Derivation and transcriptional reprogramming of border-forming wound repair astrocytes after spinal cord injury or stroke in mice.

Central nervous system (CNS) lesions become surrounded by neuroprotective borders of newly proliferated reactive astrocytes; however, fundamental features of these cells are poorly understood. Here we show that following spinal cord injury or stroke, 90% and 10% of border-forming astrocytes derive, respectively, from proliferating local astrocytes and oligodendrocyte progenitor cells in adult mice of both sexes. Temporal transcriptome analysis, single-nucleus RNA sequencing and immunohistochemistry show that after focal CNS injury, local mature astrocytes dedifferentiate, proliferate and become transcriptionally reprogrammed to permanently altered new states, with persisting downregulation of molecules associated with astrocyte-neuron interactions and upregulation of molecules associated with wound healing, microbial defense and interactions with stromal and immune cells. These wound repair astrocytes share morphologic and transcriptional features with perimeningeal limitans astrocytes and are the predominant source of neuroprotective borders that re-establish CNS integrity around lesions by separating neural parenchyma from stromal and immune cells as occurs throughout the healthy CNS.

Trehalose-based coacervates for local bioactive protein delivery to the central nervous system.

Therapeutic outcomes of local biomolecule delivery to the central nervous system (CNS) using bulk biomaterials are limited by inadequate drug loading, neuropil disruption, and severe foreign body responses. Effective CNS delivery requires addressing these issues and developing well-tolerated, highly-loaded carriers that are dispersible within local neural parenchyma. Here, we synthesized biodegradable trehalose-based polyelectrolyte oligomers using facile A2:B3:AR thiol-ene Michael addition reactions that form complex coacervates upon mixing of oppositely charged oligomers. Coacervates permit high concentration loading and controlled release of bioactive growth factors, enzymes, and antibodies, with modular formulation parameters that confer tunable release kinetics. Coacervates are cytocompatible with cultured neural cells in vitro and can be formulated to either direct intracellular protein delivery or sequester media containing proteins and remain extracellular. Coacervates serve as effective vehicles for precisely delivering biomolecules, including bioactive neurotrophins, to the mouse striatum following intraparenchymal injection. These results support the use of trehalose-based coacervates as part of therapeutic protein delivery strategies for CNS disorders.

Alteration of mechanical stresses in the murine brain by age and hemorrhagic stroke.

Residual mechanical stresses, also known as solid stresses, emerge during rapid differential growth or remodeling of tissues, as observed in morphogenesis and tumor growth. While residual stresses typically dissipate in most healthy adult organs, as the growth rate decreases, high residual stresses have been reported in mature, healthy brains. However, the origins and consequences of residual mechanical stresses in the brain across health, aging, and disease remain poorly understood. Here, we utilized and validated a previously developed method to map residual mechanical stresses in the brains of mice across three age groups: 5-7 days, 8-12 weeks, and 22 months. We found that residual solid stress rapidly increases from 5-7 days to 8-12 weeks and remains high in mature 22 months mice brains. Three-dimensional mapping revealed unevenly distributed residual stresses from the anterior to posterior coronal brain sections. Since the brain is rich in negatively charged hyaluronic acid, we evaluated the contribution of charged extracellular matrix (ECM) constituents in maintaining solid stress levels. We found that lower ionic strength leads to elevated solid stresses, consistent with its unshielding effect and the subsequent expansion of charged ECM components. Lastly, we demonstrated that hemorrhagic stroke, accompanied by loss of cellular density, resulted in decreased residual stress in the murine brain. Our findings contribute to a better understanding of spatiotemporal alterations of residual solid stresses in healthy and diseased brains, a crucial step toward uncovering the biological and immunological consequences of this understudied mechanical phenotype in the brain.

Ischemic and hemorrhagic stroke lesion environments differentially alter the glia repair potential of neural progenitor cell and immature astrocyte grafts.

