Neuropathological findings in fatal COVID-19 and their associated neurological clinical manifestations

9 p.Severe cases of Coronavirus Disease 2019 (COVID-19) can present with multiple neurological symptoms. The available neuropathological studies have described different lesions; the most frequent was the presence of neuroinflammation and vascular-related lesions. The objective of this study was to report the neuropathological studies performed in a medical institution, with abundant long intensive care unit stays, and their associated clinical manifestations. This is a retrospective monocentric case series study based on the neuropathological reports of 13 autopsies with a wide range of illness duration (13-108 days). A neuroinflammatory score was calculated based on the quantification of CD8- and CD68-positive cells in representative areas of the central nervous system. This score was correlated afterwards with illness duration and parameters related to systemic inflammation. Widespread microglial and cytotoxic T-cell activation was found in all patients. There was no correlation between the neuroinflammatory score and the duration of the illness; nor with parameters of systemic inflammation such as the peak of IL-6 or the HScore (a parameter of systemic macrophage activation syndrome). Two patients had global hypoxic ischaemic damage and five patients had subacute infarcts. One patient had many more brain vascular microthrombi compared to the others and multiple subacute pituitary infarcts. SARS-CoV-2 RNA was not detected with qRT-PCR. The proportion of brain lesions in severe COVID-19 patients could be related to illness duration. In our series, with abundant long hospitalisation stays, neuroinflammation was present in all patients and was more prominent between day 34 and day 45 after onset of symptoms. Clinical correlation showed that two patients with the highest neuroinflammatory scores had severe encephalopathies that were not attributable to any other cause. The second most frequent lesions were related to vascular pathology.Instituto de Salud Carlos IIICIBERONCInstituto Ramón y Cajal de Investigación SanitariaMerck, Sharp & Dohme (MSD

Tranilast increases vasodilator response to acetylcholine in rat mesenteric resistance arteries through increased EDHF participation

Background and Purpose: Tranilast, in addition to its capacity to inhibit mast cell degranulation, has other biological effects, including inhibition of reactive oxygen species, cytokines, leukotrienes and prostaglandin release. In the current study, we analyzed whether tranilast could alter endothelial function in rat mesenteric resistance arteries (MRA). Experimental Approach: Acetylcholine-induced relaxation was analyzed in MRA (untreated and 1-hour tranilast treatment) from 6 month-old Wistar rats. To assess the possible participation of endothelial nitric oxide or prostanoids, acetylcholineinduced relaxation was analyzed in the presence of L-NAME or indomethacin. The participation of endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced response was analyzed by preincubation with TRAM-34 plus apamin or by precontraction with a high K+ solution. Nitric oxide (NO) and superoxide anion levels were measured, as well as vasomotor responses to NO donor DEA-NO and to large conductance calcium-activated potassium channel opener NS1619. Key Results: Acetylcholine-induced relaxation was greater in tranilast-incubated MRA. Acetylcholine-induced vasodilation was decreased by L-NAME in a similar manner in both experimental groups. Indomethacin did not modify vasodilation. Preincubation with a high K+ solution or TRAM-34 plus apamin reduced the vasodilation to ACh more markedly in tranilastincubated segments. NO and superoxide anion production, and vasodilator responses to DEA-NO or NS1619 remained unmodified in the presence of tranilast. Conclusions and Implications: Tranilast increased the endothelium-dependent relaxation to acetylcholine in rat MRA. This effect is independent of the nitric oxide and cyclooxygenase pathways but involves EDHF, and is mediated by an increased role of small conductance calcium-activated K+ channelsThis study was supported by Ministerio de Ciencia e Innovación (SAF 2009-10374), Ministerio de Economía y Competitividad (SAF 2012-38530), and Fundación Mapfre. F.E. Xavier is recipient of research fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil

Ammonite stratigraphy of a Toarcian (Lower Jurassic) section on Nagy-Pisznice Hill (Gerecse Mts, Hungary)

