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At one time considered a possible form of neuromyelitis optica (NMO) spectrum disorder (NMOSD), it is now accepted that myelin oligodendrocyte glycoprotein (MOG) antibody (Ab)-associated disorder (MOGAD) is a distinct entity from either NMO or multiple sclerosis (MS) and represents a broad spectrum of clinical phenotypes. Whereas Abs targeting aquaporin-4 (AQP4) in NMO are pathogenic, the extent that anti-MOG Abs contribute to CNS damage in MOGAD is unclear. Both AQP4-specific Abs in NMO and MOG-specific Abs in MOGAD are predominantly IgG1, a T cell-dependent immunoglobulin (Ig) subclass. Key insights in neuroimmunology and MOGAD pathogenesis have been learned from MOG experimental autoimmune encephalomyelitis (EAE), described 2 decades before the term MOGAD was introduced. MOG-specific T cells are required in MOG EAE, and while anti-MOG Abs can exacerbate EAE and CNS demyelination, those Abs are neither necessary nor sufficient to cause EAE. Knowledge regarding the spectrum of MOGAD clinical and radiologic presentations is advancing rapidly, yet our grasp of MOGAD pathogenesis is incomplete. Understanding both the humoral and cellular immunology of MOGAD has implications for diagnosis, treatment, and prognosis.

BACKGROUND: Surgeons have come under increased scrutiny for postoperative pain management, particularly for opioid prescribing. To decrease opioid use but still provide pain control, nonopioid medications such as muscle relaxants are being used, which can be harmful in older adults. However, the prevalence of muscle relaxant prescribing, trends in use over time, and risk of prolonged use are unknown. STUDY DESIGN: Using a 20% representative Medicare sample, we conducted a retrospective analysis of muscle relaxant prescribing to patients ≥ 65 years of age. We merged patient data from Medicare Carrier, MedPAR, and Outpatient Files with Medicare Part D for the years 2013-2018. A total of 14 surgical procedures were included to represent a wide range of anatomic regions and specialties. RESULTS: The study cohort included 543,929 patients. Of the cohort, 8111 (1.5%) received a new muscle relaxant prescription at discharge. Spine procedures accounted for 12% of all procedures but 56% of postoperative prescribing. Overall, the rate of prescribing increased over the time period (1.4-2.0%, p < 0.001), with increases in prescribing primarily in the spine (7-9.6%, p < 0.0001) and orthopedic procedure groups (0.9-1.4%, p < 0.0001). Of patients discharged with a new muscle relaxant prescription, 10.7% had prolonged use. CONCLUSIONS: The use of muscle relaxants in the postoperative period for older adults is low, but increasing over time, especially in ortho and spine procedures. While pain control after surgery is crucial, surgeons should carefully consider the risks of muscle relaxant use, especially for older adults who are at higher risk for medication-related problems.

BACKGROUND: Management of elevated blood pressure (BP) during hospitalization varies widely, with many hospitalized adults experiencing BPs higher than those recommended for the outpatient setting. PURPOSE: To systematically identify guidelines on elevated BP management in the hospital. DATA SOURCES: MEDLINE, Guidelines International Network, and specialty society websites from 1 January 2010 to 29 January 2024. STUDY SELECTION: Clinical practice guidelines pertaining to BP management for the adult and older adult populations in ambulatory, emergency department, and inpatient settings. DATA EXTRACTION: Two authors independently screened articles, assessed quality, and extracted data. Disagreements were resolved via consensus. Recommendations on treatment targets, preferred antihypertensive classes, and follow-up were collected for ambulatory and inpatient settings. DATA SYNTHESIS: Fourteen clinical practice guidelines met inclusion criteria (11 were assessed as high-quality per the AGREE II [Appraisal of Guidelines for Research & Evaluation II] instrument), 11 provided broad BP management recommendations, and 1 each was specific to the emergency department setting, older adults, and hypertensive crises. No guidelines provided goals for inpatient BP or recommendations for managing asymptomatic moderately elevated BP in the hospital. Six guidelines defined hypertensive urgency as BP above 180/120 mm Hg, with hypertensive emergencies requiring the addition of target organ damage. Hypertensive emergency recommendations consistently included use of intravenous antihypertensives in intensive care settings. Recommendations for managing hypertensive urgencies were inconsistent, from expert consensus, and focused on the emergency department. Outpatient treatment with oral medications and follow-up in days to weeks were most often advised. In contrast, outpatient BP goals were clearly defined, varying between 130/80 and 140/90 mm Hg. LIMITATION: Exclusion of non-English-language guidelines and guidelines specific to subpopulations. CONCLUSION: Despite general consensus on outpatient BP management, guidance on inpatient management of elevated BP without symptoms is lacking, which may contribute to variable practice patterns. PRIMARY FUNDING SOURCE: National Institute on Aging. (PROSPERO: CRD42023449250).

