Sex and Age Differences in Glucocorticoid Signaling After an Aversive Experience in Mice.

Background: glucocorticoids may play an important role in the formation of fear memory, which is relevant to the neurobiology of post-traumatic stress disorder (PTSD). In our previous study, we showed the glucocorticoid receptor (GR) forms a protein complex with FKBP51, which prevents translocation of GR into the nucleus to affect gene expression; this complex is elevated in PTSD patients and by fear-conditioned learning in mice, and disrupting this complex blocks the storage and retrieval of fear-conditioned memories. The timing of release of glucocorticoid relative to the formation of a traumatic memory could be important in this process, and remains poorly understood.

Combined plasma protein and memory T cell profiling discern IBD-patient-immunotypes related to intestinal disease and treatment outcomes.

Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn's disease, CD: n = 62; ulcerative colitis, UC: n = 20; age-matched controls n = 43), and after 10-12 weeks' induction therapy.

PolyI:C Maternal Immune Activation on E9.5 Causes the Deregulation of Microglia and the Complement System in Mice, Leading to Decreased Synaptic Spine Density.

Maternal immune activation (MIA) is a risk factor for multiple neurodevelopmental disorders; however, animal models developed to explore MIA mechanisms are sensitive to experimental factors, which has led to complexity in previous reports of the MIA phenotype. We sought to characterize an MIA protocol throughout development to understand how prenatal immune insult alters the trajectory of important neurodevelopmental processes, including the microglial regulation of synaptic spines and complement signaling. We used polyinosinic:polycytidylic acid (polyI:C) to induce MIA on gestational day 9.

Excessive left anterior hippocampal and caudate activation in schizophrenia underlie cognitive underperformance in a virtual navigation task.

We used a virtual navigation paradigm in a city environment to assess neuroanatomical correlates of cognitive deficits in schizophrenia spectrum disorders (SSD). We studied a total of N = 36 subjects: 18 with SSD and 18 matched unaffected controls. Participants completed 10 rapid, single-trial navigation tasks within the virtual city while undergoing functional magnetic resonance imaging (fMRI).

Management of Autoimmune Encephalitis in a 7-Year-Old Child With CTLA-4 Haploinsufficiency and AMPA Receptor Antibodies: A Case Report.

Objectives: We report on the therapeutic management of early-onset severe neurologic symptoms in cytotoxic T lymphocyte antigen-4 haploinsufficiency (CTLA-4h) and the presence of antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) as an important finding.

Methods: This is a case report from a Dutch academic hospital. Repeated clinical examinations, repeated brain MRI and extended diagnostics on serum and CSF were performed.

EF1α-associated protein complexes affect dendritic spine plasticity by regulating microglial phagocytosis in Fmr1 knock-out mice.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. There is no specific treatment for FXS due to the lack of therapeutic targets. We report here that Elongation Factor 1α (EF1α) forms a complex with two other proteins: Tripartite motif-containing protein 3 (TRIM3) and Murine double minute (Mdm2).

Small-molecule targeting AMPA-mediated excitotoxicity has therapeutic effects in mouse models for multiple sclerosis.

While most research and treatments for multiple sclerosis (MS) focus on autoimmune reactions causing demyelination, it is possible that neurodegeneration precedes the autoimmune response. Hence, glutamate receptor antagonists preventing excitotoxicity showed promise in MS animal models, though blocking glutamate signaling prevents critical neuronal functions. This study reports the discovery of a small molecule that prevents AMPA-mediated excitotoxicity by targeting an allosteric binding site.

Serum Immune Profiling in Paediatric Crohn's Disease Demonstrates Stronger Immune Modulation With First-Line Infliximab Than Conventional Therapy and Pre-Treatment Profiles Predict Clinical Response to Both Treatments.

Background: Despite its efficacy, rational guidance for starting/stopping first-line biologic treatment in individual paediatric Crohn's disease [CD] patients is needed. We assessed how serum immune profiles before and after first-line infliximab [FL-IFX] or conventional [CONV] induction therapy associate with disease remission at week 52.

Methods: Pre- [n = 86], and 10-14-week post-treatment [n = 84] sera were collected from patients with moderate-to-severe paediatric CD in the TISKids trial, randomized to FL-IFX [n = 48; five 5-mg/kg infusions over 22 weeks] or CONV [n = 43; exclusive enteral nutrition or oral prednisolone]; both groups received azathioprine maintenance.

Endogenous secretory leukocyte protease inhibitor inhibits microbial-induced monocyte activation.

