Molecular mechanisms activating the NAIP‐NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer

Cytosolic innate immune sensing is a cornerstone of innate immunity in mammalian cells and provides a surveillance system for invading pathogens and endogenous danger signals. The NAIP‐NLRC4 inflammasome responds to cytosolic flagellin, and the inner rod and needle proteins of the type 3 secretion system of bacteria. This complex induces caspase‐1‐dependent proteolytic cleavage of the proinflammatory cytokines IL‐1β and IL‐18, and the pore‐forming protein gasdermin D, leading to inflammation and pyroptosis, respectively. Localized responses triggered by the NAIP‐NLRC4 inflammasome are largely protective against bacterial pathogens, owing to several mechanisms, including the release of inflammatory mediators, liberation of concealed intracellular pathogens for killing by other immune mechanisms, activation of apoptotic caspases, caspase‐7, and caspase‐8, and expulsion of an entire infected cell from the mammalian host. In contrast, aberrant activation of the NAIP‐NLRC4 inflammasome caused by de novo gain‐of‐function mutations in the gene encoding NLRC4 can lead to macrophage activation syndrome, neonatal enterocolitis, fetal thrombotic vasculopathy, familial cold autoinflammatory syndrome, and even death. Some of these clinical manifestations could be treated by therapeutics targeting inflammasome‐associated cytokines. In addition, the NAIP‐NLRC4 inflammasome has been implicated in the pathogenesis of colorectal cancer, melanoma, glioma, and breast cancer. However, no consensus has been reached on its function in the development of any cancer types. In this review, we highlight the latest advances in the activation mechanisms and structural assembly of the NAIP‐NLRC4 inflammasome, and the functions of this inflammasome in different cell types. We also describe progress toward understanding the role of the NAIP‐NLRC4 inflammasome in infectious diseases, autoinflammatory diseases, and cancer.Australian National University; National Health and Medical Research Council, Grant/Award Number: APP1141504,, APP1146864, APP1162103 and APP1163358; R.D. Wright Career Development Fellowship, Grant/Award Number: APP116202

Voluntary exercise modulates pathways associated with amelioration of retinal degenerative diseases

Background: Exercise has been shown to promote a healthier and longer life and linked to a reduced risk of developing neurodegenerative diseases including retinal degenerations. However, the molecular pathways underpinning exercise-induced cellular protection are not well understood. In this work we aim to profile the molecular changes underlying exercise-induced retinal protection and investigate how exercise-induced inflammatory pathway modulation may slow the progression of retinal degenerations. Methods: Female C57Bl/6J mice at 6 weeks old were given free access to open voluntary running wheels for a period of 28 days and then subjected to 5 days of photo-oxidative damage (PD)-induced retinal degeneration. Following, retinal function (electroretinography; ERG), morphology (optical coherence tomography; OCT) and measures of cell death (TUNEL) and inflammation (IBA1) were analysed and compared to sedentary controls. To decipher global gene expression changes as a result of voluntary exercise, RNA sequencing and pathway and modular gene co-expression analyses were performed on retinal lysates of exercised and sedentary mice that were subjected to PD, as well as healthy dim-reared controls. Results: Following 5 days of PD, exercised mice had significantly preserved retinal function, integrity and reduced levels of retinal cell death and inflammation, compared to sedentary controls. In response to voluntary exercise, inflammatory and extracellular matrix integrity pathways were significantly modulated, with the gene expression profile of exercised mice more closely trending towards that of a healthy dim-reared retina. Conclusion: We suggest that voluntary exercise may mediate retinal protection by influencing key pathways involved in regulating retinal health and shifting the transcriptomic profile to a healthy phenotype

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Impact of baseline cases of cough and fever on UK COVID-19 diagnostic testing rates: estimates from the Bug Watch community cohort study [version 1; peer review: awaiting peer review]

Background: Diagnostic testing forms a major part of the UK’s response to the current coronavirus disease 2019 (COVID-19) pandemic with tests offered to anyone with a continuous cough, high temperature or anosmia. Testing capacity must be sufficient during the winter respiratory season when levels of cough and fever are high due to non-COVID-19 causes. This study aims to make predictions about the contribution of baseline cough or fever to future testing demand in the UK. Methods: In this analysis of the Bug Watch prospective community cohort study, we estimated the incidence of cough or fever in England in 2018-2019. We then estimated the COVID-19 diagnostic testing rates required in the UK for baseline cough or fever cases for the period July 2020-June 2021. This was explored for different rates of the population requesting tests and four COVID-19 second wave scenarios. Estimates were then compared to current national capacity. Results: The baseline incidence of cough or fever in the UK is expected to rise rapidly from 154,554 (95%CI 103,083 - 231,725) cases per day in August 2020 to 250,708 (95%CI 181,095 - 347,080) in September, peaking at 444,660 (95%CI 353,084 - 559,988) in December. If 80% of baseline cough or fever cases request tests, average daily UK testing demand would exceed current capacity for five consecutive months (October 2020 to February 2021), with a peak demand of 147,240 (95%CI 73,978 - 239,502) tests per day above capacity in December 2020. Conclusions: Our results show that current national COVID-19 testing capacity is likely to be exceeded by demand due to baseline cough and fever alone. This study highlights that the UK’s response to the COVID-19 pandemic must ensure that a high proportion of people with symptoms request tests, and that testing capacity is immediately scaled up to meet this high predicted demand

Impact of baseline cases of cough and fever on UK COVID-19 diagnostic testing rates: estimates from the Bug Watch community cohort study.

