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Understanding the brain’s perception algorithm is a highly intricate problem, as the inherent complexity of sensory inputs and the brain’s nonlinear processing make characterizing sensory representations difficult. Recent studies have shown that functional models—capable of predicting large-scale neuronal activity in response to arbitrary sensory input—can be powerful tools for characterizing neuronal representations by enabling high-throughputin silicoexperiments. However, accurately modeling responses to dynamic and ecologically relevant inputs like videos remains challenging, particularly when generalizing to new stimulus domains outside the training distribution. Inspired by recent breakthroughs in artificial intelligence, where foundation models—trained on vast quantities of data— have demonstrated remarkable capabilities and generalization, we developed a “foundation model” of the mouse visual cortex: a deep neural network trained on large amounts of neuronal responses to ecological videos from multiple visual cortical areas and mice. The model accurately predicted neuronal responses not only to natural videos but also to various new stimulus domains, such as coherent moving dots and noise patterns, underscoring its generalization abilities. The foundation model could also be adapted to new mice with minimal natural movie training data. We applied the foundation model to the MICrONS dataset: a study of the brain that integrates structure with function at unprecedented scale, containing nanometer-scale morphology, connectivity with >500,000,000 synapses, and function of >70,000 neurons within a ∼ 1mm3volume spanning multiple areas of the mouse visual cortex. This accurate functional model of the MICrONS data opens the possibility for a systematic characterization of the relationship between circuit structure and function. By precisely capturing the response properties of the visual cortex and generalizing to new stimulus domains and mice, foundation models can pave the way for a deeper understanding of visual computation.

To understand how the neocortex underlies our ability to perceive, think, and act, it is important to study the relationship between circuit connectivity and function. Previous research has shown that excitatory neurons in layer 2/3 of the primary visual cortex of mice with similar response properties are more likely to form connections. However, technical challenges of combining synaptic connectivity and functional measurements have limited these studies to few, highly local connections. Utilizing the millimeter scale and nanometer resolution of the MICrONS dataset, we studied the connectivity-function relationship in excitatory neurons of the mouse visual cortex across interlaminar and interarea projections, assessing connection selectivity at the coarse axon trajectory and fine synaptic formation levels. A digital twin model of this mouse, that accurately predicted responses to arbitrary video stimuli, enabled a comprehensive characterization of the function of neurons. We found that neurons with highly correlated responses to natural videos tended to be connected with each other, not only within the same cortical area but also across multiple layers and visual areas, including feedforward and feedback connections, whereas we did not find that orientation preference predicted connectivity. The digital twin model separated each neuron’s tuning into a feature component (what the neuron responds to) and a spatial component (where the neuron’s receptive field is located). We show that the feature, but not the spatial component, predicted which neurons were connected at the fine synaptic scale. Together, our results demonstrate the “like-to-like” connectivity rule generalizes to multiple connection types, and the rich MICrONS dataset is suitable to further refine a mechanistic understanding of circuit structure and function.

Autoantibodies that recognize extracellular proteins (the exoproteome) exert potent biological effects but are challenging to detect. Here, we developed rapid extracellular antigen profiling (REAP), a high-throughput technique for the comprehensive discovery of exoproteome-targeting autoantibodies. Patient samples are applied to a genetically barcoded yeast surface display library containing 2,688 human extracellular proteins. Antibody-coated yeast are isolated, and sequencing of barcodes is used to identify displayed antigens. To benchmark REAP's performance, we screened 77 patients with autoimmune polyglandular syndrome type 1 (APS-1). REAP sensitively and specifically detected both known and previously unidentified autoantibodies in APS-1. We further screened 106 patients with systemic lupus erythematosus (SLE) and identified numerous autoantibodies, several of which were associated with disease severity or specific clinical manifestations and exerted functional effects on cell signaling

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses

A growing body of evidence indicates sex differences in the clinical outcomes of coronavirus disease 2019 (COVID-19)1-4. However, whether immune responses against SARS-CoV-2 differ between sexes, and whether such differences explain male susceptibility to COVID-19, is currently unknown. In this study, we examined sex differences in viral loads, SARS-CoV-2-specific antibody titers, plasma cytokines, as well as blood cell phenotyping in COVID-19 patients. By focusing our analysis on patients with mild to moderate disease who had not received immunomodulatory medications, our results revealed that male patients had higher plasma levels of innate immune cytokines and chemokines including IL-8, IL-18, and CCL5, along with more robust induction of non-classical monocytes. In contrast, female patients mounted significantly more robust T cell activation than male patients during SARS-CoV-2 infection, which was sustained in old age. Importantly, we found that a poor T cell response negatively correlated with patients’ age and was predictive of worse disease outcome in male patients, but not in female patients. Conversely, higher innate immune cytokines in female patients associated with worse disease progression, but not in male patients. These findings reveal a possible explanation underlying observed sex biases in COVID-19, and provide important basis for the development of sex-based approach to the treatment and care of men and women with COVID-19.