Abstract In the Jurassic rocks exposed in a small abandoned quarry on the northwestern edge of Nagy-Pisznice Hill in the Gerecse Mts, fairly well preserved parts of a crocodile skeleton was found in 1996. The bed which yielded the skeletal remains is the uppermost layer of the Kisgerecse Marl Formation exposed here and was determined as belonging to the Upper Toarcian Grammoceras thouarsense Zone. The beds of the sequence above and below were carefully sampled in the late 1990s, and the encountered ammonites were evaluated biostratigraphically. As a result, the Lower Toarcian Harpoceras serpentinum Zone, the Middle Toarcian Hildoceras bifrons and Merlaites gradatus Zones, and the Upper Toarcian Grammoceras thouarsense and Geczyceras speciosum Zones were identified. Within most of these zones the subzones and even the faunal horizons were successfully recognized. The lowermost beds above the underlying Pliensbachian red limestone did not yield any fossils; thus the lowermost Toarcian Dactylioceras tenuicostatum Zone could not be documented. The highest Toarcian ammonite zones also remained unidentified, because the beds of the Tölgyhát Limestone above were not sampled all the way up. This paper presents the lithostratigraphic and biostratigraphic details of the sequence, and the paleontological descriptions of the most important ammonites

Pep1, a Secreted Effector Protein of Ustilago maydis, Is Required for Successful Invasion of Plant Cells

The basidiomycete Ustilago maydis causes smut disease in maize. Colonization of the host plant is initiated by direct penetration of cuticle and cell wall of maize epidermis cells. The invading hyphae are surrounded by the plant plasma membrane and proliferate within the plant tissue. We identified a novel secreted protein, termed Pep1, that is essential for penetration. Disruption mutants of pep1 are not affected in saprophytic growth and develop normal infection structures. However, Δpep1 mutants arrest during penetration of the epidermal cell and elicit a strong plant defense response. Using Affymetrix maize arrays, we identified 116 plant genes which are differentially regulated in Δpep1 compared to wild type infections. Most of these genes are related to plant defense. By in vivo immunolocalization, live-cell imaging and plasmolysis approaches, we detected Pep1 in the apoplastic space as well as its accumulation at sites of cell-to-cell passages. Site-directed mutagenesis identified two of the four cysteine residues in Pep1 as essential for function, suggesting that the formation of disulfide bridges is crucial for proper protein folding. The barley covered smut fungus Ustilago hordei contains an ortholog of pep1 which is needed for penetration of barley and which is able to complement the U. maydis Δpep1 mutant. Based on these results, we conclude that Pep1 has a conserved function essential for establishing compatibility that is not restricted to the U. maydis / maize interaction

A Novel Pathogenicity Gene Is Required in the Rice Blast Fungus to Suppress the Basal Defenses of the Host

For successful colonization and further reproduction in host plants, pathogens need to overcome the innate defenses of the plant. We demonstrate that a novel pathogenicity gene, DES1, in Magnaporthe oryzae regulates counter-defenses against host basal resistance. The DES1 gene was identified by screening for pathogenicity-defective mutants in a T-DNA insertional mutant library. Bioinformatic analysis revealed that this gene encodes a serine-rich protein that has unknown biochemical properties, and its homologs are strictly conserved in filamentous Ascomycetes. Targeted gene deletion of DES1 had no apparent effect on developmental morphogenesis, including vegetative growth, conidial germination, appressorium formation, and appressorium-mediated penetration. Conidial size of the mutant became smaller than that of the wild type, but the mutant displayed no defects on cell wall integrity. The Δdes1 mutant was hypersensitive to exogenous oxidative stress and the activity and transcription level of extracellular enzymes including peroxidases and laccases were severely decreased in the mutant. In addition, ferrous ion leakage was observed in the Δdes1 mutant. In the interaction with a susceptible rice cultivar, rice cells inoculated with the Δdes1 mutant exhibited strong defense responses accompanied by brown granules in primary infected cells, the accumulation of reactive oxygen species (ROS), the generation of autofluorescent materials, and PR gene induction in neighboring tissues. The Δdes1 mutant displayed a significant reduction in infectious hyphal extension, which caused a decrease in pathogenicity. Notably, the suppression of ROS generation by treatment with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidases, resulted in a significant reduction in the defense responses in plant tissues challenged with the Δdes1 mutant. Furthermore, the Δdes1 mutant recovered its normal infectious growth in DPI-treated plant tissues. These results suggest that DES1 functions as a novel pathogenicity gene that regulates the activity of fungal proteins, compromising ROS-mediated plant defense

Global Sustainability Under Uncertainty: How Do Multinationals Craft Regulatory Policies?