BackgroundPrescribing cascades are important contributors to polypharmacy. Little is known about which older adults are at highest risk of experiencing prescribing cascades. We explored which older veterans are at highest risk of the gabapentinoid (including gabapentin and pregabalin)-loop diuretic (LD) cascade, given the dramatic increase in gabapentinoid prescribing in recent years.MethodsUsing Veterans Affairs and Medicare claims data (2010-2019), we performed a prescription sequence symmetry analysis (PSSA) to assess loop diuretic initiation before and after gabapentinoid initiation among older veterans (≥66 years). To identify the cascade, we calculated the adjusted sequence ratio (aSR), which assesses the temporality of LD relative to gabapentinoid initiation. To explore high-risk groups, we used multivariable logistic regression with prescribing order modeled as a binary dependent variable. We calculated adjusted odds ratios (aORs), measuring the extent to which factors are associated with one prescribing order versus another.ResultsOf 151,442 veterans who initiated a gabapentinoid, there were 1,981 patients who initiated a LD within 6 months after initiating a gabapentinoid compared to 1,599 patients who initiated a LD within 6 months before initiating a gabapentinoid. In the gabapentinoid-LD group, the mean age was 73 years, 98% were male, 13% were Black, 5% were Hispanic, and 80% were White. Patients in each group were similar across patient and health utilization factors (standardized mean difference

COVID-19 disproportionally impacted the health and well-being of older adults--many of whom live with chronic conditions--due to their higher risk of dying and being hospitalized. It also created several secondary pandemics, including increased falls risk, sedentary behavior, social isolation, and physical inactivity due to limitations in mobility from lock-down policies. With falls as the leading cause of preventable death and hospitalizations, it became vital for in-person evidence-based falls prevention programs (EBFPPs) to pivot to remote delivery. In Spring 2020, many EBFPP administrators began re-designing programs for remote delivery to accommodate physical distancing guidelines necessitated by the pandemic. Transition to remote delivery was essential for older adults and persons with disabilities to access EBFPPs for staying healthy, falls and injury free, out of hospitals, and also keeping them socially engaged. We collaborated with the Administration on Community Living (ACL), the National Council on Aging (NCOA), and the National Falls Prevention Resource Center (NFPRC), for an in-depth implementation evaluation of remotely delivered EBFPPs. We examined the process of adapting and implementing four EBFPPs for remote delivery, best practices for implementing the programs remotely within the RE-AIM evaluation framework. This enhances NFPRC's ongoing work supporting dissemination, implementation, and sustainability of EBFPPs. We purposively sampled organizations for maximum variation in organization and provider type, geographic location, and reach of underserved older populations (Black, Indigenous, or other People of Color (BIPOC), rural, disabilities). This qualitative evaluation includes provider-level data from semi-structured interviews (N = 22) with program administrators, staff, and leaders. The interview guide included what, why, and how adaptations were made to EBFPP interventions and implementation strategies using Wiltsey-Stirman (2019) adaptations framework (FRAME), reach, and implementation outcomes (acceptability, feasibility, fidelity, and costs; Proctor et al., 2011), focusing on equity to learn for whom these programs were working and opportunities to address inequities. Findings demonstrate remote EBFPPs made planned and fidelity-consistent adaptations to remote delivery in partnership with researchers and community organizations, focusing on participant safety both in program content and delivery. Supports using and accessing technology were needed for delivery sites and leaders to facilitate engagement, and improved over time. While remote EBFPP delivery has increased access to EBFPPs for some populations from the perspective of program administrator, leaders, and staff (e.g., caregivers, rural-dwellers, persons with physical disabilities), the digital divide remains a barrier in access to and comfort using technology. Remote-delivered EBFPPs were acceptable and feasible to delivery organizations and leaders, were able to be delivered with fidelity using adaptations from program developers, but were more resource intensive and costly to implement compared to in-person. This work has important implications beyond the pandemic. Remote delivery has expanded access to groups traditionally underserved by in-person programming, particularly disability communities. This work will help answer important questions about reach, accessibility, feasibility, and cost of program delivery for older adults and people with disabilities at risk for falls, those living with chronic conditions, and communities most vulnerable to disparities in access to health care, health promotion programming, and health outcomes. It will also provide critical information to funders about elements required to adapt EBFPPs proven effective in in-person settings for remote delivery with fidelity to achieve comparable outcomes.

