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Cofactor mimicry represents an attractive strategy for the development of enzyme inhibitors but can lead to off-target effects due to the evolutionary conservation of binding sites across the proteome. Here, we uncover the ADP-ribose (ADPr) hydrolase NUDT5 as an unexpected, noncovalent, off-target of clinical BTK inhibitors. Using a combination of biochemical, biophysical, and intact cell NanoBRET assays as well as X-ray crystallography, we confirm catalytic inhibition and cellular target engagement of NUDT5 and reveal an unusual binding mode that is independent of the reactive acrylamide warhead. Further investigation of the prototypical BTK inhibitor ibrutinib also revealed potent inhibition of the largely unstudied NUDIX hydrolase family member NUDT14. By exploring structure–activity relationships (SARs) around the core scaffold, we identify a potent, noncovalent, and cell-active dual NUDT5/14 inhibitor. Cocrystallization experiments yielded new insights into the NUDT14 hydrolase active site architecture and inhibitor binding, thus providing a basis for future chemical probe design.

Gastroenterology (GE) hospitalist teams provide high-quality acute care to hospitalized patients with GI conditions. Advanced practice providers (APPs) are increasingly being incorporated into these teams to improve the quality of care that is delivered. This article details how GE APPs can streamline workflows, increase access to care and timeliness of consultation, and improve interdisciplinary communication. The role of the GE APP is discussed in both the academic practice and private practice settings. Various challenges to adopting the GE APP model are outlined, including the need for formal institution-specific onboarding programs and supportive physician collaborators. Ongoing educational opportunities are key to further developing the medical knowledge and skills of the GE APP. Finally, considerations for designing a rewarding and sustainable GE APP work schedule are discussed.

Since the release of the Truth and Reconciliation Commission (TRC) of Canada’s Calls to Action in 2015, many post-secondary institutions have hired educational developers (EDs) to support instructors in the Indigenization of curricula and pedagogy. Drawing from a Canada-wide study, and best practices identified in the literature, this article explores the experiences of educational developers EDs in these roles, and proposes strategies for how institutions of higher education can better foster transformative change and practices inclusive of First Peoples in Canada.

Various people were chosen to educate people about drugs and this dissemination of information to a large sector of the community, such as parents and teachers, was effective. However, it is unclear whether giving young people information will change their behaviour. None of the young people doing the educating used drugs themselves and they were unable to pass information on to those who did. It is very important that this group is reached. More evaluation is needed to establish whether or not peer education is more useful than other methods of education.

Inhibition of inflammasome and pyroptotic pathways are promising strategies for clinical treatment of autoimmune and inflammatory disorders. MCC950, a potent inhibitor of the NLR-family inflammasome pyrin domain-containing 3 (NLRP3) protein, has shown encouraging results in animal models for a range of conditions; however, until now, no off-targets have been identified. Herein, we report the design, synthesis, and application of a novel photoaffinity alkyne-tagged probe for MCC950 (IMP2070) which shows direct engagement with NLRP3 and inhibition of inflammasome activation in macrophages. Affinity-based chemical proteomics in live macrophages identified several potential off-targets, including carbonic anhydrase 2 (CA2) as a specific target of IMP2070, and independent cellular thermal proteomic profiling revealed stabilization of CA2 by MCC950. MCC950 displayed noncompetitive inhibition of CA2 activity, confirming carbonic anhydrase as an off-target class for this compound. These data highlight potential biological mechanisms through which MCC950 and derivatives may exhibit off-target effects in preclinical or clinical studies.

Deubiquitinating enzymes (DUBs) are a growing target class across multiple disease states, with several inhibitors now reported. b-AP15 and VLX1570 are two structurally related USP14/UCH-37 inhibitors. Through a proteomic approach, we demonstrate that these compounds target a diverse range of proteins, resulting in the formation of higher molecular weight (MW) complexes. Activity-based proteome profiling identified CIAPIN1 as a submicromolar covalent target of VLX1570, and further analysis demonstrated that high MW complex formation leads to aggregation of CIAPIN1 in intact cells. Our results suggest that in addition to DUB inhibition, these compounds induce nonspecific protein aggregation, providing molecular explanation for general cellular toxicity.

20,000 Leagues Under the Sea. By Jules Verne. 12 CDs. 15:10 hrs. Prod. by Listening Library. Dist. by Listening Library/Books on Tape. 2011. ISBN 978-0-307-74795-2. $30. Gr 9 Up--Sensational news [...]

