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The inositol 1,4,5-triphosphate receptor-associated 2 (IRAG2) is also known as Jaw1 or lymphoid-restricted membrane protein (LRMP) and shares homology with the inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate 1 (IRAG1). IRAG1 interacts with inositol trisphosphate receptors (IP3 receptors /IP3R) via its coiled-coil domain and modulates Ca2+ release from intracellular stores. Due to the homology of IRAG1 and IRAG2, especially in its coiled-coil domain, it is possible that IRAG2 has similar interaction partners like IRAG1 and that IRAG2 also modulates intracellular Ca2+ signaling. In our study, we localized IRAG2 in pancreatic acinar cells of the exocrine pancreas, and we investigated the interaction of IRAG2 with IP3 receptors and its impact on intracellular Ca2+ signaling and exocrine pancreatic function, like amylase secretion. We detected the interaction of IRAG2 with different subtypes of IP3R and altered Ca2+ release in pancreatic acinar cells from mice lacking IRAG2. IRAG2 deficiency decreased basal levels of intracellular Ca2+, suggesting that IRAG2 leads to activation of IP3R under unstimulated basal conditions. Moreover, we observed that loss of IRAG2 impacts the secretion of amylase. Our data, therefore, suggest that IRAG2 modulates intracellular Ca2+ signaling, which regulates exocrine pancreatic function.

PKGs are serine/threonine kinases. PKG1 has two isoforms—PKG1α and β. Inositol trisphosphate receptor (IP3R)-associated cGMP-kinase substrate 1 (IRAG1) is a substrate for PKG1β. IRAG1 is also known to further interact with IP3RI, which mediates intracellular Ca2+ release. However, the role of IRAG1 in PH is not known. Herein, WT and IRAG1 KO mice were kept under normoxic or hypoxic (10% O2) conditions for five weeks. Animals were evaluated for echocardiographic variables and went through right heart catheterization. Animals were further sacrificed to prepare lungs and right ventricular (RV) for immunostaining, western blotting, and pulmonary artery smooth muscle cell (PASMC) isolation. IRAG1 is expressed in PASMCs and downregulated under hypoxic conditions. Genetic deletion of IRAG1 leads to RV hypertrophy, increase in RV systolic pressure, and RV dysfunction in mice. Absence of IRAG1 in lung and RV have direct impacts on PKG1β expression. Attenuated PKG1β expression in IRAG1 KO mice further dysregulates other downstream candidates of PKG1β in RV. IRAG1 KO mice develop PH spontaneously. Our results indicate that PKG1β signaling via IRAG1 is essential for the homeostasis of PASMCs and RV. Disturbing this signaling complex by deleting IRAG1 can lead to RV dysfunction and development of PH in mice.

Background The main challenge in the study of schizophrenia is its high heterogeneity. While it is generally accepted that there exist several biological mechanisms that may define distinct schizophrenia subtypes, they have not been identified yet. We performed comprehensive gene expression analysis to search for molecular signals that differentiate schizophrenia patients from healthy controls and examined whether an identified signal was concentrated in a subgroup of the patients. Methods Transcriptome sequencing of 14 superior temporal gyrus (STG) samples of subjects with schizophrenia and 15 matched controls from the Stanley Medical Research Institute (SMRI) was performed. Differential expression and pathway enrichment analysis results were compared to an independent cohort. Replicability was tested on 6 additional independent datasets. Results The 2 STG cohorts showed high replicability. Pathway enrichment analysis of the down-regulated genes pointed to proteasome-related pathways. Meta-analysis of differential expression identified down-regulation of 12 of 39 proteasome subunit genes in schizophrenia. The signal of proteasome subunits down-regulation was replicated in 6 additional datasets (overall 8 cohorts with 267 schizophrenia and 266 control samples, from 5 brain regions). The signal was concentrated in a subgroup of patients with schizophrenia. Conclusions We detected global down-regulation of proteasome subunits in a subgroup of patients with schizophrenia. We hypothesize that the down-regulation of proteasome subunits leads to proteasome dysfunction that causes accumulation of ubiquitinated proteins, which has been recently detected in a subgroup of schizophrenia patients. Thus, down-regulation of proteasome subunits might define a biological subtype of schizophrenia.