Human milk, due to its unique composition, is the optimal standard for infant nutrition. Osteopontin (OPN) is abundant in human milk but not bovine milk. The addition of bovine milk osteopontin (bmOPN) to formula may replicate OPNs concentration and function in human milk. To address safety concerns, we convened an expert panel to assess the adequacy of safety data and physiological roles of dietary bmOPN in infancy. The exposure of breastfed infants to human milk OPN (hmOPN) has been well-characterized and decreases markedly over the first 6 months of lactation. Dietary bmOPN is resistant to gastric and intestinal digestion, absorbed and cleared from circulation within 8-24 h, and represents a small portion (

Abstract High-amplitude quasi-stationary atmospheric Rossby waves with zonal wave numbers 6–8 associated with the phenomenon of quasi-resonant amplification (QRA) have been linked to persistent summer extreme weather events in the Northern Hemisphere. QRA is not well-resolved in current generation climate models, therefore, necessitating an alternative approach to assessing their behavior. Using a previously-developed fingerprint-based semi-empirical approach, we project future occurrence of QRA events based on a QRA index derived from the zonally averaged surface temperature field, comparing results from CMIP 5 and 6 (Coupled Model Intercomparison Project). There is a general agreement among models, with most simulations projecting substantial increase in QRA index. Larger increases are found among CMIP6-SSP5-8.5 (42 models, 46 realizations), with 85% of models displaying a positive trend, as compared with 60% of CMIP5-RCP8.5 (33 models, 75 realizations), with a reduced spread among CMIP6-SSP5-8.5 models. CMIP6-SSP3-7.0 (23 models, 26 realizations) simulations display qualitatively similar behavior to CMIP6-SSP5-8.5, indicating a substantial increase in QRA events under business-as-usual emissions scenarios, and the results hold regardless of the increase in climate sensitivity in CMIP6. Projected aerosol reductions in CMIP6-SSP3-7.0-lowNTCF (5 models, 16 realizations) lead to halting effect in QRA index and Arctic Amplification during the 1st half of the twenty-first century. Our analysis suggests that anthropogenic warming will likely lead to an even more substantial increase in QRA events (and associated summer weather extremes) than indicated by past analyses.

This paper is an exploration of the pedagogic challenges experienced in teaching emerging Jewish educational leaders about how to lead with a diversity mindset and create inclusive spaces for teaching and learning. Employing elements of self-study and phenomenology, we identify felt difficulties, examining how those were evident in our planning and teaching of the course and in student work. From those challenges we name lessons to be learned and questions for further study about the professional development of Jewish educational leaders who are responsible for creating cultures of belonging in their institutions.