UnlabelledSurvivors of preterm birth are at high risk of pervasive cognitive and learning impairments, suggesting disrupted early brain development. The limits of viability for preterm birth encompass the third trimester of pregnancy, a "precritical period" of activity-dependent development characterized by the onset of spontaneous and evoked patterned electrical activity that drives neuronal maturation and formation of cortical circuits. Reduced background activity on electroencephalogram (EEG) is a sensitive marker of brain injury in human preterm infants that predicts poor neurodevelopmental outcome. We studied a rodent model of very early hypoxic-ischemic brain injury to investigate effects of injury on both general background and specific patterns of cortical activity measured with EEG. EEG background activity is depressed transiently after moderate hypoxia-ischemia with associated loss of spindle bursts. Depressed activity, in turn, is associated with delayed expression of glutamate receptor subunits and transporters. Cortical pyramidal neurons show reduced dendrite development and spine formation. Complementing previous observations in this model of impaired visual cortical plasticity, we find reduced somatosensory whisker barrel plasticity. Finally, EEG recordings from human premature newborns with brain injury demonstrate similar depressed background activity and loss of bursts in the spindle frequency band. Together, these findings suggest that abnormal development after early brain injury may result in part from disruption of specific forms of brain activity necessary for activity-dependent circuit development.Significance statementPreterm birth and term birth asphyxia result in brain injury from inadequate oxygen delivery and constitute a major and growing worldwide health problem. Poor outcomes are noted in a majority of very premature (

Endothelial vascular adhesion protein-1 (VAP-1) facilitates leukocyte adhesion and infiltration. This relates partly to the function of VAP-1 as a semicarbazide-sensitive amine oxidase (SSAO). We examined the effects of VAP-1/SSAO inhibition [via LJP-1207 (N'-(2-phenyl-allyl)-hydrazine hydrochloride)] on pial venular leukocyte adhesion and infiltration (at 2-10 h of reperfusion) and neuropathology (at 72 h of reperfusion) after transient forebrain ischemia (TFI). A model associated with increased postischemic inflammation was used-i.e., diabetic ovariectomized (OVX) female rats given chronic estrogen replacement therapy (ERT). We compared rats treated, either at the onset or at 6 h of reperfusion, with saline or LJP-1207. Additional rats, rendered neutropenic 24 h before TFI, were studied. In saline-treated controls, intravascular accumulation of adherent leukocytes gradually increased, reaching 15 to 20% of the venular area, at which point neutrophil infiltration commenced (at approximately 6 h). In the rats given LJP-1207 at the onset of reperfusion, limited neutrophil adhesion ( approximately 5% maximum) and no infiltration were observed. These results generally paralleled those in neutropenic rats. In rats treated at 6 h of reperfusion, the pattern of neutrophil adhesion was similar to that of the saline-treated group up to 6 h, but further infiltration was essentially prevented. Neurologic outcomes and histopathology were similar to one another in the LJP-1207-treated and neutropenic groups and significantly improved over those in saline-treated controls. Thus, VAP-1-mediated post-TFI leukocyte adhesion/infiltration in diabetic OVX females given chronic ERT contributes substantially to neuropathology. One implication is that specifically preventing leukocyte infiltration provides a substantial measure of neuroprotection. This could explain the finding of LJP-1207 having at least a 6-h therapeutic window in this model.

