The best-laid plans go oft awry: synaptogenic growth factor signaling in neuropsychiatric disease

Growth factors play important roles in synapse formation. Mouse models of neuropsychiatric diseases suggest that defects in synaptogenic growth factors, their receptors, and signaling pathways can lead to disordered neural development and various behavioral phenotypes, including anxiety, memory problems, and social deficits. Genetic association studies in humans have found evidence for similar relationships between growth factor signaling pathways and neuropsychiatric phenotypes. Accumulating data suggest that dysfunction in neuronal circuitry, caused by defects in growth factor-mediated synapse formation, contributes to the susceptibility to multiple neuropsychiatric diseases, including epilepsy, autism, and disorders of thought and mood (e.g., schizophrenia and bipolar disorder, respectively). In this review, we will focus on how specific synaptogenic growth factors and their downstream signaling pathways might be involved in the development of neuropsychiatric diseases

Permeability and mineralogy of the Újfalu Formation, Hungary, from production tests and experimental rock characterization: implications for geothermal heat projects

Hundreds of geothermal wells have been drilled in Hungary to exploit Pannonian Basin sandstones for district heating, agriculture, and industrial heating projects. Most of these sites suffer from reinjection issues, limiting efficient use of this vast geothermal resource and imposing significant extra costs for the required frequent workovers and maintenance. To better understand the cause of this issue requires details of reservoir rock porosity, permeability, and mineralogy. However, publicly available data for the properties of reservoir rocks at geothermal project sites in Hungary is typically very limited, because these projects often omit or limit data acquisition. Many hydrocarbon wells in the same rocks are more extensively documented, but their core, log, or production data are typically decades old and unavailable in the public domain. Furthermore, because many Pannonian sandstone formations are poorly consolidated, coring was always limited and the collected core often unsuitable for conventional analysis, only small remnant fragments typically being available from legacy hydrocarbon wells. This study aims to reduce this data gap and to showcase methods to derive reservoir properties without using core for flow experiments. The methods are thin-section analysis, XRD analysis and mercury intrusion porosimetry, and X-CT scanning followed by numerical flow simulation. We validate our results using permeability data from conventional production testing, demonstrating the effectiveness of our method for detailed reservoir characterization and to better constrain the lateral variation in reservoir properties across the Pannonian Basin. By eliminating the need for expensive bespoke coring to obtain reservoir properties, such analysis will contribute to reducing the capital cost of developing geothermal energy projects, thus facilitating decarbonization of global energy supply

Association Between the Epigenetic Lifespan Predictor GrimAge and History of Suicide Attempt in Bipolar Disorder

Bipolar disorder (BD) has been previously associated with premature mortality and aging, including acceleration of epigenetic aging. Suicide attempts (SA) are greatly elevated in BD and are associated with decreased lifespan, biological aging, and poorer clinical outcomes. We investigated the relationship between GrimAge, an epigenetic clock trained on time-to-death and associated with mortality and lifespan, and SA in two independent cohorts of BD individuals (discovery cohort - controls (n = 50), BD individuals with (n = 77, BD/SA) and without (n = 67, BD/non-SA) lifetime history of SA; replication cohort - BD/SA (n = 48) and BD/non-SA (n = 47)). An acceleration index for the GrimAge clock (GrimAgeAccel) was computed from blood DNA methylation (DNAm) and compared between groups with multiple general linear models. Differences in epigenetic aging from the discovery cohort were validated in the independent replication cohort. In the discovery cohort, controls, BD/non-SA, and BD/SA significantly differed on GrimAgeAccel (F = 5.424, p = 0.005), with the highest GrimAgeAccel in BD/SA (p = 0.004, BD/SA vs. controls). Within the BD individuals, BD/non-SA and BD/SA differed on GrimAgeAccel in both cohorts (p = 0.008) after covariate adjustment. Finally, DNAm-based surrogates revealed possible involvement of plasminogen activator inhibitor 1, leptin, and smoking pack-years in driving accelerated epigenetic aging. These findings pair with existing evidence that not only BD, but also SA, may be associated with an accelerated biological aging and provide putative biological mechanisms for morbidity and premature mortality in this population

Blood Epigenome-Wide Association Studies of Suicide Attempt in Adults With Bipolar Disorder

Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at \u3e700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold changes at the discovery cohort\u27s significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical classifier in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD

Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial

Purpose Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs . Methods We tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) . Results Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N = 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N = 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N = 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (− 1, 21) vs 10 (− 1, to 21) in subphenotype-2; 1.5 (− 1, 21) vs 12 (− 1, to 21) in suphenotype-3, and 0 (− 1, 21) vs 0 (− 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects p = 0.008). Conclusions We reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Characterising the Upper Devonian sandstones as a low-enthalpy sedimentary aquifer within the Clackmannan Syncline

Abstract not currently available

Mind the gap: how Canada's attempt to bridge the democracy gap in Egypt will endanger its interests in the Middle East

Bibliography: p. 113-120Some pages are in colour

IP3 receptors and associated Ca2+ signals localize to satellite cells and to components of the neuromuscular junction in skeletal muscle.

IP3 receptors and associated Ca2+ signals localize to satellite cells and to components of the neuromuscular junction in skeletal muscle. (Powell, Jeanne A., Molgó, Jordi, Adams, Dany S., Colasante, Cesare, Williams, Aislinn, Bohlen, MacKenzie and Jaimovich, Enrique.) This paper was published on The Journal of Neuroscience, August 27, 2003This paper is dedicated to Jeanne A. Powell, to honor her [email protected] monográfic

IP3 receptors and associated Ca2+ signals localize to satellite cells and to components of the neuromuscular junction in skeletal muscle.

Recently, we described an inositol 1,4,5-trisphosphate (IP3) signaling system in cultured rodent skeletal muscle, triggered by high K+ and affecting gene transcription (Powell et al., 2001). Now, in a study of adult rodent skeletal muscle, using immunocytology and confocal microscopy, we have found a high level of IP3 receptor (IP3R) staining in satellite cells, which have been shown recently to contribute to nuclei in adult fibers after muscle exercise. These IP3R staining cells are positively identified as satellite cells by their position, morphology and staining with satellite-cell-specific antibodies such as desmin and neural cell adhesion molecule. IP3Rs are also localized to postsynaptic components of the neuromuscular junction (NMJ), in areas surrounding the nuclei of the motor end plate, and in perisynaptic Schwann cells, and localized close to nicotinic acetylcholine receptors of the endplate gutters. Ca2+ imaging experiments show calcium release at the motor endplate upon K+ depolarization precisely in these IP3R-rich regions. We suggest that electrical activity stimulates IP3-associated Ca2+ signals that may be involved in gene regulation in satellite cells and in elements of the NMJ, contributing both to muscle fiber growth and stabilization of the NMJ