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Abstract Molecular markers of autoimmunity, such as antibodies to citrullinated protein antigens (ACPA), are detectable prior to inflammatory arthritis (IA) in rheumatoid arthritis (RA) and may define a state that is ‘at-risk’ for future RA. Here we present a cross-sectional comparative analysis among three groups that include ACPA positive individuals without IA (At-Risk), ACPA negative individuals and individuals with early, ACPA positive clinical RA (Early RA). Differential methylation analysis among the groups identifies non-specific dysregulation in peripheral B, memory and naïve T cells in At-Risk participants, with more specific immunological pathway abnormalities in Early RA. Tetramer studies show increased abundance of T cells recognizing citrullinated (cit) epitopes in At-Risk participants, including expansion of T cells reactive to citrullinated cartilage intermediate layer protein I (cit-CILP); these T cells have Th1, Th17, and T stem cell memory-like phenotypes. Antibody-antigen array analyses show that antibodies targeting cit-clusterin, cit-fibrinogen and cit-histone H4 are elevated in At-Risk and Early RA participants, with the highest levels of antibodies detected in those with Early RA. These findings indicate that an ACPA positive at-risk state is associated with multifaceted immune dysregulation that may represent a potential opportunity for targeted intervention.

Neural activity from perception is thought to be reactivated during memory recall. Here, the authors show that memory reactivation in visual cortex exhibits different tuning properties from those observed during perception.

When two memories are similar, their encoding and retrieval can be disrupted by each other. Here the authors show that memory interference is resolved through abrupt remapping of activity patterns in the human hippocampal CA3 and dentate gyrus.

There is limited evidence linking learning related changes in hippocampal representations and memory interference. Here Favila and colleagues demonstrate that learning reduces overlap in hippocampal activity patterns corresponding to similar events, which benefits subsequent learning by preventing interference.

Lyme disease (Borrelia burgdorferi infection) is increasingly recognized as a significant source of morbidity worldwide. Here, we show that blood plasmablasts and CD27− memory B cells are elevated in untreated Lyme disease, with higher plasmablast levels associated with more rapid resolution of clinical symptoms. Stronger serum reactivity to surface proteins and peptides from B. burgdorferi was also associated with faster resolution of clinical symptoms. Through molecular identifier-enabled antibody heavy-chain sequencing of bulk B cells and single-cell paired-chain antibody sequencing of blood plasmablasts, we characterized immunoglobulin gene usage patterns specific to B. burgdorferi infection. Recombinantly expressed antibodies from expanded lineages bound B. burgdorferi antigens, confirming that these clones are driven by the infection. Furthermore, recombinant sequence-derived antibodies were functional, inhibiting growth of B. burgdorferi in vitro. Elevations and clonal expansion of blood plasmablasts were associated with rapid return to health, while poor plasmablast responses were associated with a longer duration of symptoms following treatment. Plasmablasts induced by B. burgdorferi infection showed preferential antibody gene segment usage, while bulk sequencing of total B cells revealed convergent CDR3 motifs specific to B. burgdorferi-infected patients. Our results show that robust plasmablast responses encoding Bb-static antibodies are associated with more rapid resolution of Lyme disease, and these antibodies could provide the basis for next-generation therapeutics for Lyme disease.

Behaving adaptively requires selection of relevant memories and sensations and suppression of competing ones. We hypothesized that these mechanisms are linked, such that hippocampal computations that resolve competition in memory also shape the precision of sensory representations to guide selective attention. We leveraged f MRI-based pattern similarity, receptive field modeling, and eye tracking to test this hypothesis in humans performing a memory-dependent visual search task. In the hippocampus, differentiation of competing memories predicted the precision of memory-guided eye movements. In visual cortex, preparatory coding of remembered target locations predicted search successes, whereas preparatory coding of competing locations predicted search failures due to interference. These effects were linked: stronger hippocampal memory differentiation was associated with lower competitor activation in visual cortex, yielding more precise preparatory representations. These results demonstrate a role for memory differentiation in shaping the precision of sensory representations, highlighting links between mechanisms that overcome competition in memory and perception.

