Overview: Systemic Inflammatory Response Derived From Lung Injury Caused by SARS-CoV-2 Infection Explains Severe Outcomes in COVID-19

Most SARS-CoV2 infections will not develop into severe COVID-19. However, in some patients, lung infection leads to the activation of alveolar macrophages and lung epithelial cells that will release proinflammatory cytokines. IL-6, TNF and IL-1β increase expression of cell adhesion molecules (CAMs) and VEGF, thereby increasing permeability of the lung endothelium and reducing barrier protection, allowing viral dissemination and infiltration of neutrophils and inflammatory monocytes. In the blood, these cytokines will stimulate the bone marrow to produce and release immature granulocytes, that return to the lung and further increase inflammation, leading to acute respiratory distress syndrome (ARDS). This lung-systemic loop leads to cytokine release syndrome (CRS). Concurrently, the acute phase response increases the production of platelets, fibrinogen and other pro-thrombotic factors. Systemic decrease in ACE2 function impacts the Renin-Angiotensin-Kallikrein-Kinin systems (RAS-KKS) increasing clotting. The combination of acute lung injury with RAS-KKS unbalance is herein called COVID-19 Associated Lung Injury (CALI). This conservative two-hit model of systemic inflammation due to the lung injury allows new intervention windows and is more consistent with the current knowledge.Indiana University Health—Indiana University School of Medicine Strategic Research Initiativ

Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites

Protozoan infections are a serious global health problem1, 2. Natural killer (NK) cells and cytolytic T lymphocytes (CTLs) eliminate pathogen-infected cells by releasing cytolytic granule contents—granzyme (Gzm) proteases and the pore-forming perforin (PFN)—into the infected cell3. However, these cytotoxic molecules do not kill intracellular parasites. CD8+ CTLs protect against parasite infections in mice primarily by secreting interferon (IFN)-γ4, 5, 6, 7, 8, 9, 10. However, human, but not rodent, cytotoxic granules contain the antimicrobial peptide granulysin (GNLY), which selectively destroys cholesterol-poor microbial membranes11, 12, 13, 14, and GNLY, PFN and Gzms rapidly kill intracellular bacteria15. Here we show that GNLY delivers Gzms into three protozoan parasites (Trypanosoma cruzi, Toxoplasma gondii and Leishmania major), in which the Gzms generate superoxide and inactivate oxidative defense enzymes to kill the parasite. PFN delivers GNLY and Gzms into infected cells, and GNLY then delivers Gzms to the intracellular parasites. Killer cell–mediated parasite death, which we term 'microbe-programmed cell death' or 'microptosis', is caspase independent but resembles mammalian apoptosis, causing mitochondrial swelling, transmembrane potential dissipation, membrane blebbing, phosphatidylserine exposure, DNA damage and chromatin condensation. GNLY-transgenic mice are protected against infection by T. cruzi and T. gondii, and survive infections that are lethal to wild-type mice. Thus, GNLY-, PFN- and Gzm-mediated elimination of intracellular protozoan parasites is an unappreciated immune defense mechanism

Platelet-Activating Factor Receptor Plays a Role in Lung Injury and Death Caused by Influenza A in Mice

Influenza A virus causes annual epidemics which affect millions of people worldwide. A recent Influenza pandemic brought new awareness over the health impact of the disease. It is thought that a severe inflammatory response against the virus contributes to disease severity and death. Therefore, modulating the effects of inflammatory mediators may represent a new therapy against Influenza infection. Platelet activating factor (PAF) receptor (PAFR) deficient mice were used to evaluate the role of the gene in a model of experimental infection with Influenza A/WSN/33 H1N1 or a reassortant Influenza A H3N1 subtype. The following parameters were evaluated: lethality, cell recruitment to the airways, lung pathology, viral titers and cytokine levels in lungs. The PAFR antagonist PCA4248 was also used after the onset of flu symptoms. Absence or antagonism of PAFR caused significant protection against flu-associated lethality and lung injury. Protection was correlated with decreased neutrophil recruitment, lung edema, vascular permeability and injury. There was no increase of viral load and greater recruitment of NK1.1+ cells. Antibody responses were similar in WT and PAFR-deficient mice and animals were protected from re-infection. Influenza infection induces the enzyme that synthesizes PAF, lyso-PAF acetyltransferase, an effect linked to activation of TLR7/8. Therefore, it is suggested that PAFR is a disease-associated gene and plays an important role in driving neutrophil influx and lung damage after infection of mice with two subtypes of Influenza A. Further studies should investigate whether targeting PAFR may be useful to reduce lung pathology associated with Influenza A virus infection in humans

