Pharmacological characterization of a homomeric nicotinic acetylcholine receptor formed by Ancylostoma caninum ACR-16

Parasitic nematode infections affect millions of people worldwide and are a significant cause of human and veterinary disease. Chronic infections cause debilitating health problems in humans, domestic animals, and livestock. Infections are treated using anthelmintic drugs, some target nicotinic acetylcholine receptors located in several different tissues. The exact mode of action of antinematode drugs is unknown. Research leading to better understand the mode of action is desirable to appreciate how resistance mechanisms develop. There is an urgent need for novel therapeutic agents to overcome resistance. This study considered Anycylstoma caninum ACR-16 as a drug target and was investigated using two-electrode voltage-clamp electrophysiology. This technique allowed us to explore several agonist and antagonists of ACR-16 and their pharmacology expressed in X. laevis oocytes. The sequence of Acn-ACR-16 was compared with Asu-ACR-16, another homomeric nicotinic acetylcholine receptor, but widely distributed in Ascaris tissue. Also, the concentration-current-response relationships and the potencies of agonists are demonstrated for Acn-ACR-16. We concluded that Acn-ACR-16 was not sensitive to many of the currently used cholinomimetic anthelmintics. Though, the A. caninum channel was most sensitive to 3-bromocytisine unlike nicotine which was the most potent agonist for A. suum ACR-16 receptor. When considering antagonist pharmacology, the A. caninum receptor was moderately inhibited by α-BTX while Asu-ACR-16 was almost insensitive.</p

Collaboration as a Form of Institutional Critique: Teaching and Learning in the Wake of Anti-DEI Legislation

How do we move forward when the legality of teaching and learning about social justice research is called into question by the state? This article demonstrates the efficacy of collaboration as a form of institutional critique that made it possible to provide a comprehensive graduate education following the emergence of anti-DEI legislation in Florida. To teach and learn in a tumultuous legal landscape without sacrificing rigor, eliding DEI-oriented scholarship, or violating state law, we piloted a collaborative disciplinary meta-analysis project that enabled students to study social justice research along with the field’s other major research topics. This portable approach allowed us to meet the professional and ethical imperative to engage research that has been targeted by state officials but remains foundational for disciplinary expertise. It also demonstrates the futility of removing politically unfavorable scholarship from curricula. After sharing an overview of the results of our meta-analysis project, with a special focus on our field’s take on social justice and collaboration, we reflect on the rhetorical strategies those of us working in highly politicized educational climates have deployed to manage increased oversight from zealous state legislatures challenging the legitimacy of disciplinary expertise

Oral Abstracts 7: RA ClinicalO37. Long-Term Outcomes of Early RA Patients Initiated with Adalimumab Plus Methotrexate Compared with Methotrexate Alone Following a Targeted Treatment Approach