Background: Diagnostic testing forms a major part of the UK's response to the current coronavirus disease 2019 (COVID-19) pandemic with tests offered to anyone with a continuous cough, high temperature or anosmia. Testing capacity must be sufficient during the winter respiratory season when levels of cough and fever are high due to non-COVID-19 causes. This study aims to make predictions about the contribution of baseline cough or fever to future testing demand in the UK. Methods: In this analysis of the Bug Watch community cohort study, we estimated the incidence of cough or fever in England in 2018-2019. We then estimated the COVID-19 diagnostic testing rates required in the UK for baseline cough or fever cases for the period July 2020-June 2021. This was explored for different rates of the population requesting tests, four COVID-19 second wave scenarios and high and low baseline cough or fever incidence scenarios. Results: Under the high baseline cough or fever scenario, incidence in the UK is expected to rise rapidly from 250,708 (95%CI 181,095 - 347,080) cases per day in September to a peak of 444,660 (95%CI 353,084 - 559,988) in December. If 80% of these cases request tests, testing demand would exceed 1.4 million tests per week for five consecutive months. Demand was significantly lower in the low cough or fever incidence scenario, with 129,115 (95%CI 111,596 - 151,679) tests per day in January 2021, compared to 340,921 (95%CI 276,039 - 424,491) tests per day in the higher incidence scenario. Conclusions: Our results show that national COVID-19 testing demand is highly dependent on background cough or fever incidence. This study highlights that the UK's response to the COVID-19 pandemic must ensure that a high proportion of people with symptoms request tests, and that testing capacity is sufficient to meet the high predicted demand

Effect of B dose and Ge preamorphization energy on the electrical and structural properties of ultrashallow junctions in silicon-on-insulator

Formation of highly activated, ultra-shallow and abrupt profiles is a key requirement for the next generations of CMOS devices, particularly for source-drain extensions. For p-type dopant implants (boron), a promising method of increasing junction abruptness is to use Ge preamorphizing implants prior to ultra-low energy B implantation and solid-phase epitaxy regrowth to re-crystallize the amorphous Si. However, for future technology nodes, new issues arise when bulk silicon is supplanted by silicon-on-insulator (SOI). Previous results have shown that the buried Si/SiO2 interface can improve dopant activation, but the effect depends on the detailed preamorphization conditions and further optimization is required. In this paper a range of B doses and Ge energies have been chosen in order to situate the end-of-range (EOR) defect band at various distances from the back interface of the active silicon film (the interface with the buried oxide), in order to explore and optimize further the effect of the interface on dopant behavior. Electrical and structural properties were measured by Hall Effect and SIMS techniques. The results show that the boron deactivates less in SOI material than in bulk silicon, and crucially, that the effect increases as the distance from the EOR defect band to the back interface is decreased. For the closest distances, an increase injunction steepness is also observed, even though the B is located close to the top surface, and thus far from the back interface. The position of the EOR defect band shows the strongest influence for lower B doses. © 2006 Materials Research Society

Impact of baseline cases of cough and fever on UK COVID-19 diagnostic testing rates: estimates from the Bug Watch community cohort study - Supplementary material, code and data

This contains the updated analysis code for the revision of this article. It also contains two new datasets which were used to conduct an additional new analysis

Correlation of local structure and electrical activation in arsenic ultrashallow junctions in silicon

The understanding of the behavior of arsenic in highly doped near surface silicon layers is of crucial importance for the formation of N-type ultrashallow junctions in current and future very large scale integrated technology. This is of particular relevance when studying recently developed implantation and annealing methods. Past theoretical as well as experimental investigations have suggested that the increase in As concentration, and therefore the reciprocal proximity of several As atoms, leads to a drastic increase in electrically inactive defects giving only marginal reduction in sheet resistance. Monoclinic SiAs aggregates as well as various arsenic-vacancy clusters contribute to the deactivation of arsenic. This study aims to correlate between the results of electrical activation measurements and x-ray absorption fine structure measurements. Samples were doped with a nominal fluence of 1×1015–3×1015 atoms/cm2, implanted at 2 keV, and annealed by rapid thermal treatments, laser submelt treatments, and a combination of both. Hall effect and sheet resistance measurements have been performed to obtain the density of charge carriers. Secondary ion mass spectrometry has been employed to measure the depth profile and the total retained fluences. The percentage of substitutional arsenic has been obtained by least-squares fits of the measured x-ray absorption spectra with simulated spectra of relaxed structures of the defects obtained by density functional theory. A good agreement with the Hall effect measured electrically active dose fraction has been obtained and a quantification of the population of the different defects involved has been attempted