BackgroundThe pathogenesis of essential hypertension is multifactorial with different underlying mechanisms contributing to disease. We have recently shown that TNF superfamily member 14 LIGHT (an acronym for homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes, also known as TNFSF14) induces hypertension when injected into mice. Research reported here was undertaken to examine the role of transglutaminase (TGase) in LIGHT‐induced hypertension. Methods and ResultsInitial experiments showed that plasma and kidney TGase activity was induced by LIGHT infusion (13.91±2.92 versus 6.75±1.92 mU/mL and 19.86±3.55 versus 12.00±0.97 mU/10 μg) and was accompanied with hypertension (169±7.16 versus 117.17±11.57 mm Hg at day 14) and renal impairment (proteinuria, 61.33±23.21 versus 20.38±9.01 μg/mg; osmolality, 879.57±93.02 versus 1407.2±308.04 mmol/kg). The increase in renal TGase activity corresponded to an increase in RNA for the tissue TGase isoform, termed TG2. Pharmacologically, we showed that LIGHT‐induced hypertension and renal impairment did not occur in the presence of cystamine, a well‐known competitive inhibitor of TGase activity. Genetically, we showed that LIGHT‐mediated induction of TGase, along with hypertension and renal impairment, was dependent on interleukin‐6 and endothelial hypoxia inducible factor‐1α. We also demonstrated that interleukin‐6, endothelial hypoxia inducible factor‐1α, and TGase are required for LIGHT‐induced production of angiotensin receptor agonistic autoantibodies. ConclusionsThus, LIGHT‐induced hypertension, renal impairment, and production of angiotensin receptor agonistic autoantibodies require TGase, most likely the TG2 isoform. Our findings establish TGase as a critical link between inflammation, hypertension, and autoimmunity.

Background Preeclampsia (PE) is a life‐threatening hypertensive disorder of pregnancy associated with autoantibodies, termed AT1‐AA, that activate the AT1 angiotensin receptor. Although the pathogenic nature of these autoantibodies has been extensively studied, little is known about the molecular cause of their generation. Methods and Results Here we show that tissue transglutaminase (TG2), an enzyme that conducts posttranslational modification of target proteins, directly modified the 7‐amino acid (7‐aa) epitope peptide that localizes to the second extracellular loop of the AT1 receptor. These findings led us to further discover that plasma transglutaminase activity was induced and contributed to the production of AT1‐AA and disease development in an experimental model of PE induced by injection of LIGHT, a tumor necrosis factor superfamily member. Key features of PE were regenerated by adoptive transfer of purified IgG from LIGHT‐injected pregnant mice and blocked by the 7‐amino acid epitope peptide. Translating our mouse research to humans, we found that plasma transglutaminase activity was significantly elevated in PE patients and was positively correlated with AT1‐AA levels and PE features. Conclusions Overall, we provide compelling mouse and human evidence that elevated transglutaminase underlies AT1‐AA production in PE and highlight novel pathogenic biomarkers and innovative therapeutic possibilities for the disease.

Neural rendering bakes global illumination and other computationally costly effects into the weights of a neural network, allowing to efficiently synthesize photorealistic images without relying on path tracing. In neural rendering approaches, G‐buffers obtained from rasterization through direct rendering provide information regarding the scene such as position, normal, and textures to the neural network, achieving accurate and stable rendering quality in real‐time. However, due to the use of G‐buffers, existing methods struggle to accurately render transparency and refraction effects, as G‐buffers do not capture any ray information from multiple light ray bounces. This limitation results in blurriness, distortions, and loss of detail in rendered images that contain transparency and refraction, and is particularly notable in scenes with refracted objects that have high‐frequency textures. In this work, we propose a neural network architecture to encode critical rendering information, including texture coordinates from refracted rays, and enable reconstruction of high‐frequency textures in areas with refraction. Our approach is able to achieve accurate refraction rendering in challenging scenes with a diversity of overlapping transparent objects. Experimental results demonstrate that our method can interactively render high quality refraction effects with global illumination, unlike existing neural rendering approaches. Our code can be found at https://github.com/ziyangz5/CrystalNet [ABSTRACT FROM AUTHOR]