Developmental and age-related synapse elimination is mediated by glial Croquemort.

Neurons and glia work together to dynamically regulate neural circuit assembly and maintenance. In this study, we show Drosophila exhibit large-scale synapse formation and elimination as part of normal CNS circuit maturation, and that glia use conserved molecules to regulate these processes. Using a high throughput ELISA-based in vivo screening assay, we identify new glial genes that regulate synapse numbers in Drosophila in vivo, including the scavenger receptor ortholog Croquemort (Crq). Crq acts as an essential regulator of glial-dependent synapse elimination during development, with glial Crq loss leading to excess CNS synapses and progressive seizure susceptibility in adults. Loss of Crq in glia also prevents age-related synaptic loss in the adult brain. This work provides new insights into the cellular and molecular mechanisms that underlie synapse development and maintenance across the lifespan, and identifies glial Crq as a key regulator of these processes.

Scholarship of Drug Information and Library Sciences Instruction in North American Pharmacy Education: A Systematic Review of English-Language Research.

OBJECTIVES: This study aimed to characterize the scholarship of teaching and learning specific to drug information and library sciences (DILS) in pharmacy education and provide a comprehensive, evidence-based resource for faculty, detailing published practices for content delivery and scholarly research gaps. FINDINGS: Systematic searches of PubMed, Embase, International Pharmaceutical Abstracts, Educational Resources Information Center, Scopus, Library Literature & Information Science Full Text, and Library, Information Science & Technology Abstracts were conducted from January 1997 through early February 2022. Included studies were published in English, involved DILS content, were specific to pharmacy education, were original research, and were conducted in North America. The review excluded abstract-only records and studies that did not include learners (ie, pharmacy students and residents) as participants. Duplicate records were removed. After screening and review, 166 articles met the eligibility criteria, 60% of which (n = 100/166) were published in the last 10 years. Most studies focused on literature evaluation (45/166, 27%), fundamentals of drug information (43/166, 25%), evidence-based medicine (21/166, 13%), and resource utilization (21/166, 13%). Studied learners were mainly pharmacy students (77%), and 82% of research included authors who were pharmacists, whereas 14% included librarians. Assessment techniques used primarily focused on student perception (61/166, 37%), followed by summative assessment (46/166, 28%), other (25/166, 15%), and formative assessment (18/166, 11%). SUMMARY: This article presents a systematically identified collection of North American literature examining the education in DILS of pharmacy learners. Areas for continued research of DILS content include evaluating underrepresented educational domains (ie, systematic approach, response development and provision, literature searching, study design), using librarians more in scholarship of teaching and learning research, and using formative and summative assessments as outcomes.

Astrocyte growth is driven by the Tre1/S1pr1 phospholipid-binding G protein-coupled receptor.

Astrocytes play crucial roles in regulating neural circuit function by forming a dense network of synapse-associated membrane specializations, but signaling pathways regulating astrocyte morphogenesis remain poorly defined. Here, we show the Drosophila lipid-binding G protein-coupled receptor (GPCR) Tre1 is required for astrocytes to establish their intricate morphology in vivo. The lipid phosphate phosphatases Wunen/Wunen2 also regulate astrocyte morphology and, via Tre1, mediate astrocyte-astrocyte competition for growth-promoting lipids. Loss of s1pr1, the functional analog of Tre1 in zebrafish, disrupts astrocyte process elaboration, and live imaging and pharmacology demonstrate that S1pr1 balances proper astrocyte process extension/retraction dynamics during growth. Loss of Tre1 in flies or S1pr1 in zebrafish results in defects in simple assays of motor behavior. Tre1 and S1pr1 are thus potent evolutionarily conserved regulators of the elaboration of astrocyte morphological complexity and, ultimately, astrocyte control of behavior.

Glial TGFß activity promotes neuron survival in peripheral nerves.

Maintaining long, energetically demanding axons throughout the life of an animal is a major challenge for the nervous system. Specialized glia ensheathe axons and support their function and integrity throughout life, but glial support mechanisms remain poorly defined. Here, we identified a collection of secreted and transmembrane molecules required in glia for long-term axon survival in vivo. We showed that the majority of components of the TGFß superfamily are required in glia for sensory neuron maintenance but not glial ensheathment of axons. In the absence of glial TGFß signaling, neurons undergo age-dependent degeneration that can be rescued either by genetic blockade of Wallerian degeneration or caspase-dependent death. Blockade of glial TGFß signaling results in increased ATP in glia that can be mimicked by enhancing glial mitochondrial biogenesis or suppressing glial monocarboxylate transporter function. We propose that glial TGFß signaling supports axon survival and suppresses neurodegeneration through promoting glial metabolic support of neurons.