* The Day the Music Stopped. DVD. approx. 60 min. Juno. 2010. ISBN 9781-936410-00-2. $17.99. PreS-K--A mix of endearing fleecy puppets, quality computer-generated graphics, and professional music set the stage [...]

From Trash to Tunes. DVD. approx. 30 min. plus approx. 4:30 hrs. bonus segments, Waring Music. 2010. ISBN 978-1-4507-1170-8. $20. Gr 4 Up--Dr. Dennis Waring, an enthusiastic musician, is eager [...]

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The Six Rules of Maybe (unabr.). 8 CDs. 9:52 hrs. Brilliance Audio. 2010. ISBN 978-1-4233-9666-6. $92.97. Gr 9 Up--Seventeen-year-old Scarlet, self-appointed savior, learns a lesson in the pitfalls of trying [...]

Deubiquitinating enzymes play an important role in a plethora of therapeutically relevant processes and are emerging as pioneering drug targets. Herein, we present a novel probe, Ubiquitin Specific Protease (USP) inhibitor, alongside an alkyne-tagged activity-based probe analogue. Activity-based proteome profiling identified 12 USPs, including USP4, USP16, and USP33, as inhibitor targets using submicromolar probe concentrations. This represents the first intact cell activity-based profiling of deubiquitinating enzymes. Further analysis demonstrated functional inhibition of USP33 and identified a synergistic relationship in combination with ATR inhibition, consistent with USP4 inhibition.

AbstractThis study explored how developmentally appropriate practices influenced the affordances of a multitouch surface in an early childhood classroom. Children, ages 4 to 5 years old, were videotaped while engaged in a storymaking application on a multitouch table. As a result of the study, we found that some challenges with the functionality undermined children's autonomous control. The researchers observed numerous instances of issues with control of the medium, including height of the table, sensitivity to multiple types of touch, and limited instructions and prompts. Implications for future research and practice are discussed.

The Summer I Learned to Fly (unabr.). 4 CDs. 4:25 hrs. Prod. by Listening Library. Dist. by Listening Library/Books on Tape. 2011. ISBN 978-0-307-91577-1. $30. Gr 6-8--Fatherless teens' paths cross [...]

The Penalty (unabr.). 5 CDs. 6:10 hrs. Brilliance Audio. 2011. ISBN 978-1-4558-0073-5. $49.97. Gr 10 Up--Mal Peet weaves past and present throughout this tale (Candlewick, 2007) -of sports, voodoo, murder, [...]

After Ever After (unabr.). 4 CDs. 4:37 hrs. Brilliance Audio. 2011. ISBN 978-1-61106-135-2. $54.97. Gr 6-9--In Jordan Sonnenblick's Dams, Girls and Dangerous Pie (2004), eighth-grader Steven deals with his younger [...]

* Artist Profiles: Musicians & Their Music (Discoveries America Special Edition Series). DVD. 1:37 hrs. Bennett-Watt HD Prods. 2010. ISBN 978-1-934682-58-6. $24.95. Gr 9 Up--Studying ethnic American music in hotspots [...]

Kilauea: Hawaii's Birth Volcano (Nature Series). DVD. 30 min. with tchr's guide. Prod. by Pangolin Pictures, Thirteen, WNET.org, and National Geographic Channel Int'l. Dist. by New Dimension Media. 2011. ISBN [...]

Monkey Monkey Music: The Videos with Meredith Levande. DVD. 36 min. Monkey Monkey Music. 2010. $19.99. PreS-K--Fifteen songs written for young children and sung by a joyful Meredith Levande set [...]

Ask Amy Green: Boy Trouble (unabr.). 5 CDs. approx. 5 hrs. Brilliance Audio. 2010. ISBN 978-1-4418-8888-4. $54.97. Gr 5-8--Sarah Webb is Ireland's Louise Rennison, although her main character, Amy Green, [...]

All the Broken Pieces (unabr.). 2 CDs. 1:51 hrs. Scholastic Andiobooks. 2010. ISBN 978-0-545-24839-6. $29.99. Gr 6-8--Sensitively read by Tobias Christian Wong, Ann E. Burg's historical fiction in verse (Scholastic, [...]

Stolen (unabr.). 7 cassettes or 7 CDs. 8:50 hrs. Recorded Books. 2010. cassette, ISBN 978-1-4498-1253-9: $51.75; CD, ISBN 978-1-4498-1257-7: $66.75. Gr 9 Up--Sixteen-year-old Gemma, traveling with her parents, is abducted [...]

