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Axon regeneration in the adult CNS is prevented by inhibitors in myelin. These inhibitors seem to modulate RhoA activity by binding to a receptor complex comprising a ligand-binding subunit (the Nogo-66 receptor NgR1) and a signal transducing subunit (the neurotrophin receptor p75). However, in reconstituted non-neuronal systems, NgR1 and p75 together are unable to activate RhoA, suggesting that additional components of the receptor may exist. Here we describe LINGO-1, a nervous system-specific transmembrane protein that binds NgR1 and p75 and that is an additional functional component of the NgR1/p75 signaling complex. In non-neuronal cells, coexpression of human NgR1, p75 and LINGO-1 conferred responsiveness to oligodendrocyte myelin glycoprotein, as measured by RhoA activation. A dominant-negative human LINGO-1 construct attenuated myelin inhibition in transfected primary neuronal cultures. This effect on neurons was mimicked using an exogenously added human LINGO-1-Fc fusion protein. Together these observations suggest that LINGO-1 has an important role in CNS biology.

BackgroundRadiotracer extravasations, caused largely by faulty tracer injections, can occur in up to 23% of 18F-fluorodeoxyglucose (FDG) PET/CT scans and negatively impact radiological review and tracer quantification. Conventional radiological assessment of extravasation severity on PET has limited performance (e.g., extravasations frequently resolve before scanning) and practical drawbacks. In this study, we develop a new topical detector-based FDG extravasation severity classifier, calibrated from semi-quantitative PET measurements, and assess its performance on human subjects.MethodsA retrospective study examined patients whose FDG injections had been monitored as part of their standard workup for PET/CT imaging. Topical uncollimated gamma ray detectors were applied proximal to the injection site and on the same location on the opposing arm, and readings were acquired continuously during radiotracer uptake. Patients were imaged with their arms in the PET field of view and total extravasation activity quantified from static PET images through a volume of interest approach. The image-derived activities were considered ground truth and used to calibrate and assess quantification of topical detector readings extrapolated to the start of PET imaging. The classifier utilizes the calibrated detector readings to produce four extravasation severity classes: none, minor, moderate, and severe. In a blinded study, a radiologist qualitatively labeled PET images for extravasation severity using the same classifications. The radiologist’s interpretations and topical detector classifications were compared to the ground truth PET results.ResultsLinear regression of log-transformed image-derived versus topical detector tracer extravasation activity estimates showed a strong correlation (R2 = 0.75). A total of 24 subject scans were cross-validated with the quantitatively based classifier through a leave-one-out methodology. For binary classification (none vs. extravasated), the topical detector classifier had the highest overall diagnostic performance for identifying extravasations. Specificity, sensitivity, accuracy, and positive predictive value were 100.0%, 80.0%, 95.8%, and 100.0%, respectively, for the topical detector classifier and 31.6%, 100.0%, 45.8%, and 27.8%, respectively, for the radiological analysis. The topical detector classifier, with an optimal detection threshold, produced a significantly higher Matthews correlation coefficient (MCC) than the radiological analysis (0.87 vs. 0.30).ConclusionsThe topical detector binary classifier, calibrated using quantitative static PET measurements, significantly improves extravasation detection compared to qualitative image analysis.

Recent studies suggest that superoxide dismutase 1 (SOD1)-linked amyotrophic lateral sclerosis results from destabilization and misfolding of mutant forms of this abundant cytosolic enzyme. Here, we have tracked the expression and fate of a misfolding-prone human SOD1, G85R, fused to YFP, in a line of transgenic G85R SOD1-YFP mice. These mice, but not wild-type human SOD1-YFP transgenics, developed lethal paralyzing motor symptoms at 9 months. In situ RNA hybridization of spinal cords revealed predominant expression in motor neurons in spinal cord gray matter in all transgenic animals. Concordantly, G85R SOD-YFP was diffusely fluorescent in motor neurons of animals at 1 and 6 months of age, but at the time of symptoms, punctate aggregates were observed in cell bodies and processes. Biochemical analyses of spinal cord soluble extracts indicated that G85R SOD-YFP behaved as a misfolded monomer at all ages. It became progressively insoluble at 6 and 9 months of age, associated with presence of soluble oligomers observable by gel filtration. Immunoaffinity capture and mass spectrometry revealed association of G85R SOD-YFP, but not WT SOD-YFP, with the cytosolic chaperone Hsc70 at all ages. In addition, 3 Hsp110's, nucleotide exchange factors for Hsp70s, were captured at 6 and 9 months. Despite such chaperone interactions, G85R SOD-YFP formed insoluble inclusions at late times, containing predominantly intermediate filament proteins. We conclude that motor neurons, initially \"compensated\" to maintain the misfolded protein in a soluble state, become progressively unable to do so.

More investment to characterize animal models can boost the ability of preclinical work to predict drug effects in humans, says Steve Perrin.