Reproductive hormone profiles were described against physical characteristics during growth and development in male and female botos (Amazon River dolphins Inia geoffrensis) and during pregnancy. We determined hormone concentrations in 226 wild botos located in Mamirauá Reserve, Amazonas State, Brazil, as a part of the long-term population monitoring program known as Projeto Boto. Additionally, we applied receiver operator characteristic (ROC) analysis to compare diagnostic probabilities of using ultrasound, hormones, or combinations of these to detect pregnancy. Based on single-point analysis of serum testosterone (T), males with 5 ng ml-1 T and 227 cm as adult botos. For females, only progesterone (P4), T, relaxin (Rlx), and the combination of P4 × T2 were significantly different between non-pregnant and pregnant females, but androstenedione (A4) and the P4:T ratio were not. ROC analysis indicated that ultrasound and P4 × T2 were considered excellent as pregnancy diagnostic tests, and P4, T, and Rlx were classified as good predictors. Results indicated that negative and positive predictive probabilities from each diagnostic test could be used to accurately predict a pregnancy and calf loss rate of 13% for this population. Application of these methods for evaluating wild population reproductive success from a single serum sample can now be used for health evaluations of wild populations of boto and provide timely information for the development or evaluation of any conservation initiatives.

Abstract Background Non-pharmacological interventions have proven effective at alleviating depression and anxiety symptoms in older adults. Methodological refinement and testing of these interventions in new contexts are needed on a small scale before their effectiveness and implementation can be evaluated. The purpose of this pilot study is to assess the feasibility of a future large-scale trial comparing an adapted mental health multi-component evidence-based intervention (VIDACTIVA) versus standard care for older adults experiencing depression symptoms in urban, resource-limited settings in Lima, Peru. Furthermore, this study will explore the acceptability, feasibility, and fidelity of implementing the intervention. Methods We will conduct an open-label, mixed methods pilot feasibility study with two parallel groups. A total of 64 older adults, stratified by sex, will be randomized at a 1:1 ratio to either the “intervention” or “control.” Participants will be followed for 22 weeks after enrollment. Those in the intervention group will receive eight VIDACTIVA sessions administered by community health workers (CHWs) over 14 weeks, with an additional eight weeks of follow-up. Participants in the control group will receive two psychoeducation sessions from a study fieldworker and will be directed to health care centers. Standard care does not involve CHWs. We will evaluate screening rates, recruitment strategies, retention rates, the acceptability of randomization, and assessments. Additionally, we will assess preliminary implementation outcomes—acceptability, feasibility, and fidelity—from the perspectives of CHWs (interventionists), older adults (main participants), older adults’ relatives, and healthcare professionals. Discussion If the findings from this feasibility trial are favorable, a fully powered randomized controlled trial will be conducted to evaluate `both the effectiveness and implementation of the intervention. This research will make a substantial contribution to the field of mental health in older adults, particularly by emphasizing a meticulous examination and documentation of the implementation process. By doing so, this study will offer valuable methodologies and metrics for adapting and assessing mental health interventions tailored to the unique needs of older adults in resource-constrained contexts and diverse cultural settings. Trial registration The current trial registration number is NCT06065020, which was registered on 26th September 2023.