Background: This analysis assessed, on a group level, whether there is a long-term advantage for early RA patients treated with adalimumab (ADA) + MTX vs those initially treated with placebo (PBO) + MTX who either responded to therapy or added ADA following inadequate response (IR). Methods: OPTIMA was a 78- week, randomized, controlled trial of ADA + MTX vs PBO + MTX in MTX-naïve early (<1 year) RA patients. Therapy was adjusted at week 26: ADA + MTX-responders (R) who achieved DAS28 (CRP) <3.2 at weeks 22 and 26 (Period 1, P1) were re-randomized to withdraw or continue ADA and PBO + MTX-R continued randomized therapy for 52 weeks (P2); IR-patients received open-label (OL) ADA + MTX during P2. This post hoc analysis evaluated the proportion of patients at week 78 with DAS28 (CRP) <3.2, HAQ-DI <0.5, and/or ΔmTSS ≤0.5 by initial treatment. To account for patients who withdrew ADA during P2, an equivalent proportion of R was imputed from ADA + MTX-R patients. Results: At week 26, significantly more patients had low disease activity, normal function, and/or no radiographic progression with ADA + MTX vs PBO + MTX (Table 1). Differences in clinical and functional outcomes disappeared following additional treatment, when PBO + MTX-IR (n = 348/460) switched to OL ADA + MTX. Addition of OL ADA slowed radiographic progression, but more patients who received ADA + MTX from baseline had no radiographic progression at week 78 than patients who received initial PBO + MTX. Conclusions: Early RA patients treated with PBO + MTX achieved comparable long-term clinical and functional outcomes on a group level as those who began ADA + MTX, but only when therapy was optimized by the addition of ADA in PBO + MTX-IR. Still, ADA + MTX therapy conferred a radiographic benefit although the difference did not appear to translate to an additional functional benefit. Disclosures: P.E., AbbVie, Merck, Pfizer, UCB, Roche, BMS—Provided Expert Advice, Undertaken Trials, AbbVie—AbbVie sponsored the study, contributed to its design, and participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. R.F., AbbVie, Pfizer, Merck, Roche, UCB, Celgene, Amgen, AstraZeneca, BMS, Janssen, Lilly, Novartis—Research Grants, Consultation Fees. S.F., AbbVie—Employee, Stocks. A.K., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, UCB—Research Grants, Consultation Fees. H.K., AbbVie—Employee, Stocks. S.R., AbbVie—Employee, Stocks. J.S., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, GlaxoSmithKline, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB—Research Grants, Consultation Fees. R.V., AbbVie, BMS, GlaxoSmithKline, Human Genome Sciences, Merck, Pfizer, Roche, UCB Pharma—Consultation Fees, Research Support. Table 1.Week 78 clinical, functional, and radiographic outcomes in patients who received continued ADA + MTX vs those who continued PBO + MTX or added open-label ADA following an inadequate response ADA + MTX, n/N (%)a PBO + MTX, n/N (%)b Outcome Week 26 Week 52 Week 78 Week 26 Week 52 Week 78 DAS28 (CRP) <3.2 246/466 (53) 304/465 (65) 303/465 (65) 139/460 (30)*** 284/460 (62) 300/460 (65) HAQ-DI <0.5 211/466 (45) 220/466 (47) 224/466 (48) 150/460 (33)*** 203/460 (44) 208/460 (45) ΔmTSS ≤0.5 402/462 (87) 379/445 (86) 382/443 (86) 330/459 (72)*** 318/440 (72)*** 318/440 (72)*** DAS28 (CRP) <3.2 + ΔmTSS ≤0.5 216/462 (47) 260/443 (59) 266/443 (60) 112/459 (24)*** 196/440 (45) 211/440 (48)*** DAS28 (CRP) <3.2 + HAQ-DI <0.5 + ΔmTSS ≤0.5 146/462 (32) 168/443 (38) 174/443 (39) 82/459 (18)*** 120/440 (27)*** 135/440 (31)** aIncludes patients from the ADA Continuation (n = 105) and OL ADA Carry On (n = 259) arms, as well as the proportional equivalent number of responders from the ADA Withdrawal arm (n = 102). bIncludes patients from the MTX Continuation (n = 112) and Rescue ADA (n = 348) arms. Last observation carried forward: DAS28 (CRP) and HAQ-DI; Multiple imputations: ΔmTSS. ***P < 0.001 and **iP < 0.01, respectively, for differences between initial treatments from chi-squar

Pharmacological characterization of a homomeric nicotinic acetylcholine receptor formed by Ancylostoma caninum ACR-16

Parasitic nematode infections affect millions of people worldwide and are a significant cause of human and veterinary disease. Chronic infections cause debilitating health problems in humans, domestic animals, and livestock. Infections are treated using anthelmintic drugs, some target nicotinic acetylcholine receptors located in several different tissues. The exact mode of action of antinematode drugs is unknown. Research leading to better understand the mode of action is desirable to appreciate how resistance mechanisms develop. There is an urgent need for novel therapeutic agents to overcome resistance. This study considered Anycylstoma caninum ACR-16 as a drug target and was investigated using two-electrode voltage-clamp electrophysiology. This technique allowed us to explore several agonist and antagonists of ACR-16 and their pharmacology expressed in X. laevis oocytes. The sequence of Acn-ACR-16 was compared with Asu-ACR-16, another homomeric nicotinic acetylcholine receptor, but widely distributed in Ascaris tissue. Also, the concentration-current-response relationships and the potencies of agonists are demonstrated for Acn-ACR-16. We concluded that Acn-ACR-16 was not sensitive to many of the currently used cholinomimetic anthelmintics. Though, the A. caninum channel was most sensitive to 3-bromocytisine unlike nicotine which was the most potent agonist for A. suum ACR-16 receptor. When considering antagonist pharmacology, the A. caninum receptor was moderately inhibited by α-BTX while Asu-ACR-16 was almost insensitive.</p