Discoidin domain receptor regulates ensheathment, survival and caliber of peripheral axons.

Most invertebrate axons and small-caliber axons in mammalian peripheral nerves are unmyelinated but still ensheathed by glia. Here, we use Drosophila wrapping glia to study the development and function of non-myelinating axon ensheathment, which is poorly understood. Selective ablation of these glia from peripheral nerves severely impaired larval locomotor behavior. In an in vivo RNA interference screen to identify glial genes required for axon ensheathment, we identified the conserved receptor tyrosine kinase Discoidin domain receptor (Ddr). In larval peripheral nerves, loss of Ddr resulted in severely reduced ensheathment of axons and reduced axon caliber, and we found a strong dominant genetic interaction between Ddr and the type XV/XVIII collagen Multiplexin (Mp), suggesting that Ddr functions as a collagen receptor to drive axon wrapping. In adult nerves, loss of Ddr decreased long-term survival of sensory neurons and significantly reduced axon caliber without overtly affecting ensheathment. Our data establish essential roles for non-myelinating glia in nerve development, maintenance and function, and identify Ddr as a key regulator of axon-glia interactions during ensheathment and establishment of axon caliber.

Solriamfetol for the Management of Excessive Daytime Sleepiness.

OBJECTIVE: To review efficacy, safety, and place in therapy of solriamfetol for management of excessive daytime sleepiness (EDS) in patients with narcolepsy and obstructive sleep apnea (OSA). METHODS: PubMed (1966 to January 2021) was searched using the terms solriamfetol, JZP-110, ADX-N05 and Sunosi. Human studies published in peer-reviewed medical journals in English language were reviewed. RESULTS: The efficacy and safety of solriamfetol has been reported in 2 phase II trials and 4 phase III trials (TONES 2, TONES 3, TONES 4, and TONES 5). Statistically significant improvements in the maintenance of wakefulness test were reported with solriamfetol 150 mg and 300 mg vs placebo in participants with narcolepsy (7.65- to 10.14-minute difference from placebo). In subjects with OSA, statistically significant improvements in maintenance of wakefulness test difference from placebo were also observed in those taking solriamfetol 75 mg, 150 mg, or 300 mg vs placebo (4.5- to 12.8-minute difference from placebo). Statistically significant reductions in Epworth Sleepiness Scale scores were also reported in phase III trials in subjects with narcolepsy or OSA taking solriamfetol vs placebo (ranging from - 4.7 to - 1.9 difference from placebo). Common adverse events in reported in phase III trials were headache, nausea, decreased appetite, anxiety, dry mouth, and diarrhea. Solriamfetol appears to have a reduced risk for drug interactions and fewer adverse effects compared to other agents available for management of EDS in patients with narcolepsy and OSA. CONCLUSIONS: Solriamfetol is an effective option for management of EDS in patients with narcolepsy and OSA.

Pharmacy students' intrinsic motivation to participate in electronic peer review of journal article critique assignments.

BACKGROUND AND PURPOSE: Journal article critiques are frequently used to teach literature evaluation to pharmacy students. Peer review is one method to improve students' competency regarding journal article critiques. The objective of this manuscript is to describe implementation of electronic peer review of journal article critique drafts and explore students' intrinsic motivation to participate in the peer-review process. Influence of students' motivation to participate in peer review on their self-competence regarding journal article critiques was also explored. EDUCATIONAL ACTIVITY AND SETTING: Second-year pharmacy students participated in three in-class, electronic, anonymous peer-review sessions for written journal article critique drafts. Students were invited to complete a 16-item survey instrument based on self-determination theory. Modified Intrinsic Motivation Inventory and Perceived Competence Scales assessed student interest in and perceived value of the peer-review sessions and their self-competence regarding journal article critiques. FINDINGS: The survey response rate was 99% (146/148). Based on a Likert scale of 1 (not at all true) to 7 (very true), students demonstrated moderate interest in the peer-review sessions (M = 3.86), viewed them as valuable (M = 5.25), and had a moderate level of self-competence regarding journal article critiques (M = 3.74). Additionally, interest and perceived value of the peer-review sessions significantly influenced self-competence in completing journal article critiques. SUMMARY: An anonymous, electronic peer-review system provides an efficient method for in-class peer review of draft assignments. Implementing strategies to increase student interest in peer review may increase their motivation for participation and ultimately improve self-competence regarding literature evaluation.