Abstract Drusen, the yellow deposits under the retina, are composed of lipids and proteins, and represent a hallmark of age-related macular degeneration (AMD). Lipid droplets are also reported in the retinal pigment epithelium (RPE) from AMD donor eyes. However, the mechanisms underlying these disease phenotypes remain elusive. Previously, we showed that Pgc-1α repression, combined with a high-fat diet (HFD), induce drastic AMD-like phenotypes in mice. We also reported increased PGC-1α acetylation and subsequent deactivation in the RPE derived from AMD donor eyes. Here, through a series of in vivo and in vitro experiments, we sought to investigate the molecular mechanisms by which PGC-1α repression could influence RPE and retinal function. We show that PGC-1α plays an important role in RPE and retinal lipid metabolism and function. In mice, repression of Pgc-1α alone induced RPE and retinal degeneration and drusen-like deposits. In vitro inhibition of PGC1A by CRISPR-Cas9 gene editing in human RPE (ARPE19- PGC1A KO) affected the expression of genes responsible for lipid metabolism, fatty acid β-oxidation (FAO), fatty acid transport, low-density lipoprotein (LDL) uptake, cholesterol esterification, cholesterol biosynthesis, and cholesterol efflux. Moreover, inhibition of PGC1A in RPE cells caused lipid droplet accumulation and lipid peroxidation. ARPE19-PGC1A KO cells also showed reduced mitochondrial biosynthesis, impaired mitochondrial dynamics and activity, reduced antioxidant enzymes, decreased mitochondrial membrane potential, loss of cardiolipin, and increased susceptibility to oxidative stress. Our data demonstrate the crucial role of PGC-1α in regulating lipid metabolism. They provide new insights into the mechanisms involved in lipid and drusen accumulation in the RPE and retina during aging and AMD, which may pave the way for developing novel therapeutic strategies targeting PGC-1α.

BackgroundUblituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity. The phase 3 ULTIMATE I and II studies showed significant improvements in annualized relapse rate, total number of gadolinium-enhancing (Gd+) T1 lesions, and total number of new or enlarging T2 at Week 96, as well as improvement in the proportion of participants with no evidence of disease activity (NEDA) from Weeks 24–96 with ublituximab vs. teriflunomide.MethodsIn ULTIMATE I (NCT03277261; www.clinicaltrials.gov) (N = 549) and II (NCT03277248; www.clinicaltrials.gov) (N = 545), participants with relapsing multiple sclerosis received ublituximab 450 mg intravenous infusion every 24 weeks (following Day 1 infusion of 150 mg and Day 15 infusion of 450 mg) or teriflunomide 14 mg oral once daily for 96 weeks. Pooled post hoc analyses evaluated NEDA by treatment epoch and participant subtype: age ( ≤ 38 or >38 years), early or later disease (3.5 at baseline. NEDA was defined as no confirmed relapses, no Gd+ T1 lesions, no new or enlarging T2 lesions, and no disability progression confirmed for ≥12 weeks.ResultsNEDA rates in the ublituximab vs. teriflunomide cohorts by treatment epoch were: Weeks 0–96, 44.6% vs. 12.4% (3.6 × improvement); Weeks 24–96 (re-baselined), 82.1% vs. 22.5% (3.6 × improvement); and Weeks 48–96 (re-baselined), 88.2% vs. 30.4% (2.9 × improvement) (all p < 0.0001). The primary driver of disease activity in ublituximab-treated participants was new or enlarging T2 lesions during Weeks 0–24. 41.8% of ublituximab-treated participants who had evidence of disease activity in the first year (Weeks 0–48) experienced NEDA in the second year of treatment (Weeks 48–96) compared with 17.3% of teriflunomide-treated participants. At Weeks 24–96 (re-baselined), rates of NEDA were significantly higher with ublituximab than teriflunomide in all participant subtypes (all p < 0.0001).ConclusionsULTIMATE I and II pooled post hoc analyses demonstrated a consistent NEDA benefit among ublituximab-treated participants across treatment epochs and key participant subpopulations.

Abstract Oxidative stress from excess H2O2 activates transcription factors that restore redox balance and repair oxidative damage. Although many transcription factors are activated by H2O2, it is unclear whether they are activated at the same H2O2 concentration, or time. Dose-dependent activation is likely as oxidative stress is not a singular state and exhibits dose-dependent outcomes including cell-cycle arrest and cell death. Here, we show that transcription factor activation is both dose-dependent and coordinated over time. Low levels of H2O2 activate p53, NRF2 and JUN. Yet under high H2O2, these transcription factors are repressed, and FOXO1, NF-κB, and NFAT1 are activated. Time-lapse imaging revealed that the order in which these two groups of transcription factors are activated depends on whether H2O2 is administered acutely by bolus addition, or continuously through the glucose oxidase enzyme. Finally, we provide evidence that 2-Cys peroxiredoxins control which group of transcription factors are activated.