Working with an Indigenous Advisory Council to facilitate effective communication and collaboration between researchers and Arctic communities&amp;#160;

&amp;lt;p&amp;gt;The Arctic Rivers Project is a National Science Foundation &amp;amp;#8211; Navigating the New Arctic funded project aimed at increasing our understanding of the impacts of climate change on rivers, fish, and Indigenous communities across the Northern Alaska and the Yukon River Watershed in Alaska and Canada.&amp;amp;#160; This will be accomplished through water-quality monitoring, a variety of modeling activities, and the development of narratives of change from community members themselves.&amp;amp;#160; Combined these methods will create storylines of climate change in the arctic.&amp;amp;#160; Storylines combine experiential narrative information with model outputs to make the predicated future more tangible regarding potential impacts.&amp;amp;#160; The project team is comprised of researchers from the natural and social sciences as well as the modeling community and two Indigenous organizations focused on science, outreach, and engagement.&amp;amp;#160; To increase the research team&amp;amp;#8217;s ability to co-produce knowledge with Indigenous communities across a large study domain we are working with an Indigenous Advisory Council (IAC).&amp;amp;#160; The IAC is comprised of 11 Indigenous community members, leaders, elders and students representing diverse communities across our study domain. The IAC meets via online video conferencing monthly to tackle tasks such as developing knowledge co-production and inclusion and protection of Indigenous Knowledge protocols to guide the project.&amp;amp;#160; Additionally, the IAC is working with a subset of the research team to create the goals, objectives, and agenda for an Arctic Rivers Summit that will bring together Tribal and First Nation resource managers, Arctic and Boreal community members, and academic, Indigenous, federal, state, and provincial researchers to unify the state of knowledge on Arctic Rivers as a community of observers, investigators, knowledge holders, and stewards. &amp;amp;#160;This presentation will discuss the steps taken to form the IAC, the role of the IAC in guiding project implementation, providing advice, and facilitating connections with Indigenous communities.&amp;amp;#160; It is our hope that we may provide an example of successful implementation and design to communicate and co-produce knowledge with communities across a large study domain from which other projects may learn.&amp;lt;/p&amp;gt;</jats:p

Physical interventions used to improve gait adaptability for individuals with non-progressive neurological injury or disease

Primary Objective: To explore the characteristics and outcomes of physical interventions used to improve walking or gait adapatability for people with non-progressive neurological injury or disease. Secondary Objective: To identify the outcome measures and tasks that have been used to quantify walking or gait adaptability

Scaling of vagus nerve stimulation parameters does not achieve equivalent nerve responses across species

Abstract Background Previous efforts to translate vagus nerve stimulation (VNS) therapies from preclinical studies to human clinical applications (e.g., for stroke, heart failure, and inflammatory diseases) did not account for individual- or species-specific differences in nerve responses when selecting stimulation parameters. Lack of explicit consideration for producing equivalent nerve responses could contribute to clinical outcomes not replicating promising results from preclinical animal studies. Methods We used models of VNS built with ASCENT (Musselman, PLoS Comput Biol 17:e1009285, 2021) to quantify nerve responses across species and simulate translation of VNS therapies via either recycling or linear scaling of stimulation parameters. For humans (n = 9) and pigs (n = 12), we used previously validated computational models with the standard clinical helical cuff electrode on individual-specific nerve morphologies (Musselman, J Neural Eng 20:acda64, 2023b). We also modeled rat VNS (n = 9) with the Micro-Leads Neuro bipolar cuff. We calculated thresholds for fiber activation (A-, B-, and C-fibers) with biphasic rectangular pulses (0.13, 0.25, 0.5 ms). We defined “K” as the ratio of activation thresholds between a pair of individuals. We used a mixed model ANOVA on the natural logarithm of K to test for differences in inter-species Ks across fiber types and pulse widths. Lastly, using the same nerve morphologies and application-specific device design (cuff and waveform), we developed models to predict nerve responses in chronic human and rat VNS studies for treatment of stroke, inflammation, and heart failure. Results Depending on the individual and species, the activation amplitude required to produce a given nerve response varied widely. Thus, applying the same VNS parameters across individuals within a species produced a large range of nerve responses. Further, applying the same or linearly scaled stimulation amplitudes across species also produced highly variable responses. Ks were greater for B fibers than A fibers (p < 0.0001) and decreased with longer pulse widths (p < 0.0001 between consecutive pairs). Conclusions The results highlight the need for systematic approaches to select stimulation parameters that account for individual- and species-specific differences in nerve responses to stimulation. Such parameter tuning may lead to higher response rates and greater therapeutic benefits from VNS therapies