Human semicarbazide-sensitive amine oxidase (SSAO) or vascular adhesion protein-1 (VAP-1) is a copper-containing amine oxidase (AOC3, EC 1.4.3.6) that has both enzymatic and adhesive function. SSAO catalyzes the oxidative deamination of primary amines, resulting in the formation of the corresponding aldehyde and release of hydrogen peroxide and ammonia. Membrane-bound SSAO is an inflammation-inducible endothelial cell adhesion molecule that mediates the interaction between leukocytes and activated endothelial cells in inflamed vessels. Both the direct adhesive and enzymatic functions seem to be involved in the adhesion cascade. LJP 1207 [N'-(2-phenyl-allyl)-hydrazine hydrochloride] is a potent (human SSAO IC(50) = 17 nM), selective, and orally available SSAO inhibitor that blocks both the enzymatic and adhesion functions of SSAO/VAP-1. In a mouse model of ulcerative colitis, LJP 1207 significantly reduces mortality, loss of body weight, and colonic cytokine levels. Quantitative histopathological assessment of colitis activity in this model showed a highly significant suppression of inflammation, injury, and ulceration scores in the animals treated with the SSAO/VAP-1 inhibitor. LJP 1207 also reduced serum levels of tumor necrosis factor-alpha and interleukin 6 in lipopolysaccharide (LPS)-challenged mice and prolonged survival post-LPS-induced endotoxemia. Therapeutic and prophylactic administration of LJP 1207 in the rat carrageenan footpad model also markedly inhibited swelling and inflammation. Overall, the data suggest that small molecule SSAO/VAP-1 inhibitors may provide clinical benefit in the treatment of acute and chronic inflammatory diseases.

The isoquinoline carboxamide derivative 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide (PK11195) has been shown to bind strongly and selectively to the peripheral benzodiazepine receptor (PBR) binding sites. A series of PK11195 analogues have been synthesized and biologically characterized. The affinities of the analogues for the PBR were determined using in vitro competitive binding assays with [3H]PK11195 in rat kidney mitochondrial membranes. The results showed that the 1-(2-iodophenyl)-N-methyl-N-(3-fluoropropyl)-3-isoquinoline carboxamide (9a) was the most potent compound (Ki = 0.26 nM) of this series and is an excellent lead ligand for additional studies for labeling with fluorine-18 to determine whether it possesses the desired in vivo performance in non-human primates by PET imaging. Thus, radiolabeling of 9a with fluorine-18 was developed.

Semicarbazide-sensitive amine oxidase (SSAO, amine oxidase, copper-containing 3, and vascular adhesion protein-1) is a copper-containing enzyme that catalyzes the oxidative deamination of primary amines to an aldehyde, ammonia, and hydrogen peroxide. SSAO is also involved in leukocyte migration to sites of inflammation, and the enzymatic activity of SSAO is essential to this role. Thus, inhibition of SSAO enzyme activity represents a target for the development of small molecule anti-inflammatory compounds. Here, we have characterized the novel SSAO inhibitor, Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride (LJP 1586), and assessed its anti-inflammatory activity. LJP 1586 is a potent inhibitor of rodent and human SSAO activity, with IC(50) values between 4 and 43 nM. The selectivity of LJP 1586 was confirmed with a broad panel of receptors and enzymes that included the monoamine oxidases A and B. Oral administration of LJP 1586 resulted in complete inhibition of rat lung SSAO, with an ED(50) between 0.1 and 1 mg/kg, and a pharmacodynamic half-life of greater than 24 h. In a mouse model of inflammatory leukocyte trafficking oral dosing with LJP 1586 resulted in significant dose-dependent inhibition of neutrophil accumulation, with an effect comparable to that of anti-leukocyte function-associated antigen-1 antibody. In a rat model of LPS-induced lung inflammation, administration of 10 mg/kg LJP 1586 resulted in a 55% significant reduction in transmigrated cells recovered by bronchoalveolar lavage. The results demonstrate that a selective, orally active small molecule inhibitor of SSAO is an effective anti-inflammatory compound in vivo and provide further support for SSAO as a therapeutic anti-inflammatory target.

In an attempt to examine the effect of inhibition of semicarbazide-sensitive amine oxidase (SSAO; EC 1.4.3.6, also known as VAP-1) as a novel anti-inflammatory target, the structure/mechanism based design and synthesis of a series of novel hydrazino-containing small molecules are described. The in vitro biological results show that compounds 4a,c are highly potent SSAO inhibitors with notable selectivity toward SSAO over monoamine oxidases A and B (MAO-A and MAO-B). SAR studies based on compound 4c were performed, and the results are discussed. The most potent and selective compound, 4a (IC(50) = 2 nM), is an orally active, competitive, and apparently irreversible inhibitor of SSAO that is effective at reducing disease incidence and severity in an in vivo animal disease model of multiple sclerosis.