Using cell grafting to direct glia-based repair mechanisms in adult CNS injuries represents a potential therapeutic strategy for supporting functional neural parenchymal repair. However, glia repair directed by neural progenitor cell (NPC) grafts is dramatically altered by increasing lesion size, severity, and mode of injury. To address this, we studied the interplay between astrocyte differentiation and cell proliferation of NPC in vitro to generate proliferating immature astrocytes (ImA) using hysteretic conditioning. ImA maintain proliferation rates at comparable levels to NPC but showed robust immature astrocyte marker expression including Gfap and Vimentin. ImA demonstrated enhanced resistance to myofibroblast-like phenotypic transformations upon exposure to serum enriched environments in vitro compared to NPC and were more effective at scratch wound closure in vitro compared to quiescent astrocytes. Glia repair directed by ImA at acute ischemic striatal stroke lesions was equivalent to NPC but better than quiescent astrocyte grafts. While ischemic injury environments supported enhanced survival of grafts compared to healthy striatum, hemorrhagic lesions were hostile towards both NPC and ImA grafts leading to poor survival and ineffective modulation of natural wound repair processes. Our findings demonstrate that lesion environments, rather than transcriptional pre-graft states, determine the survival, cell-fate, and glia repair competency of cell grafts applied to acute CNS injuries.

Ethnoracial disparities in care on a consultation-liaison service at an academic hospital.

BACKGROUND: There is currently an increasing recognition of and focus on structural and institutional racism and its impacts on health disparities. In psychiatry and mental health, research has focused on racial and ethnic disparities in the availability and utilization of mental health services, care in emergency departments, and inpatient psychiatric services. Little is known about disparities in care on general hospital psychiatry consultation-liaison (CL) services. METHODS: In this exploratory study, we conducted a retrospective chart review using electronic health record (EHR) data of all adults (≥ 18 years of age) admitted to inpatient medical or surgical floors at an urban academic medical center for whom a psychiatric consultation was requested during the study period. We examined differences by race and ethnicity in: rates of consultation requests; use of legal holds, constant observation, restraints; follow-up by the CL service; and ultimate disposition. RESULTS: The service received 310 unique consults during the study period. Compared to hospital-wide numbers, Black-identifying patients were over-represented in our sample (11.9% vs 6.6%), while Latinx patients were underrepresented (6.1% vs 9.8%). Of the clinical and outcome variables collected, there were higher odds of being placed on a legal hold both prior to (OR 2.6) and after the consult question (OR 2.98) and in the odds of having a one-to-one observer prior to (OR 2.47) and after (OR 2.9) the initial consult visit for Black-identifying patients, when adjusting for confounders. There were no other measurable differences in care or outcomes by racial or ethnic categories. CONCLUSION: Black-identifying patients may be more likely to receive psychiatric consultation and be placed on legal holds because of a combination of chronic adverse social determinants of health and race-based bias. Conversely, Latinx patients may be less likely to receive psychiatric consultation because of language barriers among other factors. The lack of disparities identified in other domains may be encouraging, but larger studies are needed. Further research is also needed to identify causality and interventions that could help close the gap in care and outcomes for racial and ethnic minorities.

Proliferation history and transcription factor levels drive direct conversion.

The sparse and stochastic nature of reprogramming has obscured our understanding of how transcription factors drive cells to new identities. To overcome this limit, we developed a compact, portable reprogramming system that increases direct conversion of fibroblasts to motor neurons by two orders of magnitude. We show that subpopulations with different reprogramming potentials are distinguishable by proliferation history. By controlling for proliferation history and titrating each transcription factor, we find that conversion correlates with levels of the pioneer transcription factor Ngn2, whereas conversion shows a biphasic response to Lhx3. Increasing the proliferation rate of adult human fibroblasts generates morphologically mature, induced motor neurons at high rates. Using compact, optimized, polycistronic cassettes, we generate motor neurons that graft with the murine central nervous system, demonstrating the potential for in vivo therapies.

Trehalose-Guanosine Glycopolymer Hydrogels Direct Adaptive Glia Responses in CNS Injury.

