Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Electrophysiological evidence for the effect of interactive imagery on episodic memory : encouraging familiarity for non-unitized stimuli during associative recognition

Episodic memory depends upon multiple processes, including familiarity and recollection. Although associative recognition tasks are traditionally viewed as requiring recollection, recent research suggests a role for familiarity if to-be-remembered stimuli are perceived as unitized. Here we use event-related potentials (ERPs) to examine the relationship between stimulus properties and encoding strategy on the engagement of familiarity during associative recognition. Participants studied word pairs containing an association (e.g. traffic-jam) or an unassociated semantic relationship (e.g. violin-guitar), using either item or interactive imagery. At test, participants were required to recognize if word pairs were presented in the same pairing as study, were rearranged, or new. We hypothesized that adopting a strategy of interactive imagery during encoding (i.e. encouraging unitization) would enhance familiarity for unassociated word pairs but would have no effect on association pairs because they are already perceived as unitized. As expected, overall recognition performance was better for word pairs encoded with interactive imagery, and for association than semantic word pairs. ERPs recorded at test revealed an interaction between encoding strategy and stimulus properties. Association word pairs elicited similar bilateral frontal (familiarity) and left parietal (recollection) old/new effects following item and interactive imagery. By contrast, for semantic word pairs, the left parietal effect was equivalent across conditions, but the bilateral frontal effect was enhanced for the interactive imagery condition. The ERP results suggest that an encoding strategy of interactive imagery can enhance familiarity during associative recognition, but this effect is ultimately dependent on the properties of the stimuli to-be-remembered and the nature of the representations that underlie them

Dissociating state and item components of recognition memory using fMRI

Cognitive functions such as memory retrieval involve a combination of state- and item-related processes. State-related processes are sustained throughout a task (e.g., "retrieval mode" associated with ongoing goals), whereas item-related processes are transient and allied to individual stimuli (e.g., "retrieval success" associated with the recovery of information from memory). The present study employed a mixed "blocked and event-related" experimental design to identify neural mechanisms that support state- and item-related processes during a recognition memory task. Subjects alternated between blocks of fixation and recognition memory (discriminating between old and new words). Critically, event-related procedures were embedded within the recognition blocks, including the jittering of sequential trials. This design ensures that the temporal profiles of state- and item-related activity differ and consequently renders them separable; without this procedure item-related activity would summate to produce a state-like response. Results suggest three classes of brain region support recognition memory, exhibiting: (1) predominantly transient activity (including regions in medial parietal, lateral parietal, and anterior left frontal cortex) reflecting item-related processing associated with "retrieval success," (2) predominantly sustained activity (including decreased activity in bilateral parahippocampal cortex) reflecting state-related processing associated with "retrieval mode," (3) concurrent sustained and transient activity (including regions in left middle frontal gyrus, bilateral frontal operculum, and medial frontal gyrus), reflecting a combination of state- and item-related processing. The present findings support the idea that recognition memory tasks are dependent upon a combination of state- and item-related processes that have dissociable neural correlates identifiable using fMRI. Moreover, the mixed "blocked and event-related" design employed here provides a general procedure for separating state- and item-related processes

Relationship between transmembrane ion movements, production of reactive oxygen species and the hypersensitive response during the challenge of tobacco suspension cells by zoospores of Phytophthora nicotianae

Copyright © 2001 Academic Press. All rights reserved.We have examined the responses of suspension cultured tobacco cells after inoculation with zoospores from compatible or incompatible faces of the Oomycete pathogen Phytophthora nicotianae. The incompatible interaction, characterized by the production of reactive oxygen species (ROS) (specifically superoxide (HO2/O2-) and hydrogen peroxide (H2O2)), and by a hypersensitive response (HR), was not dependent upon the presence of exogenous calcium. However, perturbation of calcium ion movements by EGTA or LaCl3 suppressed both ROS production and the extent of cell death. The Ca2+-specific ionophore, A23187, slightly enhanced ROS production during the incompatible interaction but had no effect on the responses of susceptible or unchallenged cells. These results confirm that both ROS production and the HR are potentiated by movement of endogenous calcium across the plasmalemma. While there was no evidence of a transmembrane K+/H+ exchange immediately following incompatible zoospore challenge, a later potassium efflux from cells coincided with the onset of the HR. Unexpectedly, medium pH drifted downwards during all host cell responses suggesting that alkaline peroxidases are not the major source of ROS generation during an incompatible tobacco cell/zoospore interaction. © 2001 Academic Press.A. J. Able, D. I. Guest and M. W. Sutherlandhttp://www.elsevier.com/wps/find/journaldescription.cws_home/622932/description#descriptio

Factors of Employees’ Effective Voice in Corporate Goverance*

Traditionally, corporate governance has focused on the problem of crafting mechanisms to align the interests of owners and managers. The key characteristic has been to minimize the potential for managers to act in their own self-interest at the expense of shareholders. The purpose of this paper is to focus on employees as stakeholders in the governance process. We argue that creating an environment where employees have help in behaving ethically, in the course of their work, is the first step in encouraging them to voice observations of wrongdoing. Seven groups of professionals in the accounting and insurance fields were surveyed during a 10-year period and asked to indicate the extent to which 14 items were helpful in dealing with ethical challenges. Over 2700 responses were analyzed. The findings indicate that professionals think that their organizational culture and policy for voice was more helpful in dealing with ethical dilemmas than was their professional association. Copyright Springer 2005boards of directors, corporate governance, ethics, employee voice, stakeholders,

Optimization of Blocked Designs in fMRI Studies

blocked design, fMRI, optimal design, efficiency, maximin,