Xenotransplantation offers a potential solution to the organ shortage crisis. A 62-year-old hemodialysis-dependent man with long-standing diabetes, advanced vasculopathy, and marked dialysis-access challenges received a gene-edited porcine kidney with 69 genomic edits, including deletion of three glycan antigens, inactivation of porcine endogenous retroviruses, and insertion of seven human transgenes. The xenograft functioned immediately. The patient’s creatinine levels decreased promptly and progressively, and dialysis was no longer needed. After a T-cell–mediated rejection episode on day 8, intensified immunosuppression reversed rejection. Despite sustained kidney function, the patient died from unexpected, sudden cardiac causes on day 52; autopsy revealed severe coronary artery disease and ventricular scarring without evident xenograft rejection. (Funded by Massachusetts General Hospital and eGenesis.) This report describes the transplantation of a gene-edited porcine kidney in a hemodialysis-dependent man with long-standing diabetes, advanced vasculopathy, and marked dialysis-access challenges.

Following our previous experience with cardiac xenotransplantation of a genetically modified porcine heart into a live human, we sought to achieve improved results by selecting a healthier recipient and through more sensitive donor screening for potential zoonotic pathogens. Here we transplanted a 10-gene-edited pig heart into a 58-year-old man with progressive, debilitating inotrope-dependent heart failure due to ischemic cardiomyopathy who was not a candidate for standard advanced heart failure therapies. He was maintained on a costimulation (anti-CD40L, Tegoprubart) blockade-based immunomodulatory regimen. The xenograft initially functioned well, with excellent systolic and diastolic function during the first several weeks posttransplantation. Subsequently, the xenograft developed rapidly progressing diastolic heart failure, biventricular wall thickening and, ultimately, near-complete loss of systolic function necessitating initiation of extracorporeal membranous oxygenation on day 31. Given these setbacks, the patient chose to transition to comfort care after 40 days. As with our first patient, histology did not reveal substantial immune cell infiltration but suggested capillary endothelial injury with interstitial edema and early fibrosis. No evidence of porcine cytomegalovirus replication in the xenograft was observed. Strategies to overcome the obstacle of antibody-mediated rejection are needed to advance the field of xenotransplantation. In the second case in which a genetically modified pig heart was transplanted into a living person, the xenografted heart functioned well initially, but antibody-mediated rejection occurred thereafter, pointing to the need for improved strategies to avoid this complication.

Knowledge of resource-use and movement patterns is a missing component in the development of horseshoe crab (Limulus polyphemus) management strategies. Available evidence indicates the potential for a variety of possible migratory behaviors, but the lack of high-resolution, spatial-temporal data has hindered development of a year-round profile of ranging behavior. This need was addressed in the present study by using acoustic telemetry to track the movements of adult horseshoe crabs in two subembayments (Egypt and Hog Bays) of the Taunton Bay Estuary, Maine, from June 2003 to June 2005. Estimated mean total home range sizes were 64.1 and 61.4 ha for breeding crabs tagged in Egypt and Hog Bays, respectively. We observed no horseshoe crab dispersal to areas outside of the subembayments where they were tagged, so no mixing was observed between Egypt and Hog Bay individuals despite a < 4-km separation. Observed shifts in movement patterns, resource use (subtidal versus intertidal), and vagility facilitated a profile of seasonally partitioned horseshoe crab activity, which included late April to early May post-wintering, June—July breeding, August—September pre-wintering, and October—April wintering, where space usage represented about 10% of the mean total home range size. The apparent isolation of these resident populations implies a heightened vulnerability to overexploitation and large-scale habitat alteration that might be more easily sustained by larger, more vagile populations. This work underscores the need to apply horseshoe crab conservation, research, and management efforts at scales that are appropriate to the ranging patterns of crabs, which first requires application of high-resolution methods to identify those patterns.

Knowledge of resource-use and movement patterns is a missing component in the development of horseshoe crab (Limulus polyphemus) management strategies. Available evidence indicates the potential for a variety of possible migratory behaviors, but the lack of high-resolution, spatial- temporal data has hindered development of a year-round profile of ranging behavior. This need was addressed in the present study by using acoustic telemetry to track the movements of adult horseshoe crabs in two subembayments (Egypt and Hog Bays) of the Taunton Bay Estuary, Maine, from June 2003 to June 2005. Estimated mean total home range sizes were 64.1 and 61.4 ha for breeding crabs tagged in Egypt and Hog Bays, respectively. We observed no horseshoe crab dispersal to areas outside of the subembayments where they were tagged, so no mixing was observed between Egypt and Hog Bay individuals despite a < 4-km separation. Observed shifts in movement patterns, resource use (subtidal versus intertidal), and vagility facilitated a profile of seasonally partitioned horseshoe crab activity, which included late April to early May post-wintering, June-July breeding, August-September pre-wintering, and October-April wintering, where space usage represented about 10% of the mean total home range size. The apparent isolation of these resident populations implies a heightened vulnerability to overexploitation and large-scale habitat alteration that might be more easily sustained by larger, more vagile populations. This work underscores the need to apply horseshoe crab conservation, research, and management efforts at scales that are appropriate to the ranging patterns of crabs, which first requires application of high-resolution methods to identify those patterns.