Neural tissue damaged after central nervous system (CNS) injury does not naturally regenerate but is instead replaced by non-neural fibrotic scar tissue that serves no neurological function. Scar-free repair to create a more permissive environment for regeneration requires altering the natural injury responses of glial cells. In this work, glycopolymer-based supramolecular hydrogels are synthesized to direct adaptive glia repair after CNS injury. Combining poly(trehalose-co-guanosine) (pTreGuo) glycopolymers with free guanosine (fGuo) generates shear-thinning hydrogels through stabilized formation of long-range G-quadruplex secondary structures. Hydrogels with smooth or granular microstructures and mechanical properties spanning three orders of magnitude are produced through facile control of pTreGuo hydrogel composition. Injection of pTreGuo hydrogels into healthy mouse brains elicits minimal stromal cell infiltration and peripherally derived inflammation that is comparable to a bioinert methyl cellulose benchmarking material. pTreGuo hydrogels alter astrocyte borders and recruit microglia to infiltrate and resorb the hydrogel bulk over 7 d. Injections of pTreGuo hydrogels into ischemic stroke alter the natural responses of glial cells after injury to reduce the size of lesions and increase axon regrowth into lesion core environments. These results support the use of pTreGuo hydrogels as part of neural regeneration strategies to activate endogenous glia repair mechanisms.

Racial and Ethnic Inequities in Inpatient Psychiatric Civil Commitment.

OBJECTIVE: Involuntary psychiatric treatment may parallel ethnoracial inequities present in the larger society. Prior studies have focused on restraint and seclusion, but less attention has been paid to the civil commitment system because of its diversity across jurisdictions. Using a generalizable framework, this study investigated inequities in psychiatric commitment. METHODS: A prospective cohort was assembled of all patients admitted to an inpatient psychiatric unit over 6 years (2012-2018). Patients were followed longitudinally throughout their admission; raters recorded legal status each day. Sociodemographic and clinical data were collected to adjust for confounding variables by using multivariate logistic regression. RESULTS: Of the 4,393 patients with an initial admission during the study period, 73% self-identified as White, 11% as Black, 10% as primarily Hispanic or Latinx, 4% as Asian, and 3% as another race or multiracial. In the sample, 28% were involuntarily admitted, and court commitment petitions were filed for 7%. Compared with White patients, all non-White groups were more likely to be involuntarily admitted, and Black and Asian patients were more likely to have court commitment petitions filed. After adjustment for confounding variables, Black patients remained more likely than White patients to be admitted involuntarily (adjusted odds ratio [aOR]=1.57, 95% confidence interval [CI]=1.26-1.95), as were patients who identified as other race or multiracial (aOR=2.12, 95% CI=1.44-3.11). CONCLUSIONS: Patients of color were significantly more likely than White patients to be subjected to involuntary psychiatric hospitalization, and Black patients and patients who identified as other race or multiracial were particularly vulnerable, even after adjustment for confounding variables.

Divergent transcriptional regulation of astrocyte reactivity across disorders.

Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder1-4. These changes include differentially expressed genes (DEGs) whose contextual diversity and regulation are poorly understood. Here we combined biological and informatic analyses, including RNA sequencing, protein detection, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and conditional gene deletion, to predict transcriptional regulators that differentially control more than 12,000 DEGs that are potentially associated with astrocyte reactivity across diverse central nervous system disorders in mice and humans. DEGs associated with astrocyte reactivity exhibited pronounced heterogeneity across disorders. Transcriptional regulators also exhibited disorder-specific differences, but a core group of 61 transcriptional regulators was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific interactions between transcriptional regulators. Notably, the same reactivity transcriptional regulators can regulate markedly different DEG cohorts in different disorders; changes in the access of transcriptional regulators to DNA-binding motifs differ markedly across disorders; and DEG changes can crucially require multiple reactivity transcriptional regulators. We show that, by modulating reactivity, transcriptional regulators can substantially alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted transcriptional regulators. Our findings show that transcriptional changes associated with astrocyte reactivity are highly heterogeneous and are customized from vast numbers of potential DEGs through context-specific combinatorial transcriptional-regulator interactions.

The impact of an integrated safer use space and safer supply program on non-fatal overdose among emergency shelter residents during a COVID-19 outbreak: a case study.

