Autoantibodies against NMDAR subunit NR1 disappear from blood upon anesthesia

Anesthetics penetrate the blood-brain-barrier (BBB) and - as confirmed preclinically – transiently disrupt it. An analogous consequence in humans has remained unproven. In mice, we previously reported that upon BBB dysfunction, the brain acts as ‘immunoprecipitator’ of autoantibodies against N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1-AB). We thus hypothesized that during human anesthesia, pre-existing NMDAR1-AB will specifically bind to brain. Screening of N = 270 subjects undergoing general anesthesia during cardiac surgery for serum NMDAR1-AB revealed N = 25 NMDAR1-AB seropositives. Only N = 14 remained positive post-surgery. No changes in albumin, thyroglobulin or CRP were associated with reduction of serum NMDAR1-AB. Thus, upon anesthesia, BBB opening likely occurs also in humans

Autoantibodies against NMDA receptor 1 modify rather than cause encephalitis

The etiology and pathogenesis of “anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis” and the role of autoantibodies (AB) in this condition are still obscure. While NMDAR1-AB exert NMDAR-antagonistic properties by receptor internalization, no firm evidence exists to date that NMDAR1-AB by themselves induce brain inflammation/encephalitis. NMDAR1-AB of all immunoglobulin classes are highly frequent across mammals with multiple possible inducers and boosters. We hypothesized that “NMDAR encephalitis” results from any primary brain inflammation coinciding with the presence of NMDAR1-AB, which may shape the encephalitis phenotype. Thus, we tested whether following immunization with a “cocktail” of 4 NMDAR1 peptides, induction of a spatially and temporally defined sterile encephalitis by diphtheria toxin-mediated ablation of pyramidal neurons (“DTA” mice) would modify/aggravate the ensuing phenotype. In addition, we tried to replicate a recent report claiming that immunizing just against the NMDAR1-N368/G369 region induced brain inflammation. Mice after DTA induction revealed a syndrome comprising hyperactivity, hippocampal learning/memory deficits, prefrontal cortical network dysfunction, lasting blood brain-barrier impairment, brain inflammation, mainly in hippocampal and cortical regions with pyramidal neuronal death, microgliosis, astrogliosis, modest immune cell infiltration, regional atrophy, and relative increases in parvalbumin-positive interneurons. The presence of NMDAR1-AB enhanced the hyperactivity (psychosis-like) phenotype, whereas all other readouts were identical to control-immunized DTA mice. Non-DTA mice with or without NMDAR1-AB were free of any encephalitic signs. Replication of the reported NMDAR1-N368/G369-immunizing protocol in two large independent cohorts of wild-type mice completely failed. To conclude, while NMDAR1-AB can contribute to the behavioral phenotype of an underlying encephalitis, induction of an encephalitis by NMDAR1-AB themselves remains to be proven

NMDAR1 autoantibodies amplify behavioral phenotypes of genetic white matter inflammation: a mild encephalitis model with neuropsychiatric relevance

Encephalitis has an estimated prevalence of ≤0.01%. Even with extensive diagnostic work-up, an infectious etiology is identified or suspected in <50% of cases, suggesting a role for etiologically unclear, noninfectious processes. Mild encephalitis runs frequently unnoticed, despite slight neuroinflammation detectable postmortem in many neuropsychiatric illnesses. A widely unexplored field in humans, though clearly documented in rodents, is genetic brain inflammation, particularly that associated with myelin abnormalities, inducing primary white matter encephalitis. We hypothesized that “autoimmune encephalitides” may result from any brain inflammation concurring with the presence of brain antigen-directed autoantibodies, e.g., against N-methyl-D-aspartate-receptor NR1 (NMDAR1-AB), which are not causal of, but may considerably shape the encephalitis phenotype. We therefore immunized young female Cnp−/− mice lacking the structural myelin protein 2′-3′-cyclic nucleotide 3′-phosphodiesterase (Cnp) with a “cocktail” of NMDAR1 peptides. Cnp−/− mice exhibit early low-grade inflammation of white matter tracts and blood–brain barrier disruption. Our novel mental-time-travel test disclosed that Cnp−/− mice are compromised in what–where–when orientation, but this episodic memory readout was not further deteriorated by NMDAR1-AB. In contrast, comparing wild-type and Cnp−/− mice without/with NMDAR1-AB regarding hippocampal learning/memory and motor balance/coordination revealed distinct stair patterns of behavioral pathology. To elucidate a potential contribution of oligodendroglial NMDAR downregulation to NMDAR1-AB effects, we generated conditional NR1 knockout mice. These mice displayed normal Morris water maze and mental-time-travel, but beam balance performance was similar to immunized Cnp−/−. Immunohistochemistry confirmed neuroinflammation/neurodegeneration in Cnp−/− mice, yet without add-on effect of NMDAR1-AB. To conclude, genetic brain inflammation may explain an encephalitic component underlying autoimmune conditions

Inducing sterile pyramidal neuronal death in mice to model distinct aspects of gray matter encephalitis