Inositol 1,4,5triphosphate receptorassociated cGMP kinase substrate 1 (IRAG1) is a substrate protein of the NO/cGMP-signaling pathway and forms a ternary complex with the cGMPdependent protein kinase Iβ (PKGIβ) and the inositol triphosphate receptor I (IP3RI). Functional studies about IRAG1 exhibited that IRAG1 is specifically phosphorylated by the PKGIβ, regulating cGMPmediated IP3dependent Ca2+release. IRAG1 is widely distributed in murine tissues, e.g., in large amounts in smooth muscle-containing tissues and platelets, but also in lower amounts, e.g., in the spleen. The NO/cGMP/PKGI signaling pathway is important in several organ systems. A loss of PKGI causes gastrointestinal disorders, anemia and splenomegaly. Due to the similar tissue distribution of the PKGIβ to IRAG1, we investigated the pathophysiological functions of IRAG1 in this context. Global IRAG1KO mice developed gastrointestinal bleeding, anemiaassociated splenomegaly and iron deficiency. Additionally, Irag1deficiency altered the protein levels of some cGMP/PKGI signaling proteins—particularly a strong decrease in the PKGIβ—in the colon, spleen and stomach but did not change mRNAexpression of the corresponding genes. The present work showed that a loss of IRAG1 and the PKGIβ/IRAG1 signaling has a crucial function in the development of gastrointestinal disorders and anemia-associated splenomegaly. Furthermore, global Irag1deficient mice are possible in vivo model to investigate PKGIβ protein functions.

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A rterial spin labeling (ASL) is one of the most recent magnetic resonance imaging (MRI) sequences used to assess brain perfusion noninvasively. It can be used in the acute phase of ischemic stroke (IS) to identify ischemic penumbra. 1 In patients in acute phase of IS, thrombus assessment is of major clinical relevance because the presence and location of the thrombus may determine therapeutic strategy. 2 An arterial bright signal (ABS), at the level of vascular occlusions, can be observed on raw data of ASL sequence performed for stroke.The aim of this study is to evaluate the relevance of this MRI sign in patients admitted for IS. Patients and MethodsWith the approval of the local ethics committee, we retrospectively analyzed MRI sequences of patients with an IS suspicion admitted in the Department of Neuroradiology (University Hospital of Martinique) from December 2011 to August 2014. MRI (GE Optima MR450W 1.5 T) was performed within 6 hours from stroke onset and included diffusion weighted imaging sequence, echo planar imaging T2* (EPI T2*), fluid attenuated inversion recovery (FLAIR) and MR angiography (Willis time of flight (TOF)). ASL sequence was performed only in case of doubtful diffusion weighted imaging or to highlight a mismatch before a thrombolytic treatment.ASL scans were performed using a pseudocontinuous mode with a repetition time of 4554 ms, an echo time of 10 ms, a postlabeling delay of 1525 ms, and a total acquisition time of 4 minutes.Main judgment criteria were the assessment and the concordance of ABS compared with other sequences (TOF, EPI T2*, and FLAIR).Moreover, a vessel occlusion was diagnosed if an artery was missing on Willis TOF. An intra-arterial clot could be diagnosed on T2* (as a focal hyposignal) and on FLAIR sequences (as a focal hypersignal). ABS was diagnosed according to 2 different patterns upstream of a hypoperfused territory: spot-like (rounded or oval, with sharp edges, on a vascular path) or vessel-like (linear hypersignal on an artery path).One neuroradiologist (AA), with 11 years of experience, first analyzed ASL data while being blinded to clinical data and other sequences. After this first analysis, ABS was definitely graded as 0 if absent or 1 if present and its grading remained unmodified thereon. Other MRI sequence findings (diffusion weighted imaging, occlusion on Willis TOF, clot on T2*, clot on FLAIR) were also studied and graded in a similar manner.A radiology resident, with a 6-month experience in neuroradiology, independently repeated the whole data analysis process in the same conditions.A stroke was considered ongoing in case of the detection of an area of restricted diffusion, identified while being blinded to ASL results.The absence of stroke diagnosis was made if no restricted diffusion area was observed, while still blinded to ASL results. This was further corroborated by clinical data and computed tomography or MRI follow-up for 1 week after patient admission for IS suspicion. Statistical AnalysisInterobserver variability for ABS was assessed usi...

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