The Dreamer (unabr.). 5 CDs. 5:26 hrs. Scholastic Audiobooks. 2010. ISBN 978-0-545-22339-3. $39.99. Gr 4-9--Pam Munoz Ryan's fictionalized biography (Scholastic, 2010) of Chilean Nobel prize-winning poet Pablo Neruda is lovingly [...]

Kitchen Math and Measuring: How It All Adds Up (In the Kitchen Series). DVD. 23 min. with tchr's, guide online. Learning Seed. 2010. ISBN 1-55740-557-3. $99. Gr 5-8-Student chefs at [...]

Gimme a Call (unabr.). 7 CDs. 7:58 hrs. Prod. by Listening Library. Dist. by Listening Library/Books on Tape. 2010. ISBN 978-0-3077-1152-6. $34. Gr 7-10--Just weeks away from high school graduation [...]

* Jumped (unabr.). 3 cassettes or 3 CDs. 3:45 hrs. Recorded Books. 2010. cassette, ISBN 978-1-4498-0916-4: $33.75; CD, ISBN 978-1-4498-0920-1: $30.75. Gr 8-10-Before writing this novel (Amistad, 2009), Rita Williams-Garcia [...]

The Science of Imagineering: Electricity. DVD. 30 min. with tchr's, guide. Disney Educational. 2010. ISBN 1-59753-250-9. $29.99. Gr 5-8--Narrated by a perky Disney Design and Development 'Imagineer,' one of the [...]

Truly Winnie (unabr.). CD. 1:20 hrs. Live Oak Media. 2009. ISBN 978-1-43010-756-9. $18.95; with paperback book, ISBN 978-1-43010-757-6: $20.95. Gr 2-4--Jennifer Richard Jacobson's enjoyable beginning chapter book (Houghton Mifflin Harcourt, [...]

While living at Pope Air Force Base last year, I decided to go hang out with some friends. We are all extreme sportsmen and are always trying new tricks, whether [...]

The article discusses the contribution of Deborah Kinzinger to Canadian horse sport. It mentions Kinzinger's passion for the sport who used to ride, do eventing and a little of dressage. It elaborates on her collaboration with Canadian dressage rider David Marcus who is training her four horses Chevi's Capital, Don Altena, Betrina, and Don Kontes. It also cites the establishment of the Canadian Dressage Athlete Assistance Program (C-DAAP) by the 2013 Dressage Canada Owner of the Year recipient.

An essay is presented in which the author discusses her hobby of collecting pins and also mentions about the interest of several people in collecting different things. She states that her mother had a habit of collecting sweat suits, Mickey Mouse imprinted soap and raincoats. She illustrates several people who had a hobby of collecting things including American author Thomas Jefferson who collected books and American newspaper publisher William Randolph Hearst who had a collection of art.

Systemic AL amyloidosis results from the aggregation of an amyloidogenic immunoglobulin (Ig) light chain (LC) usually produced by a plasma cell clone in the bone marrow. AL is the most rapidly fatal of the systemic amyloidoses, as amyloid fibrils can rapidly accumulate in tissues including the heart, kidneys, autonomic or peripheral nervous systems, gastrointestinal tract, and liver. Chemotherapy is used to eradicate the cellular source of the amyloidogenic precursor. Currently, there are no therapies that target the process of LC aggregation, fibril formation, or organ damage. We developed transgenic mice expressing an amyloidogenic λ6 LC using the cytomegalovirus (CMV) promoter to circumvent the disruption of B cell development by premature expression of recombined LC. The CMV-λ6 transgenic mice develop neurologic dysfunction and Congophilic amyloid deposits in the stomach. Amyloid deposition was inhibited in vivo by the antibiotic doxycycline. In vitro studies demonstrated that doxycycline directly disrupted the formation of recombinant LC fibrils. Furthermore, treatment of ex vivo LC amyloid fibrils with doxycycline reduced the number of intact fibrils and led to the formation of large disordered aggregates. The CMV-λ6 transgenic model replicates the process of AL amyloidosis and is useful for testing the antifibril potential of orally available agents.

The article presents a lesson plan for primary education based on books promoting the environment, such as "Just a Dream," by Chris Van Allsburg," "I Can Save the Earth! One Little Monster Learns to Reduce, Reuse and Recycle," by Alison Inches, and "We Are Extremely Very Good Recyclers," by Lauren Child.