In the intestine, epithelial factors condition incoming immune cells including monocytes to adapt their threshold of activation and prevent undesired inflammation. Colonic epithelial cells express Secretory Leukocyte Protease Inhibitor (SLPI), an inhibitor of NF kappa light chain enhancer of activated B cells (NF-κB) that mediates epithelial hyporesponsiveness to microbial stimuli. Uptake of extracellular SLPI by monocytes has been proposed to inhibit monocyte activation.

Serum amyloid P component (SAP) modulates antidepressant effects through promoting membrane insertion of the serotonin transporter.

Serum amyloid P component (SAP) is a universal constituent of human amyloid deposits including those in Alzheimer's disease. SAP has been observed to be elevated in patients with depression, and higher SAP levels are associated with better response to the antidepressant escitalopram. The mechanisms underlying these clinical observations remain unclear.

Proteomic analyses do not reveal subclinical inflammation in fatigued patients with clinically quiescent inflammatory bowel disease.

Fatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD), occurring in ~ 50% of patients with quiescent disease. In this study, we aimed to investigate whether fatigue in patients with clinically quiescent IBD is reflected by circulating inflammatory proteins, which might reflect ongoing subclinical inflammation. Ninety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with clinically quiescent IBD.

High expression of secretory leukocyte protease inhibitor (SLPI) in stage III micro-satellite stable colorectal cancer is associated with reduced disease recurrence.

Secretory leukocyte protease inhibitor (SLPI) is a pleiotropic protein produced by healthy intestinal epithelial cells. SLPI regulates NF-κB activation, inhibits neutrophil proteases and has broad antimicrobial activity. Recently, increased SLPI expression was found in various types of carcinomas and was suggested to increase their metastatic potential.

The GR-FKBP51 interaction modulates fear memory but not spatial or recognition memory.

The glucocorticoid receptor (GR) forms a protein complex with FKBP51 that is increased in post-traumatic stress disorder (PTSD) and by fear conditioned learning. Disrupting the GR-FKBP51 complex with a synthetic peptide can block the storage or retrieval of fear conditioned memories, which could be a novel approach to the alleviate fear associated memory in PTSD. However, a potential unacceptable side effect could be the impairment of other types of memory.

Long-Term Dietary Patterns Are Reflected in the Plasma Inflammatory Proteome of Patients with Inflammatory Bowel Disease.

Diet plays an important role in the development and progression of inflammatory bowel disease (IBD, comprising Crohn’s disease (CD) and ulcerative colitis (UC)). However, little is known about the extent to which different diets reflect inflammation in IBD beyond measures such as faecal calprotectin or C-reactive protein. In this study, we aimed to unravel associations between dietary patterns and circulating inflammatory proteins in patients with IBD.

The D2R-DISC1 protein complex and associated proteins are altered in schizophrenia and normalized with antipsychotic treatment.

Background: For decades, the dopamine D2 receptor (D2R) has been known as the main target of antipsychotic medications, but the mechanism for antipsychotic effects beyond this pharmacological target remains unclear. Disrupted-in-schizophrenia 1 () is a gene implicated in the etiology of schizophrenia, and we have found elevated levels of the D2R-DISC1 complex in the postmortem brain tissue of patients with schizophrenia.

Methods: We used coimmunoprecipitation to measure D2R-DISC1 complex levels in peripheral blood samples from patients with schizophrenia and unaffected controls in 3 cohorts (including males and females) from different hospitals.

The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease.

Background And Aims: Protein profiling in patients with inflammatory bowel diseases [IBD] for diagnostic and therapeutic purposes is underexplored. This study analysed the association between phenotype, genotype, and the plasma proteome in IBD.

Methods: A total of 92 inflammation-related proteins were quantified in plasma of 1028 patients with IBD (567 Crohn's disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess protein-phenotype associations.

Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease.

FOXP3 regulatory T cells (Treg cells) are a specialized population of CD4 T cells that restrict immune activation and are essential to prevent systemic autoimmunity. In the intestine, the major function of Treg cells is to regulate inflammation as shown by a wide array of mechanistic studies in mice. While Treg cells originating from the thymus can home to the intestine, the majority of Treg cells residing in the intestine are induced from FOXP3 conventional CD4 T cells to elicit tolerogenic responses to microbiota and food antigens.

Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis.

Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy.

Secretory Leukocyte Protease Inhibitor (SLPI) in mucosal tissues: Protects against inflammation, but promotes cancer.

The immune system is continuously challenged with large quantities of exogenous antigens at the barriers between the external environment and internal human tissues. Antimicrobial activity is essential at these sites, though the immune responses must be tightly regulated to prevent tissue destruction by inflammation. Secretory Leukocyte Protease Inhibitor (SLPI) is an evolutionarily conserved, pleiotropic protein expressed at mucosal surfaces, mainly by epithelial cells.