PTPN22 Silencing in the NOD Model Indicates the Type 1 Diabetes–Associated Allele Is Not a Loss-of-Function Variant

PTPN22 encodes the lymphoid tyrosine phosphatase (LYP) and is the second strongest non-HLA genetic risk factor for type 1 diabetes. The PTPN22 susceptibility allele generates an LYP variant with an arginine-to-tryptophan substitution at position 620 (R620W) that has been reported by several studies to impart a gain of function. However, a recent report investigating both human cells and a knockin mouse model containing the R620W homolog suggested that this variation causes faster protein degradation. Whether LYP R620W is a gain- or loss-of-function variant, therefore, remains controversial. To address this issue, we generated transgenic NOD mice (nonobese diabetic) in which Ptpn22 can be inducibly silenced by RNA interference. We found that Ptpn22 silencing in the NOD model replicated many of the phenotypes observed in C57BL/6 Ptpn22 knockout mice, including an increase in regulatory T cells. Notably, loss of Ptpn22 led to phenotypic changes in B cells opposite to those reported for the human susceptibility allele. Furthermore, Ptpn22 knockdown did not increase the risk of autoimmune diabetes but, rather, conferred protection from disease. Overall, to our knowledge, this is the first functional study of Ptpn22 within a model of type 1 diabetes, and the data do not support a loss of function for the PTPN22 disease variant

T Cell Costimulation through CD28 Depends on Induction of the Bcl-xγ Isoform: Analysis of Bcl-xγ–deficient Mice

The molecular basis of CD28-dependent costimulation of T cells is poorly understood. Bcl-xγ is a member of the Bcl-x family whose expression is restricted to activated T cells and requires CD28-dependent ligation for full expression. We report that Bcl-xγ–deficient (Bcl-xγ−/−) T cells display defective proliferative and cytokine responses to CD28-dependent costimulatory signals, impaired memory responses to proteolipid protein peptide (PLP), and do not develop PLP-induced experimental autoimmune encephalomyelitis (EAE). In contrast, enforced expression of Bcl-xγ largely replaces the requirement for B7-dependent ligation of CD28. These findings identify the Bcl-xγ cytosolic protein as an essential downstream link in the CD28-dependent signaling pathway that underlies T cell costimulation

Collective cancer invasion forms an integrin-dependent radioresistant niche

Cancer fatalities result from metastatic dissemination and therapy resistance, both processes that depend on signals from the tumor microenvironment. To identify how invasion and resistance programs cooperate, we used intravital microscopy of orthotopic sarcoma and melanoma xenografts. We demonstrate that these tumors invade collectively and that, specifically, cells within the invasion zone acquire increased resistance to radiotherapy, rapidly normalize DNA damage, and preferentially survive. Using a candidate-based approach to identify effectors of invasion-associated resistance, we targeted beta 1 and alpha V beta 3/beta 5 integrins, essential extracellular matrix receptors in mesenchymal tumors, which mediate cancer progression and resistance. Combining radiotherapy with beta 1 or alpha V integrin monotargeting in invading tumors led to relapse and metastasis in 40-60% of the cohort, in line with recently failed clinical trials individually targeting integrins. However, when combined, anti-beta 1/alpha V integrin dual targeting achieved relapse-free radiosensitization and prevented metastatic escape. Collectively, invading cancer cells thus withstand radiotherapy and DNA damage by beta 1/alpha V beta 3/beta 5 integrin cross-talk, but efficient radiosensitization can be achieved by multiple integrin targeting

Gamma Oscillation in Schizophrenia

Dysfunctional neural circuitry has been found to be involved in abnormalities of perception and cognition in patients with schizophrenia. Gamma oscillations are essential for integrating information within neural circuits and have therefore been associated with many perceptual and cognitive processes in healthy human subjects and animals. This review presents an overview of the neural basis of gamma oscillations and the abnormalities in the GABAergic interneuronal system thought to be responsible for gamma-range deficits in schizophrenia. We also review studies of gamma activity in sensory and cognitive processes, including auditory steady state response, attention, object representation, and working memory, in animals, healthy humans and patients with schizophrenia

