Variants in Miro1 cause alterations of ER-mitochondria contact sites in fibroblasts from Parkinson's disease patients

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD‐associated proteins are involved in mitochondrial quality control, e.g., PINK1, Parkin, and LRRK2, which were recently identified as regulators of mitochondrial‐endoplasmic reticulum (ER) contact sites (MERCs) linking mitochondrial homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly recognized to play a role in PD pathology. Recently, we identified the first PD patients carrying mutations in RHOT1, the gene coding for Miro1. Here, we describe two novel RHOT1 mutations identified in two PD patients and the characterization of the cellular phenotypes. Methods: Using whole exome sequencing we identified two PD patients carrying heterozygous mutations leading to the amino acid exchanges T351A and T610A in Miro1. We analyzed calcium homeostasis and MERCs in detail by live cell imaging and immunocytochemistry in patient‐derived fibroblasts. Results: We show that fibroblasts expressing mutant T351A or T610A Miro1 display impaired calcium homeostasis and a reduced amount of MERCs. All fibroblast lines from patients with pathogenic variants in Miro1, revealed alterations of the structure of MERCs. Conclusion: Our data suggest that Miro1 is important for the regulation of the structure and function of MERCs. Moreover, our study supports the role of MERCs in the pathogenesis of PD and further establishes variants in RHOT1 as rare genetic risk factors for neurodegeneration

Cognitive processes behind the shooter bias: Dissecting response bias, motor preparation and information accumulation

A rich body of research points to racial biases in so-called police officer dilemma tasks: participants are generally faster and less error-prone to “shoot” (vs. not “shoot”) Black (vs. White) targets. In three experimental (and two supplemental) studies (total N = 914), we aimed at examining the cognitive processes underlying these findings under fully standardized conditions. To be able to dissect a-priori decision bias, biased information processing and motor preparation, we rendered video sequences of virtual avatars that differed in nothing but the tone of their skin. Modeling the data via drift diffusion models revealed that the threat of a social group can be explicitly learned and mapped accordingly on an a-priori response bias within the model (Study 1). Studies 2 and 3 replicated the racial shooter bias as apparent in faster reaction times in stereotype-consistent trials. This, however, appears to result from stereotype-consistent motoric preparations and execution readiness, but not from pre-judicial threat biases. The results have implications especially for automatic stereotypes in the public

Cognitive processes behind the shooter bias: Dissecting response bias, motor preparation and information accumulation

A rich body of research points to racial biases in so-called police officer dilemma tasks: participants are generally faster and less error-prone to “shoot” (vs. not “shoot”) Black (vs. White) targets. In three experimental (and two supplemental) studies (total N = 914), we aimed at examining the cognitive processes underlying these findings under fully standardized conditions. To be able to dissect a-priori decision bias, biased information processing and motor preparation, we rendered video sequences of virtual avatars that differed in nothing but the tone of their skin. Modeling the data via drift diffusion models revealed that the threat of a social group can be explicitly learned and mapped accordingly on an a-priori response bias within the model (Study 1). Studies 2 and 3 replicated the racial shooter bias as apparent in faster reaction times in stereotype-consistent trials. This, however, appears to result from stereotype-consistent motoric preparations and execution readiness, but not from pre-judicial threat biases. The results have implications especially for automatic stereotypes in the public

"Anglo-Saxon and Related Entries in the Oxford Dictionary of National Biography (2004)"

International audienc

Use of Immune Profiling Panel to assess the immune response of septic patients for prediction of worsening as a composite endpoint