Multinational corporations are increasingly mindful of the significance of sustainability transitions and the need for operations that are energy efficient and environmentally sound. Achieving sustainability under conditions of uncertainty entails the involvement of multiple stakeholders in initiating and carrying outsustainability-focused initiatives. Using longitudinal analysis of Royal Dutch Shell’s sustainability policies, we developed an integrated model to elucidate how uncertainty influences sustainability policies in the specific context of multinational corporations (hereinafter – MNCs). We identified three phases in theevolution of Shell’s sustainability innovation: a self-reflective phase (2000–2003) characterized by intense pressure from climate advocacy groups, an investment phase (2004–2006) for which the MNC attempted to rise to the waste disposal and pollution challenge through renewable sources of energy, and a reorganization phase (2007–2010) to streamline operations. We also uncovered themes that influence how regulatory policies are crafted: responding positively to the “community’s voice”, risk spreading through joint ventures, revenue transparency for government accountability and reporting innovation that confronts hard truths. The practical implications are outlined

Multinationals’ Accountability on Sustainability: The Evolution of Third-party Assurance of Sustainability Reports

In this article we explore how multinational corporations (MNCs) adopt assurance practices to develop and sustain organizational accountability for sustainability. Using a panel of Fortune Global 250 firms over a period of 10 years, we document the diffusion patterns of third-party assurance of sustainability reports. We specifically investigate how evolving auditing practices, namely diversity of assurance standards and type of assurance providers, shape the quality of sustainability assurance statements. The results illustrate great variability in the adoption of assurance practices in the formative stages of this novel market. Our descriptive analysis indicates the relevance of external institutional pressures as well as internal resources and capabilities as underlying factors driving the adoption of assurance. Our evidence also suggests that several MNCs project a decoupled or symbolic image of accountability through assurance, thereby undermining the credibility of these verification practices. The paper contributes to the emerging literature on international accountability standards and emphasizes the need to enhance theory-based, cross-disciplinary knowledge related to auditing and accountability processes for sustainability

Multivariate analysis of the systemic response to auditory stimulation: An integrative approach

New Findings: What is the central question of this study? Auditory stimulation produces a response in different physiological systems: cardiac, peripheral blood flow, electrodermal, cortical and peripheral haemodynamic responses and auditory event-related potentials. Do all these subsystems covary when responding to auditory stimulation, suggesting a unified locus of control, or do they not covary, suggesting independent loci of control for these physiological responses? What is the main finding and its importance? Auditory sensory gating reached a fixed level of neural activity independently of the intensity of auditory stimulation. The use of multivariate techniques revealed the presence of different regulatory mechanisms for the different physiologically recorded signals. Abstract: We studied the effects of an increasing amplitude of auditory stimulation on a variety of autonomic and CNS responses and their possible interdependence. The subjects were stimulated with an increasing amplitude of auditory tones while the auditory event-related potentials (ERPs), the cortical and extracerebral functional near-infrared spectroscopy (fNIRS) signal of standard and short separation channel recordings, the peripheral pulse measured by photoplethysmography, heart rate and electrodermal responses were recorded. Trials with eight tones of equal amplitude were presented. The results showed a parallel increase of activity in ERPs, fNIRS and peripheral responses with the increase in intensity of auditory stimulation. The ERPs, measured as peak-to-peak N1\u2013P2, showed an increase in amplitude with auditory stimulation and a high attenuation from the first presentation with respect to the second to eighth presentations. Peripheral signals and standard and short channel fNIRS responses showed a decrease in amplitude in the high-intensity auditory stimulation conditions. Principal components analysis showed independent sources of variance for the recorded signals, suggesting independent control of the recorded physiological responses. The present results suggest a complex response associated to the increase of auditory stimulation with a fixed amplitude for ERPs, and a decrease in the peripheral and cortical haemodynamic response, possibly mediated by activation of the sympathetic nervous system, constituting a defensive reflex to excessive auditory stimulation