Up to one person in a population of 10,000 is diagnosed once in lifetime with an encephalitis, in 50–70% of unknown origin. Recognized causes amount to 20–50% viral infections. Approximately one third of affected subjects develops moderate and severe subsequent damage. Several neurotropic viruses can directly infect pyramidal neurons and induce neuronal death in cortex and hippocampus. The resulting encephalitic syndromes are frequently associated with cognitive deterioration and dementia, but involve numerous parallel and downstream cellular and molecular events that make the interpretation of direct consequences of sudden pyramidal neuronal loss difficult. This, however, would be pivotal for understanding how neuroinflammatory processes initiate the development of neurodegeneration, and thus for targeted prophylactic and therapeutic interventions. Here we utilized adult male NexCre‑ ERT2xRosa26-eGFP-DTA (= ‘DTA’) mice for the induction of a sterile encephalitis by diphtheria toxin-mediated ablation of cortical and hippocampal pyramidal neurons which also recruits immune cells into gray matter. We report multifaceted aftereffects of this defined process, including the expected pathology of classical hippocampal behaviors, evaluated in Morris water maze, but also of (pre)frontal circuit function, assessed by prepulse inhibition. Importantly, we modelled in encephalitis mice novel translationally relevant sequelae, namely altered social interaction/cognition, accompanied by compromised thermoreaction to social stimuli as convenient readout of parallel autonomic nervous system (dys)function. High resolution magnetic resonance imaging disclosed distinct abnormalities in brain dimensions, including cortical and hippocampal layering, as well as of cerebral blood flow and volume. Fluorescent tracer injection, immunohistochemistry and brain flow cytometry revealed persistent blood–brain-barrier perturbance and chronic brain inflammation. Surprisingly, blood flow cytometry showed no abnormalities in circulating major immune cell subsets and plasma high-mobility group box 1 (HMGB1) as proinflammatory marker remained unchanged. The present experimental work, analyzing multidimensional outcomes of direct pyramidal neuronal loss, will open new avenues for urgently needed encephalitis research

Avaliação da produtividade de forragem de aveia branca na região da Campanha do Rio Grande do Sul.

SIEPE

Matricellular Proteins Produced by Melanocytes and Melanomas: In Search for Functions

Matricellular proteins are modulators of cell-matrix interactions and cellular functions. The group includes thrombospondin, osteopontin, osteonectin/SPARC, tenascin, disintegrins, galectins and CCN proteins. The production of matricellular proteins such as osteopontin, SPARC or tenascin is highly upregulated in melanoma and other tumors but little is known about their functions in tumor growth, survival, and metastasis. The distribution pattern of CCN3 differs from most other matricellular proteins, such that it is produced abundantly by normal melanocytes, but is not significantly expressed in melanoma cells. CCN3 is known to inhibit melanocyte proliferation and stimulate adhesion to collagen type IV, the main component of the basement membrane. CCN3 has a unique role in securing adhesion of melanocytes to the basement membrane distinct from other melanoma-produced matricellular proteins which act as de-adhesive molecules and antagonists of focal adhesion. Qualitative and quantitative changes in matricellular protein expression contribute to melanoma progression similar to the E-cadherin to N-cadherin class switch, allowing melanoma cells to escape from keratinocyte control

Exploring Data Provenance in Handwritten Text Recognition Infrastructure: Sharing and Reusing Ground Truth Data, Referencing Models, and Acknowledging Contributions. Starting the Conversation on How We Could Get It Done

This paper discusses best practices for sharing and reusing Ground Truth in Handwritten Text Recognition infrastructures, as well as ways to reference and acknowledge contributions to the creation and enrichment of data within these systems. We discuss how one can place Ground Truth data in a repository and, subsequently, inform others through HTR-United. Furthermore, we want to suggest appropriate citation methods for ATR data, models, and contributions made by volunteers. Moreover, when using digitised sources (digital facsimiles), it becomes increasingly important to distinguish between the physical object and the digital collection. These topics all relate to the proper acknowledgement of labour put into digitising, transcribing, and sharing Ground Truth HTR data. This also points to broader issues surrounding the use of machine learning in archival and library contexts, and how the community should begin to acknowledge and record both contributions and data provenance

Exploring data provenance in handwritten text recognition infrastructure:Sharing and reusing ground truth data, referencing models, and acknowledging contributions. Starting the conversation on how we could get it done

This paper discusses best practices for sharing and reusing Ground Truth in Handwritten Text Recognition infrastructures, and ways to reference and acknowledge contributions to the creation and enrichment of data within these Machine Learning systems. We discuss how one can publish Ground Truth data in a repository and, subsequently, inform others. Furthermore, we suggest appropriate citation methods for HTR data, models, and contributions made by volunteers. Moreover, when using digitised sources (digital facsimiles), it becomes increasingly important to distinguish between the physical object and the digital collection. These topics all relate to the proper acknowledgement of labour put into digitising, transcribing, and sharing Ground Truth HTR data. This also points to broader issues surrounding the use of Machine Learning in archival and library contexts, and how the community should begin toacknowledge and record both contributions and data provenance

Synthesis of functional ‘polyolefins’: state of the art and remaining challenges

Functional polyolefins (i.e., polyethene or polypropene bearing functional groups) are highly desired materials, due to their beneficial surface properties. Many different pathways exist for the synthesis of these materials, each with its own advantages and drawbacks. This review focuses on those synthetic pathways that build up a polymer chain from ethene/propene and functionalised polar vinyl monomers. Despite many recent advances in the various fields of olefin polymerisation, it still remains a challenge to synthesise high molecular- weight copolymers with tuneable amounts of functional groups, preferably with consecutive insertions of polar monomers occurring in a stereoselective way. To overcome some of these challenges, polymerisation of alternative functionalised monomers is explored as well