TSG101 negatively regulates mitochondrial biogenesis in axons.

There is a tight association between mitochondrial dysfunction and neurodegenerative diseases and axons that are particularly vulnerable to degeneration, but how mitochondria are maintained in axons to support their physiology remains poorly defined. In an in vivo forward genetic screen for mutants altering axonal mitochondria, we identified tsg101 Neurons mutant for tsg101 exhibited an increase in mitochondrial number and decrease in mitochondrial size. TSG101 is best known as a component of the endosomal sorting complexes required for transport (ESCRT) complexes; however, loss of most other ESCRT components did not affect mitochondrial numbers or size, suggesting TSG101 regulates mitochondrial biology in a noncanonical, ESCRT-independent manner. The TSG101-mutant phenotype was not caused by lack of mitophagy, and we found that autophagy blockade was detrimental only to the mitochondria in the cell bodies, arguing mitophagy and autophagy are dispensable for the regulation of mitochondria number in axons. Interestingly, TSG101 mitochondrial phenotypes were instead caused by activation of PGC-1ɑ/Nrf2-dependent mitochondrial biogenesis, which was mTOR independent and TFEB dependent and required the mitochondrial fission-fusion machinery. Our work identifies a role for TSG101 in inhibiting mitochondrial biogenesis, which is essential for the maintenance of mitochondrial numbers and sizes, in the axonal compartment.

Implementation of a Teaching Electronic Medical Record within Didactic Instruction Using a Drug Information Question Assignment.

BACKGROUND: Pharmacy graduates are expected to be practice-ready to deliver quality patient care, which includes having comprehensive knowledge of health informatics and electronic medical records (EMRs). The purpose of this study was to (1) incorporate an EMR within a pharmacy student assignment, and (2) assess student perceptions of use of the EMR. METHODS: Student pharmacists received a patient-specific drug-related question and were required to use an EMR to provide an accurate response. Following completion of the assignment, students were invited to complete a retrospective, pre-post survey instrument to collect their perceptions. RESULTS: Only 28.8% of respondents reported prior experience using an EMR. Student perceptions about use of an EMR within the didactic setting significantly improved from before to after the assignment. Differences were found in respondents who agreed that didactic use of an EMR increased their confidence in obtaining information from an EMR (20.5% to 82.8%) and improved their knowledge of EMR systems (61.4% to 89.3%). CONCLUSIONS: Implementation of an EMR within didactic instruction may serve as the first exposure to health informatics for students and positively impacts student perceptions of these tools prior to entry into pharmacy practice.

The Current Landscape of College-Sponsored Postgraduate Teaching and Learning Curriculum Programs.

Objective. To describe the landscape of teaching and learning curriculum (TLC) programs sponsored by US schools and colleges of pharmacy and evaluate their adoption of best practice recommendations. Methods. A 28-item electronic survey instrument was developed based on best practice recommendations published by the American Association of Colleges of Pharmacy (AACP), American Society of Health-System Pharmacists (ASHP), and American College of Clinical Pharmacy (ACCP) for the conduct of TLC programs. The survey instrument was electronically distributed to 137 accredited colleges and schools of pharmacy in the United States. Results. Eighty-eight institutions responded, resulting in a response rate of 64%. Sixty-one TLC programs were included in the final analysis. Seventy-five percent of TLC programs reported using best practice recommendations; however, 10% of respondents indicated they were not aware of the published recommendations. Inconsistencies among programs were noted in required teaching experiences, participant evaluation, and ongoing programmatic assessment. Conclusion. Most institutions offering TLC programs are aware of published best practice guidelines and have adopted a majority of the published best practices. However, considerable variability exists across the country. Development of a formal external validation process for TLC programs is necessary to ensure consistent quality.

Global collaboration to deliver a live pharmacy teaching and learning curriculum.