ASCENT (Automated Simulations to Characterize Electrical Nerve Thresholds): A pipeline for sample-specific computational modeling of electrical stimulation of peripheral nerves

Electrical stimulation and block of peripheral nerves hold great promise for treatment of a range of disease and disorders, but promising results from preclinical studies often fail to translate to successful clinical therapies. Differences in neural anatomy across species require different electrodes and stimulation parameters to achieve equivalent nerve responses, and accounting for the consequences of these factors is difficult. We describe the implementation, validation, and application of a standardized, modular, and scalable computational modeling pipeline for biophysical simulations of electrical activation and block of nerve fibers within peripheral nerves. The ASCENT (Automated Simulations to Characterize Electrical Nerve Thresholds) pipeline provides a suite of built-in capabilities for user control over the entire workflow, including libraries for parts to assemble electrodes, electrical properties of biological materials, previously published fiber models, and common stimulation waveforms. We validated the accuracy of ASCENT calculations, verified usability in beta release, and provide several compelling examples of ASCENT-implemented models. ASCENT will enable the reproducibility of simulation data, and it will be used as a component of integrated simulations with other models (e.g., organ system models), to interpret experimental results, and to design experimental and clinical interventions for the advancement of peripheral nerve stimulation therapies.</jats:p

wmglab-duke/ascent: ASCENT v1.3.0

&lt;p&gt;DOI: &lt;a href="https://doi.org/10.5281/zenodo.10608262"&gt;10.5281/zenodo.10608262&lt;/a&gt;&lt;/p&gt; &lt;p&gt;ASCENT v1.3.0 Release Notes&lt;/p&gt; &lt;p&gt;v1.2.2 -&gt; v1.3.0: new features&lt;/p&gt; &lt;ul&gt; &lt;li&gt;extended framework to model two cuffs (stimulation and recording)&lt;/li&gt; &lt;li&gt;modeling a recording cuff will produce a single fiber action potential, and optionally a transmembrane current matrix, output file per fiber simulation&lt;/li&gt; &lt;li&gt;model.json now can additionally accept a list of cuff JSON objects in the "cuff" property&lt;/li&gt; &lt;li&gt;sim.json now contains an "active_recs" property for defining electrode weighting for recording cuffs&lt;/li&gt; &lt;li&gt;added analysis scripts to plot recorded single fiber and compound action potentials&lt;/li&gt; &lt;li&gt;added analysis script to import transmembrane current matrices and generate current templates&lt;/li&gt; &lt;li&gt;submit.py now checks for successful compilation of NEURON files&lt;/li&gt; &lt;/ul&gt; &lt;p&gt;v1.2.2 -&gt; v1.3.0: docs&lt;/p&gt; &lt;ul&gt; &lt;li&gt;added documentation for modeling neural recording and new JSON configuration properties&lt;/li&gt; &lt;li&gt;added documentation for using ASCENT on oSPARC&lt;/li&gt; &lt;li&gt;added refs for new papers using ASCENT&lt;/li&gt; &lt;/ul&gt; &lt;p&gt;v1.2.2 -&gt; v1.3.0: bug fixes&lt;/p&gt; &lt;ul&gt; &lt;li&gt;fixed error with coordinate handling of supersampled fibers&lt;/li&gt; &lt;li&gt;fixed bug where submit.py would fail if on windows and the user name started with an n&lt;/li&gt; &lt;/ul&gt; &lt;p&gt;v1.2.2 -&gt; v1.3.0: miscellaneous&lt;/p&gt; &lt;ul&gt; &lt;li&gt;upgraded to Python 3.10&lt;/li&gt; &lt;li&gt;upgraded pre-commit hooks&lt;/li&gt; &lt;li&gt;changed default dataset export behavior to include sectionwise 2D files&lt;/li&gt; &lt;/ul&gt;&lt;p&gt;Research supported by the National Institutes of Health SPARC Program (OT2 OD025340)&lt;/p&gt