Abstract Sepsis induces intense, dynamic and heterogeneous host response modulations. Despite improvement of patient management, the risk of mortality and healthcare-associated infections remains high. Treatments to counterbalance immune response are under evaluation, but effective biomarkers are still lacking to perform patient stratification. The design of the present study was defined to alleviate the limitations of existing literature: we selected patients who survived the initial hyperinflammatory response and are still hospitalized at day 5–7 after ICU admission. Using the Immune Profiling Panel (IPP), a fully automated RT-qPCR multiplex prototype, we optimized a machine learning model combining the IPP gene expression levels for the identification of patients at high risk of worsening, a composite endpoint defined as death or secondary infection, within one week after sampling. This was done on 332 sepsis patients selected from two retrospective studies. The IPP model identified a high-risk group comprising 30% of patients, with a significant increased proportion of worsening events at day 28 compared to the low-risk group (49% vs. 28%, respectively). These preliminary results underline the potential clinical application of IPP for sepsis patient stratification in a personalized medicine perspective, that will be confirmed in a larger prospective multicenter study

Anglo-Saxon and related entries in the Oxford Dictionary of National Biography (2004)

The Oxford Dictionary of National Biography (ODNB), originally designated the New Dictionary of National Biography, was published in 2004 as a successor to the renowned Dictionary of National Biography (DNB), edited by Sir Leslie Stephen (1832–1904) and itself published in sixty-three volumes between 1885 and 1900, with supplements. All of the subjects in the old DNB were retained for the ODNB; new entries were commissioned for a significant proportion of the existing subjects (including almost all of those falling within the early medieval period); and of course the opportunity was taken to add entries for a large number of new subjects. In its print version, the ODNB occupies sixty volumes, though it is unlikely to be found in that form outside reference libraries; most importantly, it is also available online, to subscribing institutions, with search facilities and other useful features. Like its most distinguished predecessor, the ODNB is already well established as an invaluable academic resource

Bardet-Biedl syndrome highlights the major role of the primary cilium in efficient water reabsorption

Studies of the primary cilium, now known to be present in all cells, have undergone a revolution, in part, because mutation of many of its proteins causes a large number of diseases, including cystic kidney disease. Bardet–Biedl syndrome (BBS) is an inherited ciliopathy characterized, among other dysfunctions, by renal defects for which the precise role of the cilia in kidney function remains unclear. We studied a cohort of patients with BBS where we found that these patients had a urinary concentration defect even when kidney function was near normal and in the absence of major cyst formation. Subsequent in vitro analysis showed that renal cells in which a BBS gene was knocked down were unciliated, but did not exhibit cell cycle defects. As the vasopressin receptor 2 is located in the primary cilium, we studied BBS-derived unciliated renal epithelial cells and found that they were unable to respond to luminal arginine vasopressin treatment and activate their luminal aquaporin 2. The ability to reabsorb water was restored by treating these unciliated renal epithelial cells with forskolin, a receptor-independent adenylate cyclase activator, showing that the intracellular machinery for water absorption was present but not activated. These findings suggest that the luminal receptor located on the primary cilium may be important for efficient transepithelial water absorption

A 9-mRNA signature measured from whole blood by a prototype PCR panel predicts 28-day mortality upon admission of critically ill COVID-19 patients

International audienceImmune responses affiliated with COVID-19 severity have been characterized and associated with deleterious outcomes. These approaches were mainly based on research tools not usable in routine clinical practice at the bedside. We observed that a multiplex transcriptomic panel prototype termed Immune Profiling Panel (IPP) could capture the dysregulation of immune responses of ICU COVID-19 patients at admission. Nine transcripts were associated with mortality in univariate analysis and this 9-mRNA signature remained significantly associated with mortality in a multivariate analysis that included age, SOFA and Charlson scores. Using a machine learning model with these 9 mRNA, we could predict the 28-day survival status with an Area Under the Receiver Operating Curve (AUROC) of 0.764. Interestingly, adding patients’ age to the model resulted in increased performance to predict the 28-day mortality (AUROC reaching 0.839). This prototype IPP demonstrated that such a tool, upon clinical/analytical validation and clearance by regulatory agencies could be used in clinical routine settings to quickly identify patients with higher risk of death requiring thus early aggressive intensive care