BACKGROUND AND PURPOSE: The Indiana Pharmacy Teaching Certificate Program (IPTeC) offered a live, two-day conference to pharmacy residents, fellows, and preceptors in Indiana, while simultaneously live-streaming to participants in Doha, Qatar. Participants engaged in longitudinal activities for a one-year period. The purpose is to evaluate this pilot extension of a teaching and learning curriculum (TLC) to experienced preceptors in a global partnership and determine whether global and local participants perceive similar quality of programming. EDUCATIONAL ACTIVITY AND SETTING: Upon completion of the two-day conference, all pharmacists from two years of the program were encouraged to complete the standard course evaluations, consisting of nine items, in order to obtain continuing education (CE) credit. Evaluations of the program were analyzed by location cohort. FINDINGS: A total of 206 eligible pharmacists attended the program, with 154 completing the course evaluations (response rate 75%). "Good" or "outstanding" median ratings were given to each learning objective by both location cohorts, with domestic participants more likely to give "outstanding" ratings (6/9 items versus 0/9 items). SUMMARY: This pilot extension was successful in providing educational content satisfying learning objectives from the perspective of domestic participants and remote participants in Qatar. This type of global collaboration can meet the needs of trainees and experienced preceptors to advance pharmacy education and training.

Reporting quality of survey research articles published in the pharmacy literature.

BACKGROUND: Survey research methodology is commonly used in the pharmacy literature and standards have been set forth for quality reporting. A systematic review to assess the reporting quality of survey research has only been completed for general medical literature. OBJECTIVES: The objective of this study is to examine the quality of survey research reporting published in the pharmacy literature and identify reporting areas researchers can focus on for increased transparency in survey research methodology. METHODS: A cross-sectional study of survey research articles published in seven key pharmacy journals in 2016 was conducted using a published 30-item checklist instrument designed for the reporting quality surveys. Each article was evaluated by two independent study investigators and assigned a final score out of 30. RESULTS: Out of 197 articles assessed for eligibility, 105 (53%) used survey research as the primary methodology and were included in the study. The average reporting score was 18.2±3.0 (range 10-25) out of 30, with the highest average scores reported for PharmacoEconomics (22.5), JMCP (20.4) and RSAP (19.8). Checklist items related to the quality of reporting survey research methodology with the highest compliance included: original reference cited for use of existing tools (100%), description of survey population and sample frame (90%); and reporting response rate (90%). Checklist items with low reporting included: psychometric properties for existing tools (14%); reliability and validity for new instruments (11%); analysis of nonresponse bias (8%); definition of complete versus partial responses (8%); methods of handling missing data (19%); and information about how non-respondents differ from respondents (14%). CONCLUSIONS: Survey research published in the pharmacy literature scored moderately on a published instrument designed for systematic appraisal of survey research reporting quality. Several areas for continued improvement exist for survey research reporting quality in the pharmacy literature.

Perceived Value of Teaching and Learning Curriculum Programs Among Pharmacy Practice Department Chairs.

Objective. To determine the perceived value that pharmacy practice department chairs ascribe to pharmacy faculty candidates having completed a teaching and learning curriculum (TLC) program and related activities.Methods. An 18-item survey instrument was created that was intended to capture the overall impressions of pharmacy practice chairs regarding the value of TLC programs, relative importance compared to other accomplishments (eg, residency completion, board certification), and importance of specific activities. Following pilot testing and establishment of intra-rater reliability, invitations to complete the electronic survey instrument were sent to pharmacy practice chairs (or their equivalent) at accredited Doctor of Pharmacy (PharmD) programs in the United States.Results. Of the 127 pharmacy practice chairs invited, 53 completed the survey (response rate of 41.7%). The majority of respondents held a PharmD degree (90.6%), had been in their role of chair for zero to five years (60.4%), and represented a private institution (54.7%). The majority of respondents who answered the question (32 of 49) felt it was very important or important (16.3% and 49.0%, respectively) that teaching experiences be completed within a formal teaching and learning curriculum program. These programs were believed to be most important for candidates with less than five years of professional experience. Teaching and learning curriculum programs were not deemed to be more important than other accomplishments by most responders. The perceived most important TLC program activities were instruction on didactic and experiential teaching strategies, and experience developing learning objectives, developing examination items, evaluating examination results, and facilitating case conferences or practice laboratory activities.Conclusion. Teaching and learning curriculum programs may provide the foundational experiences needed for pharmacy graduates to stand out among other candidates, although department chairs' perceptions of the value of teaching and learning curriculum experiences varied.