BACKGROUND: Opioid-related harms, including fatal and non-fatal overdoses, rose dramatically during the COVID-19 pandemic and presented unique challenges during outbreaks in congregate settings such as shelters. People who are deprived of permanent housing have a high prevalence of substance use and substance use disorders, and need nimble, rapid, and portable harm reduction interventions to address the harms of criminalized substance use in an evidence-based manner. CASE STUDY: In February 2021, a COVID-19 outbreak was declared at an emergency men's shelter in Hamilton, Ontario, Canada. Building on pre-existing relationships, community and hospital-based addictions medicine providers and a local harm reduction group collaborated to establish a shelter-based opioid agonist treatment and safer supply program, and a volunteer run safer drug use space that also distributed harm reduction supplies. In the 4 weeks preceding the program, the rate of non-fatal overdoses was 0.93 per 100 nights of shelter bed occupancy. During the 26 days of program operation, there were no overdoses in the safer use space and the rate of non-fatal overdoses in the shelter was 0.17 per 100 nights of shelter bed occupancy. The odds ratio of non-fatal overdose pre-intervention to during intervention was 5.5 (95% CI 1.63-18.55, p = 0.0059). We were not able to evaluate the impact of providing harm reduction supplies and did not evaluate the impact of the program on facilitating adherence to public health isolation and quarantine orders. The program ended as the outbreak waned, as per the direction from the shelter operator. CONCLUSIONS: There was a significant reduction in the non-fatal overdose rate after the safer drug use and safer supply harm reduction program was introduced. Pre-existing relationships between shelter providers, harm reduction groups, and healthcare providers were critical to implementing the program. This is a promising approach to reducing harms from the criminalization of substance use in congregate settings, particularly in populations with a higher prevalence of substance use and substance use disorders.

Comparison of Prophylactic Intravenous Antibiotic Regimens After Endoprosthetic Reconstruction for Lower Extremity Bone Tumors: A Randomized Clinical Trial.

IMPORTANCE: The use of perioperative, prophylactic, intravenous antibiotics is standard practice to reduce the risk of surgical site infection after oncologic resection and complex endoprosthetic reconstruction for lower extremity bone tumors. However, evidence guiding the duration of prophylactic treatment remains limited. OBJECTIVE: To assess the effect of a 5-day regimen of postoperative, prophylactic, intravenous antibiotics compared with a 1-day regimen on the rate of surgical site infections within 1 year after surgery. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical superiority trial was performed at 48 clinical sites in 12 countries from January 1, 2013, to October 29, 2019. The trial included patients with a primary bone tumor or a soft tissue sarcoma that had invaded the femur or tibia or oligometastatic bone disease of the femur or tibia with expected survival of at least 1 year who required surgical management by excision and endoprosthetic reconstruction. A total of 611 patients were enrolled, and 7 were excluded for ineligibility. INTERVENTIONS: A 1- or 5-day regimen of postoperative prophylactic intravenous cephalosporin (cefazolin or cefuroxime) that began within 8 hours after skin closure and was administered every 8 hours thereafter. Those randomized to the 1-day regimen received identical saline doses every 8 hours for the remaining 4 days; patients, care providers, and outcomes assessors were blinded to treatment regimen. MAIN OUTCOMES AND MEASURES: The primary outcome in this superiority trial was a surgical site infection (superficial incisional, deep incisional, or organ space) classified according to the criteria established by the Centers for Disease Control and Prevention within 1 year after surgery. Secondary outcomes included antibiotic-related complications, unplanned additional operations, oncologic and functional outcomes, and mortality. RESULTS: Of the 604 patients included in the final analysis (mean [SD] age, 41.2 [21.9] years; 361 [59.8%] male; 114 [18.9%] Asian, 43 [7.1%] Black, 34 [5.6%] Hispanic, 15 [2.5%] Indigenous, 384 [63.8%] White, and 12 [2.0%] other), 293 were randomized to a 5-day regimen and 311 to a 1-day regimen. A surgical site infection occurred in 44 patients (15.0%) allocated to the 5-day regimen and in 52 patients (16.7%) allocated to the 1-day regimen (hazard ratio, 0.93; 95% CI, 0.62-1.40; P = .73). Antibiotic-related complications occurred in 15 patients (5.1%) in the 5-day regimen and in 5 patients (1.6%) allocated to the 1-day regimen (hazard ratio, 3.24; 95% CI, 1.17-8.98; P = .02). Other secondary outcomes did not differ significantly between treatment groups. CONCLUSIONS AND RELEVANCE: This randomized clinical trial did not confirm the superiority of a 5-day regimen of postoperative intravenous antibiotics over a 1-day regimen in preventing surgical site infections after surgery for lower extremity bone tumors that required an endoprosthesis. The 5-day regimen group had significantly more antibiotic-related complications. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01479283.