Abstract Background Equine piroplasmosis is caused by two tick-borne protozoan parasites, Theileria equi and Babesia caballi,, which are clinically relevant in susceptible horses, donkeys, and mules. Moreover, equine piroplasmosis significantly constrains international trading and equestrian events. Rapidly diagnosing both parasites in carrier animals is essential for implementing effective control measures. Here, a rapid immunochromatographic test for the simultaneous detection of antibodies to T. equi and B. caballi was evaluated using samples from horses and donkeys collected in Greece, Israel, and Italy. The results were compared with an improved competitive enzyme-linked immunosorbent assay (cELISA) for detecting antibodies to both parasites using the same panel of samples. Methods Blood samples were collected from 255 horses and donkeys. The panel consisted of 129 horses sampled at four locations in northern Greece, 105 donkeys sampled at four locations in Sicily, and 21 horses sampled at two locations in Israel. The rapid test and the cELISA were performed according to the manufacturer’s instructions, and the results were subjected to a statistical analysis to determine the sensitivity and specificity of both tests and their association. Results The immunochromatographic test provided a result within 15 min and can be performed in the field, detecting both pathogens simultaneously. The overall coincidence rate between the rapid test and the cELISA for detecting antibodies against T. equi was 93% and 92.9% for B. caballi. The rapid test’s sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for T. equi were above 91.5%. Sixteen samples were positive for both parasites in the rapid test and eight in the cELISA. Either test had no significant association between T. equi and B. caballi detection. The detection rates of both parasites were significantly higher in Italy than in Greece or Israel and in donkeys than in horses. The agreement for T. equi between the results of both tests was high in Greece (93.8%) and Italy (95.2%) and moderate in Israel (76.2%). For B. caballi, the specificity and NPV of the rapid test were high (94.2% and 98.3%, respectively), although the sensitivity and PPV were moderate (69.2% and 39.1%, respectively) due to the small sample size. However, for B. caballi, the sensitivity was higher with the rapid test. Conclusions The rapid test detected T. equi and B. caballi simultaneously in the field, potentially replacing laborious cELISA testing and is recommended for import/export purposes. The test can also be helpful for the differential diagnosis of clinical cases, since seropositivity may rule out equine piroplasmosis since it does not indicate current or active infection. Graphical Abstract

BackgroundEvidence-based programs (EBPs) for health promotion were developed to reach older adults where they live, work, pray, and play. When the COVID-19 pandemic placed a disproportionate burden on older adults living with chronic conditions and the community-based organizations that support them, these in-person programs shifted to remote delivery. While EBPs have demonstrated effectiveness when delivered in person, less is known about outcomes when delivered remotely. ObjectiveThis study evaluated changes in remote EBP participants’ health and well-being in a national mixed methods outcome evaluation in January 1, 2021, to March 31, 2022. MethodsWe used the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) for equity framework to guide the evaluation. We purposively sampled for diverse remote EBP delivery modes and delivery organizations, staff, and traditionally underserved older adults, including people of color and rural dwellers. We included 5 EBPs for self-management, falls prevention, and physical activity: videoconferencing (Chronic Disease Self-Management Program, Diabetes Self-Management Program, and EnhanceFitness), telephone plus mailed materials (Chronic Pain Self-Management Program), and enhanced self-directed mailed materials (Walk With Ease). Participant and provider data included validated surveys, in-depth interviews, and open-ended survey questions. We used descriptive statistics to characterize the sample and the magnitude of change and paired t tests (2-tailed) and the Fisher exact test to test for change in outcomes between enrollment and 6-month follow-up. Thematic analysis was used to identify similarities and differences in outcomes within and across programs. Joint display tables facilitated the integration of quantitative and qualitative findings. ResultsA total of 586 older adults, 198 providers, and 37 organizations providing EBPs participated in the evaluation. Of the 586 older adults, 289 (49.3%) provided follow-up outcome data. The mean age of the EBP participants was 65.4 (SD 12.0) years. Of the 289 EBP participants, 241 (83.4%) were female, 108 (37.3%) were people of color, 113 (39.1%) lived alone, and 99 (34.3%) were experiencing financial hardship. In addition, the participants reported a mean of 2.5 (SD 1.7) chronic conditions. Overall, the remote EBP participants showed statistically significant improvements in health, energy, sleep quality, loneliness, depressive symptoms, and technology anxiety. Qualitatively, participants shared improvements in knowledge, attitudes, and skills for healthier living; reduced their social isolation and loneliness; and gained better access to programs. Three-fourths of the providers (149/198, 75.2%) felt that effectiveness was maintained when switching from in-person to remote delivery. ConclusionsThe findings suggest that participating in remote EBPs can improve health, social, and technological outcomes of interest for older adults and providers, with benefits extending to policy makers. Future policy and practice can better support remote EBP delivery as one model for health promotion, improving access for all older adults.