Polymodal Nociception in Drosophila Requires Alternative Splicing of TrpA1.

Transcripts of noxious stimulus-detecting TrpA1 channels are alternatively spliced. Despite the importance of nociception for survival, the in vivo significance of expressing different TrpA1 isoforms is largely unknown. Here, we develop a novel genetic approach to generate Drosophila knockin strains expressing single TrpA1 isoforms. Drosophila TrpA1 mediates heat and UVC-triggered nociception. We show that TrpA1-C and TrpA1-D, two alternative isoforms, are co-expressed in nociceptors. When examined in heterologous cells, both TrpA1-C and TrpA1-D are activated by heat and UVC. By contrast, analysis of knockin flies reveals the striking functional specificity; TrpA1-C mediates UVC-nociception, whereas TrpA1-D mediates heat-nociception. Therefore, in vivo functions of TrpA1-C and TrpA1-D are different from each other and are different from their in vitro properties. Our results indicate that a given sensory stimulus preferentially activates a single TrpA1 isoform in vivo and that polymodal nociception requires co-expression of TrpA1 isoforms, providing novel insights of how alternative splicing regulates nociception.

Glutathione S-Transferase Regulates Mitochondrial Populations in Axons through Increased Glutathione Oxidation.

Mitochondria are essential in long axons to provide metabolic support and sustain neuron integrity. A healthy mitochondrial pool is maintained by biogenesis, transport, mitophagy, fission, and fusion, but how these events are regulated in axons is not well defined. Here, we show that the Drosophila glutathione S-transferase (GST) Gfzf prevents mitochondrial hyperfusion in axons. Gfzf loss altered redox balance between glutathione (GSH) and oxidized glutathione (GSSG) and initiated mitochondrial fusion through the coordinated action of Mfn and Opa1. Gfzf functioned epistatically with the thioredoxin peroxidase Jafrac1 and the thioredoxin reductase 1 TrxR-1 to regulate mitochondrial dynamics. Altering GSH:GSSG ratios in mouse primary neurons in vitro also induced hyperfusion. Mitochondrial changes caused deficits in trafficking, the metabolome, and neuronal physiology. Changes in GSH and oxidative state are associated with neurodegenerative diseases like Alzheimer's. Our demonstration that GSTs are key in vivo regulators of axonal mitochondrial length and number provides a potential mechanistic link.

Ixekizumab: A Review of Its Use for the Management of Moderate to Severe Plaque Psoriasis.

OBJECTIVE: To review the efficacy, safety, and place in therapy of ixekizumab for the treatment of moderate to severe plaque psoriasis. DATA SOURCES: PubMed (1966 to July 2018) and clinicaltrials.gov were searched using the terms ixekizumab, LY2439821, interleukin-17, and psoriasis. STUDY SELECTION AND DATA EXTRACTION: Human studies published in peer-reviewed medical journals in English were used. DATA SYNTHESIS: The efficacy and safety of ixekizumab has been primarily reported by 4 phase III trials (UNCOVER-1, UNCOVER-2, UNCOVER-3, and UNCOVER-J) and multiple post hoc analyses. The average proportions of patients achieving a 75%, 90%, and 100% reduction in their Psoriasis Area and Severity Index (PASI) were 89%, 70%, and 38%, respectively, after 12 weeks of therapy. PASI75 was maintained for up to 3 years in 80.5% of participants. Ixekizumab was statistically significantly more effective than ustekinumab, with 76.5%, compared with 59%, of patients achieving PASI90 in 52 weeks. The most common adverse events include nasopharyngitis (14.1%), upper respiratory tract infections (7.9%), and injection-site reactions (6.8%), which are similar to that for other biological agents. The risk of inflammatory bowel disease may be increased with ixekizumab. Relevance to Patient Care and Clinical Practice: This review summarizes and evaluates clinical data regarding the efficacy and safety of ixekizumab and discusses relevant differences compared with other biological agents used for the management of chronic plaque psoriasis. CONCLUSIONS: Ixekizumab is a highly efficacious and well-tolerated treatment option for patients with moderate to severe plaque psoriasis.

Factors associated with mentor satisfaction among teaching and learning curriculum program participants.