Monitoring extinction risk and threats of the world's fishes based on the Sampled Red List Index

Global biodiversitytargets require us to identify species at risk of extinction and quantify status and trends of biodiversity. The Red List Index (RLI) tracks trends in the conservation status of entire species groups over time by monitoring changes in categories assigned to species. Here, we calculate this index for the world's fishes in 2010, using a sampled approach to the RLI based on a randomly selected sample of 1,500 species, and also present RLI splits for freshwater and marine systems separately. We further compare specific traits of a worldwide fish list to our sample to assess its representativeness. Overall, 15.1% of species in the sample were estimated to be threatened with extinction, resulting in a sampled RLI of 0.914 for all species, 0.968 in marine and 0.862 in freshwater ecosystems. Our sample showed fishing as the principal threat for marine species, and pollution by agricultural and forestry effluents for freshwater fishes. The sampled list provides a robust representation for tracking trends in the conservation status of the world's fishes, including disaggregated sampled indices for marine and freshwater fish. Reassessment and backcasting of this index is urgent to check the achievement of the commitments proposed in global biodiversity targets

Monitoring extinction risk and threats of the world's fishes based on the Sampled Red List Index

Global biodiversitytargets require us to identify species at risk of extinction and quantify status and trends of biodiversity. The Red List Index (RLI) tracks trends in the conservation status of entire species groups over time by monitoring changes in categories assigned to species. Here, we calculate this index for the world's fishes in 2010, using a sampled approach to the RLI based on a randomly selected sample of 1,500 species, and also present RLI splits for freshwater and marine systems separately. We further compare specific traits of a worldwide fish list to our sample to assess its representativeness. Overall, 15.1% of species in the sample were estimated to be threatened with extinction, resulting in a sampled RLI of 0.914 for all species, 0.968 in marine and 0.862 in freshwater ecosystems. Our sample showed fishing as the principal threat for marine species, and pollution by agricultural and forestry effluents for freshwater fishes. The sampled list provides a robust representation for tracking trends in the conservation status of the world's fishes, including disaggregated sampled indices for marine and freshwater fish. Reassessment and backcasting of this index is urgent to check the achievement of the commitments proposed in global biodiversity targets

Reconfigurable Class S Power Amplifiers at RF and Microwave Frequencies

When a delta-sigma modulator (DSM) is placed before a class D switching stage the combination can be used to amplify time varying envelope signals. However a bandpass DSM is commonly employed and is required to have a sampling frequency approximately four times the carrier frequency. At RF or microwave frequencies proprietary hardware was previously needed to implement the DSM. However, it is shown here in simulation and from experimental measurement that a suitable DSM for class S power amplifiers can be implemented at RF and microwave frequencies using mid-range FPGA technology. Index Terms- Class S, efficiency, power amplifiers, sigma-delta modulatio

Global statistical assessment of biological replicates.

<p>Heat-map <b>(A)</b> and Principal Component Analysis (PCA) plots <b>(B)</b> of RNA-Seq data generated from the libraries mapped to the <i>T</i>. <i>cruzi</i> genome following removal of rRNA/tRNA features. Once the outlier sample was removed and data passed through normalization and surrogate variable analysis, the strong clustering by condition became evident in both analyses. In both plots, each sample is color coded by developmental stage/strain (Tryp: trypomastigotes; A60: amastigotes collected 60 hpi; A96: amastigotes collected 96 hpi).</p

Differential gene expression across <i>T</i>. <i>cruzi</i> CL-14 and CL Brener developmental stages.

<p>Bar plots of the numbers of genes deemed significantly differentially expressed (adjusted P value <0.05) in (A) CL-14 and (B) CL Brener. The numbers of genes in each category are defined as: log2 fold changes |0–1| (light cyan for positive, light plum for negative), |1–2| (light sky blue for positive, orchid for negative), and |2+| (dodger blue and purple respectively). The diverging patterns of expression are shown by changing bar patterns.</p