Human milk, due to its unique composition, is the optimal standard for infant nutrition. Osteopontin (OPN) is abundant in human milk but not bovine milk. The addition of bovine milk osteopontin (bmOPN) to formula may replicate OPN’s concentration and function in human milk. To address safety concerns, we convened an expert panel to assess the adequacy of safety data and physiological roles of dietary bmOPN in infancy. The exposure of breastfed infants to human milk OPN (hmOPN) has been well-characterized and decreases markedly over the first 6 months of lactation. Dietary bmOPN is resistant to gastric and intestinal digestion, absorbed and cleared from circulation within 8–24 h, and represents a small portion (

Abstract Although FOXP3+ regulatory T cells (Treg) depend on IL-2 produced by other cells for their survival and function, the levels of IL-2 in inflamed tissue are low, making it unclear how Treg access this critical resource. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed central nervous system tissue. HPSE expression distinguishes human and murine Treg from conventional T cells and is regulated by the availability of IL-2. HPSE-/- Treg have impaired stability and function in vivo, including in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing monoclonal antibody-directed chimeric antigen receptor (mAbCAR) Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their ability to suppress neuroinflammation in vivo. Together, these data identify a role for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity.

When cyanobacterial phytoplankton form harmful cyanobacterial blooms (HCBs), the toxins they produce threaten freshwater ecosystems. Hydrogen peroxide is often used to control HCBs, but it is broadly toxic and dangerous to handle. Previously, we demonstrated that glucose addition to lake water could suppress the abundance of cyanobacteria. In this study, glucose was compared to hydrogen peroxide for the treatment of cyanobacterial phytoplankton communities. The six-week study was conducted in the large mesocosms facility at Grand Valley State University’s Annis Water Resources Institute in Michigan. To 1000 L of Muskegon Lake water, glucose was added at either 150 mg or 30 mg glucose/L. Hydrogen peroxide was added at 3 mg/L to two 1000 L mesocosms. And two mesocosms were left untreated as controls. Triplicate 100 mL samples were collected weekly from each mesocosm, which were then filtered and frozen at −80 °C for 16S rRNA amplicon sequencing. The 16S rRNA amplicon sequencing results revealed that hydrogen peroxide treatment quickly reduced the relative abundance of the cyanobacteria compared to the control mesocosms, but the cyanobacteria population returned over the course of the 6-week study. On the other hand, both glucose concentrations caused a rapid proliferation of multiple low abundance proteobacterial and bacteroidotal taxa resulting in notable increases in taxonomic richness over the duration of the study and reducing the relative abundance of cyanobacteria. Although hydrogen peroxide quickly suppressed the cyanobacteria, the population later returned to near starting levels. The glucose suppressed the cyanobacterial phytoplankton apparently by promoting competitive heterotrophic bacteria.