OBJECTIVES: To evaluate participants' satisfaction with their teaching mentor relationship in a teaching and learning curriculum (TLC) and determine characteristics that are associated with high mentee satisfaction. METHODS: A 31-item survey instrument was administered to all 2015-2016 participants of the Teaching Certificate Program. RESULTS: Seventy percent of program participants (n = 60/86) responded to the survey. Overall, 80% of program participants were satisfied or very satisfied with their mentor relationship. Characteristics associated with participants reporting that they were very satisfied with their teaching mentor relationship included mentor availability for face-to-face contact and affiliation with the same institution. Mentor actions associated with high mentee satisfaction included reviewing lecture slides, providing midpoint feedback, providing career advice, and attending mentee lectures. CONCLUSIONS: Teaching certificate program participants perceive increased mentor accessibility and frequent interaction as key factors to a satisfying mentor-mentee relationship. Optimizing and standardizing mentorship programs are essential to the success of postgraduate teaching curriculums.

Student perceptions of digital badges in a drug information and literature evaluation course.

BACKGROUND AND PURPOSE: The purpose of this article is to describe student perceptions of implementation of digital badges in a drug information and literature evaluation course. EDUCATIONAL ACTIVITY AND SETTING: Two digital badges were developed as voluntary learning opportunities. Student perceptions were obtained through pre- and post-survey instruments consisting of selected questions from the Motivated Strategies for Learning Questionnaire. FINDINGS: The response rate was 69% (106/153). At baseline, 53% of respondents agreed that digital badges could help them better understand course material. More students agreed they would share earned digital badges on LinkedIn (68%) than Facebook (19%). Most students who earned digital badges agreed that badges helped increase their confidence in course material (73%), focus on specific learning objectives (55%), look deeper into course competencies (64%), and were a useful adjunct to the traditional teaching method (82%). DISCUSSION AND SUMMARY: Digital badges were perceived by students as a positive adjunct to learning and may provide a novel mechanism for development of an electronic skills-based portfolio.

The secreted neurotrophin Spätzle 3 promotes glial morphogenesis and supports neuronal survival and function.

Most glial functions depend on establishing intimate morphological relationships with neurons. Significant progress has been made in understanding neuron-glia signaling at synaptic and axonal contacts, but how glia support neuronal cell bodies is unclear. Here we explored the growth and functions of Drosophila cortex glia (which associate almost exclusively with neuronal cell bodies) to understand glia-soma interactions. We show that cortex glia tile with one another and with astrocytes to establish unique central nervous system (CNS) spatial domains that actively restrict glial growth, and selective ablation of cortex glia causes animal lethality. In an RNAi-based screen, we identified αSNAP (soluble NSF [N-ethylmalemeide-sensitive factor] attachment protein α) and several components of vesicle fusion and recycling machinery as essential for the maintenance of cortex glial morphology and continued contact with neurons. Interestingly, loss of the secreted neurotrophin Spätzle 3 (Spz3) phenocopied αSNAP phenotypes, which included loss of glial ensheathment of neuron cell bodies, increased neuronal cell death, and defects in animal behavior. Rescue experiments suggest that Spz3 can exert these effects only over very short distances. This work identifies essential roles for glial ensheathment of neuronal cell bodies in CNS homeostasis as well as Spz3 as a novel signaling factor required for maintenance of cortex glial morphology and neuron-glia contact.

Axon Death Pathways Converge on Axundead to Promote Functional and Structural Axon Disassembly.

Axon degeneration is a hallmark of neurodegenerative disease and neural injury. Axotomy activates an intrinsic pro-degenerative axon death signaling cascade involving loss of the NAD+ biosynthetic enzyme Nmnat/Nmnat2 in axons, activation of dSarm/Sarm1, and subsequent Sarm-dependent depletion of NAD+. Here we identify Axundead (Axed) as a mediator of axon death. axed mutants suppress axon death in several types of axons for the lifespan of the fly and block the pro-degenerative effects of activated dSarm in vivo. Neurodegeneration induced by loss of the sole fly Nmnat ortholog is also fully blocked by axed, but not dsarm, mutants. Thus, pro-degenerative pathways activated by dSarm signaling or Nmnat elimination ultimately converge on Axed. Remarkably, severed axons morphologically preserved by axon death pathway mutations remain integrated in circuits and able to elicit complex behaviors after stimulation, indicating that blockade of axon death signaling results in long-term functional preservation of axons.