Pandemic Planning in Homeless Shelters: A Pilot Study of a Coronavirus Disease 2019 (COVID-19) Testing and Support Program to Mitigate the Risk of COVID-19 Outbreaks in Congregate Settings.

We tested 104 residents and 141 staff for coronavirus disease 2019 who failed daily symptom screening in homeless shelters in Hamilton, Canada. We detected 1 resident (1%), 7 staff (5%), and 1 case of secondary spread. Shelter restructuring to allow physical distancing, testing, and isolation can decrease outbreaks in shelters.

Foreign body responses in mouse central nervous system mimic natural wound responses and alter biomaterial functions.

Biomaterials hold promise for therapeutic applications in the central nervous system (CNS). Little is known about molecular factors that determine CNS foreign body responses (FBRs) in vivo, or about how such responses influence biomaterial function. Here, we probed these factors in mice using a platform of injectable hydrogels readily modified to present interfaces with different physiochemical properties to host cells. We found that biomaterial FBRs mimic specialized multicellular CNS wound responses not present in peripheral tissues, which serve to isolate damaged neural tissue and restore barrier functions. We show that the nature and intensity of CNS FBRs are determined by definable properties that significantly influence hydrogel functions, including resorption and molecular delivery when injected into healthy brain or stroke injuries. Cationic interfaces elicit stromal cell infiltration, peripherally derived inflammation, neural damage and amyloid production. Nonionic and anionic formulations show minimal levels of these responses, which contributes to superior bioactive molecular delivery. Our results identify specific molecular mechanisms that drive FBRs in the CNS and have important implications for developing effective biomaterials for CNS applications.

Comparison of four COVID-19 screening strategies to facilitate early case identification within the homeless shelter population: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: 1. To compare the effectiveness of four different surveillance strategies in detecting COVID-19 within the homeless shelter population. 2. To assess the participant adherence over time for each surveillance method. TRIAL DESIGN: This is a prospective cluster-randomized study to compare the effectiveness of four different surveillance regimens across eight homeless shelters in the city of Hamilton. PARTICIPANTS: Participants will include both residents of, and the staff working within, the homeless shelters. All participants aged 18 or older who consent to the study and are able to collect a swab sample (where relevant) are eligible for the study. The study will take place across eight homeless shelters (four men-only and four women-only) in the City of Hamilton in Ontario, Canada. INTERVENTION AND COMPARATOR GROUPS: The comparator group will receive active daily surveillance of symptoms and testing will only be completed in symptomatic participants (i.e. those who fail screening or who seek care for potential COVID-19 related symptoms). The three intervention arms will all receive active daily surveillance of symptoms and testing of symptomatic participants (as in the comparator group) in addition to one of the following: 1. Once weekly self-collected oral swabs (OS) regardless of symptoms using written and visual instructions. 2. Once weekly self-collected oral-nares swab (O-NS) regardless of symptoms using written and visual instructions. 3. Once weekly nurse collected nasopharyngeal swab (NPS) regardless of symptoms. Participants will follow verbal and written instructions for the collection of OS and O-NS specimens. For OS collection, participants are instructed to first moisten the swab on their tongue, insert the swab between the cheek and the lower gums and rotate the swab three times. This is repeated on the other side. For O-NS collection, after oral collection, the swab is inserted comfortably (about 2-3 cm) into one nostril, parallel to the floor and turned three times, then repeated in the other nostril. NPS specimens were collected by the nurse following standard of care procedure. All swabs were placed into a viral inactivation medium and transported to the laboratory for COVID-19 testing. Briefly, total nucleic acid was extracted from specimens and then amplified by RT-PCR for the UTR and Envelope genes of SARS-CoV-2 and the human RNase P gene, which is used as a sample adequacy marker. MAIN OUTCOMES: 1. PRIMARY OUTCOME: COVID-19 detection rate, i.e. the number of new positive cases over the study period of 8 weeks in each arm of the study. 2. SECONDARY OUTCOMES: Qualitative assessment of study enrollment over 8 weeks. Percentage of participants who performed 50% or more of the weekly swabs in the intervention arms in the 8 week study period. RANDOMIZATION: We will use a computer-generated random assignment list to randomize the shelters to one of four interventions. Shelters were stratified by gender, and the simple randomization scheme was applied within each stratum. The randomization scheme was created using WinPEPI. BLINDING: This is an open-label study in which neither participants nor assessors are blinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Since we are including our total sample frame, a sample size estimation at the cluster level is not required. However, if we succeed to enroll 50 participants per shelter from 8 shelters (n=400), and the detection rate is 3 times higher in the intervention groups (0.15) than in the comparator groups (0.05), we will have 90% power to detect a statistically significant and clinically important difference at a type I error rate of alpha=0.05 (one tailed), assuming an intraclass correlation of ~0.008. These computations were done using WinPEPI, and informed by conservative estimates from other studies on respiratory illness in the homeless (see Full protocol). TRIAL STATUS: The protocol version number is 3.0. Recruitment began on April 17, 2020 and is ongoing. Due to low numbers of COVID cases in the community and shelter system during the initial study period, the trial was extended. The estimated date for the end of the extended recruitment period is Feb 1, 2021. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov on June 18, 2020 with the identifier NCT04438070 . FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Injectable diblock copolypeptide hydrogel provides platform to deliver effective concentrations of paclitaxel to an intracranial xenograft model of glioblastoma.

