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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.

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.

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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.

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.

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.

The article presents books and activities which will develop a long-term love for reading among primary school students. Books recommended for reading include "The Way I Love You," by David Bedfore and Ann James, "The Biggest Valentine Ever," by Steven Kroll and "Roses are Pink, Your Feet Really Stink," by Diane deGroat. Activities include a book swap with classmates, an invited guest to read for the class and learning about the life and work of a favorite author.

The article describes activity programs for primary education which teach concepts about nature using books by author and photographer Nic Bishop.

The article describes activity programs for preschool, primary, and intermediate education which teach concepts about nature and the outdoors.

The article describes an activity program for grades K-4 which lets students share their reactions to various books on pets.

The article describes an activity program for primary education which encourages kids to engage in science through reading, outdoor activities and doing simple science experiments.

Correlation properties of speckle fields at the output of quadratic phase systems with hard square and circular apertures are examined. Using the linear canonical transform and ABCD ray matrix techniques to describe these general optical systems, we first derive analytical formulas for determining axial and lateral speckle sizes. Then using a numerical technique, we extend the analysis so that the correlation properties of nonaxial speckles can also be considered. Using some simple optical systems as examples, we demonstrate how this approach may be conveniently applied. The results of this analysis apply broadly both to the design of metrology systems and to speckle control schemes.

Correlation properties of speckle fields at the output of quadratic phase systems with hard square and circular apertures are examined. Using the linear canonical transform and ABCD ray matrix techniques to describe these general optical systems, we first derive analytical formulas for determining axial and lateral speckle sizes. Then using a numerical technique, we extend the analysis so that the correlation properties of nonaxial speckles can also be considered. Using some simple optical systems as examples, we demonstrate how this approach may be conveniently applied. The results of this analysis apply broadly both to the design of metrology systems and to speckle control schemes.

Correlation properties of speckle fields at the output of quadratic phase systems with hard square and circular apertures are examined. Using the linear canonical transform and ABCD ray matrix techniques to describe these general optical systems, we first derive analytical formulas for determining axial and lateral speckle sizes. Then using a numerical technique, we extend the analysis so that the correlation properties of nonaxial speckles can also be considered. Using some simple optical systems as examples, we demonstrate how this approach may be conveniently applied. The results of this analysis apply broadly both to the design of metrology systems and to speckle control schemes.

Lucky imaging, used with some success in astronomical and even horizontal-path imaging, relies on fleeting conditions of the atmosphere that allow momentary improvements in image quality, at least in portions of an image. Aperture synthesis allows a larger aperture and, thus, a higher-resolution imaging system to be synthesized through the superposition of image spatial-frequency components gathered by cooperative combinations of smaller subapertures. A combination of lucky imaging and aperture synthesis strengthens both methods for obtaining improved images through the turbulent atmosphere. We realize the lucky imaging condition appropriate for aperture synthesis imaging for a pair of rectangular subapertures and demonstrate that this condition occurs when the signal energy associated with bandpass spatial-frequency components achieves its maximum value.

The red grouse Lagopus lagopus scoticus differs from the willow grouse L. l. lagopus of mainland Europe in not developing a white winter plumage. Previous studies have suggested that plumage colouration in birds can have important consequences for heat transfer through the feather layer. We examined the thermal consequences of plumage colouration in both subspecies of grouse. There were no differences in feather density, plumage depth or thermal resistance of the plumage between dark rufous Scottish and white Scandinavian grouse. In still air, heat gained from simulated solar radiation was greater through dark than through white plumage. However, in wind there was no difference in heat load between dark and white plumages. Our study suggests that there may be a trade-off between thermal and camouflage benefits of plumage colour for grouse in the wild.

Digital speckle photography can be used in the analysis of surface motion in combination with an optical linear canonical transform (LCT). Previously [D. P. Kelly et al. Appl. Opt.44, 2720 (2005)] it has been shown that optical fractional Fourier transforms (OFRTs) can be used to vary the range and sensitivity of speckle-based metrology systems, allowing the measurement of both the magnitude and direction of tilting (rotation) and translation motion simultaneously, provided that the motion is captured in two separate OFRT domains. This requires two bulk optical systems. We extend the OFRT analysis to more general LCT systems with a single limiting aperture. The effect of a limiting aperture in LCT systems is examined in more detail by deriving a generalized Yamaguchi correlation factor. We demonstrate the benefits of using an LCT approach to metrology design. Using this technique, we show that by varying the curvature of the illuminating field, we can effectively change the output domain. From a practical perspective this means that estimation of the motion of a target can be achieved by using one bulk optical system and different illuminating conditions. Experimental results are provided to support our theoretical analysis.

The conditions that lead to successful economic development are diverse and place sensitive. Recent research supports the notion that there is a correlation between the presence of natural amenities and rural economic development. This case explores the situation of a rural county that is faced with constrained development options as a result of a significant federal footprint on the county's land area. The actions of the federal agencies managing the resources impact the economic vitality of the region. Two issues currently under review challenge the county to think critically about its potential for using nature as an economic development tool.

The design of novel biomaterials for applications in biological recognition, drug delivery, or diagnostics requires a judicious choice of preparation conditions and methods for the production of well-characterized 3-dimensional structures, preferably by benign processes. In this work, the polymerization of poly(ethylene glycol) (PEG) methacrylates was examined by kinetic gelation modeling and kinetic analysis in order to ascertain the factors affecting the resulting structure. The kinetics of the polymerization and structure of the final polymer network are strongly affected by the length of the PEG graft chain. The propagation of the polymer chains becomes increasingly diffusion limited with the incorporation of longer PEG grafts. In addition, a more heterogeneous network consisting of numerous microgel regions is produced as the length of the PEG graft is increased. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 3506–3519, 2003

The “living” radical polymerization with an iniferter was used to create micropatterned biomedical surfaces. Novel, photosensitive biomedical polymers were created by the incorporation of dithiocarbamate groups from iniferters. A second monomer layer was then irradiated onto the photosensitive polymer substrate created with the iniferter to form a copolymer. Patterns were created on the films by application of modified microfabricationbased photolithographic techniques. The technique was used to create patterns with depths from 5 to 80 μm. In addition, various polymers were incorporated, including polyethylene glycol methacrylates, styrene, and methacrylic acid, to synthesize regions with different physicochemical properties. Applications include novel surfaces for biosensors and biomaterials for the selective adhesion of cells and proteins. © 2001 John Wiley & Sons, Inc. J Biomed Mater Res 56: 351–360, 2001

A robust H∞ controller was developed to deliver insulin via a mechanical pump in Type I diabetic patients. A fundamental nonlinear diabetic patient model was linearized and then reduced to a third‐order linear form for controller synthesis. Uncertainty in the nonlinear model was characterized by up to ±40% variation in eight physiological parameters. A sensitivity analysis identified the three‐parameter set having the most significant effect on glucose and insulin dynamics over the frequency range of interest ω = [0.002, 0.2] (rad/min). This uncertainty was represented in the frequency domain and incorporated in the controller design. Controller performance was assessed in terms of its ability to track a normoglycemic set point (81.1 mg/dL) in response to a 50 g meal disturbance. In the nominal continuous‐time case, the controller maintained glucose concentrations within ±3.3 mg/dL of set point. A controller tuned to accommodate uncertainty yielded a maximum deviation of 17.6 mg/dL for the worst‐case parameter variation.