The autoimmunity-associated gene RGS1 affects the frequency of T follicular helper cells

RGS1 (regulator of G-protein signaling 1) has been associated with multiple autoimmune disorders including type 1 diabetes. RGS1 desensitizes the chemokine receptors CCR7 and CXCR4 that are critical to the localization of T and B cells in lymphoid organs. To explore how RGS1 variation contributes to autoimmunity, we generated Rgs1 knockdown (KD) mice in the nonobese diabetic (NOD) model for type 1 diabetes. We found that Rgs1 KD increased the size of germinal centers, but decreased the frequency of T follicular helper (TFH) cells. We show that loss of Rgs1 in T cells had both a T cell-intrinsic effect on migration and TFH cell frequency, and an indirect effect on B cell migration and germinal center formation. Notably, several recent publications described an increase in circulating TFH cells in patients with type 1 diabetes, suggesting this cell population is involved in pathogenesis. Though Rgs1 KD was insufficient to alter diabetes frequency in the NOD model, our findings raise the possibility that RGS1 plays a role in autoimmunity owing to its function in TFH cells. This mechanistic link, while speculative at this time, would lend support to the notion that TFH cells are key participants in autoimmunity and could explain RGS1’s association with several immune-mediated diseases

Source Distribution of Neuromagnetic Slow Waves and MEG-Delta Activity in Schizophrenic Patients

Background: Schizophrenic patients exhibit more activityin the electroencephalographic delta and theta frequencyrange than do control subjects. Using magnetic sourceimaging (MSI) our study aimed to explore this phenomenonin the magnetoencephalogram (MEG), the distributionof its sources, and associations between symptomprofiles and sources of low-frequency activity in the brain.Methods: Whole-head MEG recordings were obtainedfrom 28 schizophrenic patients and 20 healthy controlsubjects during a resting condition. The generators of thefocal magnetic slow waves were located employing asingle moving dipole model. Distributed or multiple deltaand theta sources were captured by the minimum normestimate.Results: Both localization procedures showed slow waveactivity to be enhanced in schizophrenic patients comparedwith control subjects. Focal slow wave activitydiffered most between groups in frontotemporal and inposterior regions. Slow wave activity was associated withsymptom characteristics in that positive symptoms variedwith frontal delta and theta activity.Conclusions: Results indicate that activity in low-frequencybands in schizophrenic patients exceeds the activityof control subjects in distinct areas, and that this focalclustering of neuromagnetic slow waves may be related to psychopathologic characteristics

Emotion and attention in face processing: Complementary evidence from surface event-related potentials and intracranial amygdala recordings

Weidner EM, Schindler S, Grewe P, Moratti S, Bien CG, Kissler J. Emotion and attention in face processing: Complementary evidence from surface event-related potentials and intracranial amygdala recordings. Biological Psychology. 2022;173: 108399

Source distribution of neuromagnetic slow-wave activity in schizophrenic patients : effects of activation

When slow waves in the EEG delta and theta frequency range appear in the waking state, they may indicate pathological conditions including psychopathology. The generators of focal slow waves can be mapped using magnetic source imaging. The resulting brain maps may possibly characterize dysfunctional brain areas. The present study examined the stability of the density and distribution of MEG slow waves during three conditions-rest, mental arithmetic and imagery-in 30 schizophrenic patients and 17 healthy controls. Schizophrenic patients displayed a higher density of delta and theta generators primarily in temporal and parietal areas. The group difference was not affected by the particular conditions. The focal concentration of delta and theta slow waves did not differ between patients with and without neuroleptic medication, whereas the prominence of theta dipoles in the temporal area correlated with neuroleptic dosage. The relative amount of temporal slow waves was correlated with the negative symptoms score (PANSS-N) suggesting that temporal dysfunction may be related to negative symptomatology. Results suggest that the distribution of slow-wave activity, measured in a standardized setting, might add diagnostic information about brain abnormalities in schizophrenia