INTRODUCTION: Surgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy. METHODS: The development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells. RESULTS: The DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment. CONCLUSIONS: These findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.

Making the Cut: Perspectives on the Surgical Management of Infective Endocarditis Among People Who Use Intravenous Drugs.

In this article we review the perspectives in the literature around surgical treatment for infective endocarditis (IE) in people who use intravenous drugs (PUID). PUID are at increased risk for IE; however, controversy exists regarding how to best manage these patients. We explore the outcomes for surgical treatment in PUID with IE, contrasting these with patients with IE who do not use drugs. We describe some of the perspectives in the literature around second valve replacement for PUID with IE, arguing that moralistic arguments are not on the basis of evidence and perpetuate the stigma experienced by PUID who seek treatment for IE. Finally, we explore the role of substance use interventions in the treatment of PUID with IE, and advocate for further evidence. PUID with IE are a highly stigmatized patient subgroup for whom best practice management strategies are not always implemented, emphasizing the need for further research and advocacy.

Affordance Compatibility Effect for Word Learning in Virtual Reality.

Rich sensorimotor interaction facilitates language learning and is presumed to ground conceptual representations. Yet empirical support for early stages of embodied word learning is currently lacking. Finding evidence that sensorimotor interaction shapes learned linguistic representations would provide crucial support for embodied language theories. We developed a gamified word learning experiment in virtual reality in which participants learned the names of six novel objects by grasping and manipulating objects with either their left or right hand. Participants then completed a word-color match task in which they were tested on the same six words and objects. Participants were faster to respond to stimuli in the match task when the response hand was compatible with the hand used to interact with the named object, an effect we refer to as affordance compatibility. In two follow up experiments, we found that merely observing virtual hands interact with the objects was sufficient to acquire a smaller affordance compatibility effect, and we found that the compatibility effect was driven primarily by responses with a compatible hand and not by responses in a compatible spatial location. Our results support theoretical views of language which ground word representations in sensorimotor experiences, and they suggest promising future routes to explore the sensorimotor foundations of higher cognition through immersive virtual experiments.

Required growth facilitators propel axon regeneration across complete spinal cord injury.

Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after injury1-3, but efficient reversal of this regrowth failure remains elusive4. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults-(i) neuron intrinsic growth capacity2,5-9, (ii) growth-supportive substrate10,11 and (iii) chemoattraction12,13-are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI14,15; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor16,17 delivered via spatially and temporally controlled release from biomaterial depots18,19, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.