper understanding of the inhibitory mechanism of JH-RE-06 and will guide the optimization of this potential chemotherapy adjuvant.Finally, we have investigated a mechanism of resistance to beta-lactam antibiotics in Neisseria gonorrhoeae, which relies on modulation of conformational dynamics. Neisseria gonorrhoeae is a major growing health concern due to the rapid spread of multi-drug resistance. We have discovered conformational exchange in PBP2, the target of beta-lactam antibiotics in Neisseria gonorrhoeae, between a low-affinity state and a high- affinity state. A histidine residue was found to be the key mediator of interconversion between these states via a network of molecular interactions, and we found that drug resistance-conferring mutations shift the equilibrium toward the low-affinity state by modulating these interactions. This work describes a novel mechanism of drug resistance in bacteria in which conformational dynamics are restricted.This document illustrates a small sample of the important roles molecular motions have in biology, and the power of dynamics studies in understanding protein function, developing drugs, and elucidating resistance mechanisms.

In Home Builders v. Norton the United States Fish and Wildlife Service (FWS) argued that the Arizona pygmy-owl should be listed endangered as a distinct population segment simply because it is the taxon's sole remaining domestic population. Ruling against the FWS, the Ninth Circuit held that based upon the FWS policy a population of a species can not be listed as endangered simply because it is found within the United States. The court explained that international boundaries can be considered in the first prong of the policy recognizing distinct population segments but not in the second prong ofthat policy – the \"significance\" prong. While the Ninth Circuit's interpretation of the FWS policy was correct, the case highlights one of the policy's flaws. As it stands it does not accord sufficient weight to domestic populations of species. International boundaries should be considered beyond the first prong of the DPS policy if the domestic population of a species is endangered. In some circumstances an endangered domestic population should be listed primarily because it is domestic.