Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract.

Since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the globe. At present, the Food and Drug Administration (FDA) has issued emergency approval for the use of some antiviral drugs. However, these drugs still have limitations in the specific treatment of COVID-19, and as such, new treatment strategies urgently need to be developed. RNA-interference-based gene therapy provides a tractable target for antiviral treatment. Ensuring cell-specific targeted delivery is important to the success of gene therapy. The use of nanoparticles (NPs) as carriers for the delivery of small interfering RNA (siRNAs) to specific tissues or organs of the human body could play a crucial role in the specific therapy of severe respiratory infections, such as COVID-19. In this review, we describe a variety of novel nanocarriers, such as lipid NPs, star polymer NPs, and glycogen NPs, and summarize the pre-clinical/clinical progress of these nanoparticle platforms in siRNA delivery. We also discuss the application of various NP-capsulated siRNA as therapeutics for SARS-CoV-2 infection, the challenges with targeting these therapeutics to local delivery in the lung, and various inhalation devices used for therapeutic administration. We also discuss currently available animal models that are used for preclinical assessment of RNA-interference-based gene therapy. Advances in this field have the potential for antiviral treatments of COVID-19 disease and could be adapted to treat a range of respiratory diseases

Analytical and numerical study on grating depth effects in grating coupled waveguide sensors

The in-coupling process for grating-coupled planar optical waveguide sensors is investigated in the case of TE waves. A simple analytical model based on the Rayleigh-Fourier-Kiselev method is applied to take into account the depth of the grating coupler, which is usually neglected in the modeling. Analytical expressions are derived both for the position and width of the in-coupling peaks to illustrate the effects of grating depth on the guided mode resonances in grating coupled waveguide sensors. Numerical computations verify the model for shallow gratings both in terms of peak shape and position and provide the limitations for the analytical formulas

The complex interplay between endoplasmic reticulum stress and the NLRP3 inflammasome: a potential therapeutic target for inflammatory disorders.

Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, particularly pathogens, to maintain homeostasis and promote tissue healing. However, dysregulation in the immune system elicits excess/abnormal inflammation resulting in unintended tissue damage and causes major inflammatory diseases including asthma, chronic obstructive pulmonary disease, atherosclerosis, inflammatory bowel diseases, sarcoidosis and rheumatoid arthritis. It is now widely accepted that both endoplasmic reticulum (ER) stress and inflammasomes play critical roles in activating inflammatory signalling cascades. Notably, evidence is mounting for the involvement of ER stress in exacerbating inflammasome-induced inflammatory cascades, which may provide a new axis for therapeutic targeting in a range of inflammatory disorders. Here, we comprehensively review the roles, mechanisms and interactions of both ER stress and inflammasomes, as well as their interconnected relationships in inflammatory signalling cascades. We also discuss novel therapeutic strategies that are being developed to treat ER stress- and inflammasome-related inflammatory disorders

Dynamic modeling of mean-reverting spreads for statistical arbitrage

Statistical arbitrage strategies, such as pairs trading and its generalizations, rely on the construction of mean-reverting spreads enjoying a certain degree of predictability. Gaussian linear state-space processes have recently been proposed as a model for such spreads under the assumption that the observed process is a noisy realization of some hidden states. Real-time estimation of the unobserved spread process can reveal temporary market inefficiencies which can then be exploited to generate excess returns. Building on previous work, we embrace the state-space framework for modeling spread processes and extend this methodology along three different directions. First, we introduce time-dependency in the model parameters, which allows for quick adaptation to changes in the data generating process. Second, we provide an on-line estimation algorithm that can be constantly run in real-time. Being computationally fast, the algorithm is particularly suitable for building aggressive trading strategies based on high-frequency data and may be used as a monitoring device for mean-reversion. Finally, our framework naturally provides informative uncertainty measures of all the estimated parameters. Experimental results based on Monte Carlo simulations and historical equity data are discussed, including a co-integration relationship involving two exchange-traded funds.Comment: 34 pages, 6 figures. Submitte

End-stage renal disease preceded by rapid declines in kidney function: a case series

<p>Abstract</p> <p>Background</p> <p>Few studies have defined alternate pathways by which chronic kidney disease (CKD) patients transition into end-stage renal disease (ESRD).</p> <p>Methods</p> <p>We studied all consecutive patients initiated on maintenance hemodialysis or peritoneal dialysis over several years at two dialysis units in Northern California. Rapid decline in kidney function was considered to have occurred if a patient was documented to have estimated GFR > 30 ml/min/1.73 m²within three months prior to the initiation of chronic dialysis.</p> <p>Results</p> <p>We found that 8 out of 105 incident chronic dialysis patients one dialysis unit (7.6%; 95% confidence interval 3.4-14.5%) and 9 out of 71 incident patients at another (12.7%, 95% CI 6.0%-22.7%) suffered rapid decline in kidney function that was the immediate precipitant for the need for permanent renal replacement therapy. All these patients started hemodialysis and all relied on catheters for vascular access. Documentation submitted to United States Renal Data System did not fully reflect the health status of these patients during their "pre-ESRD" period.</p> <p>Conclusions</p> <p>A sizeable minority of ESRD cases are preceded by rapid declines in kidney function. The importance of these periods of rapid decline may have been under-appreciated in prior studies of the natural history of CKD and ESRD.</p

Physics–Dynamics Coupling in weather, climate and Earth system models: Challenges and recent progress

This is the final version. Available from American Meteorological Society via the DOI in this record.Numerical weather, climate, or Earth system models involve the coupling of components. At a broad level, these components can be classified as the resolved fluid dynamics, unresolved fluid dynamical aspects (i.e., those represented by physical parameterizations such as subgrid-scale mixing), and nonfluid dynamical aspects such as radiation and microphysical processes. Typically, each component is developed, at least initially, independently. Once development is mature, the components are coupled to deliver a model of the required complexity. The implementation of the coupling can have a significant impact on the model. As the error associated with each component decreases, the errors introduced by the coupling will eventually dominate. Hence, any improvement in one of the components is unlikely to improve the performance of the overall system. The challenges associated with combining the components to create a coherent model are here termed physics–dynamics coupling. The issue goes beyond the coupling between the parameterizations and the resolved fluid dynamics. This paper highlights recent progress and some of the current challenges. It focuses on three objectives: to illustrate the phenomenology of the coupling problem with references to examples in the literature, to show how the problem can be analyzed, and to create awareness of the issue across the disciplines and specializations. The topics addressed are different ways of advancing full models in time, approaches to understanding the role of the coupling and evaluation of approaches, coupling ocean and atmosphere models, thermodynamic compatibility between model components, and emerging issues such as those that arise as model resolutions increase and/or models use variable resolutions.Natural Environment Research Council (NERC)National Science FoundationDepartment of Energy Office of Biological and Environmental ResearchPacific Northwest National Laboratory (PNNL)DOE Office of Scienc

Expression of targets of the RNA-binding protein AUF-1 in human airway epithelium indicates its role in cellular senescence and inflammation

INTRODUCTION: The RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, two pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described in bronchiolar epithelium of COPD patients versus controls and in vitro cytokine- and cigarette smoke-challenged human airway epithelial cells, prompting the identification of epithelial AUF-1-targeted transcripts and function, and investigation on the mechanism of its loss. RESULTS: RNA immunoprecipitation-sequencing (RIP-Seq) identified, in the human airway epithelial cell line BEAS-2B, 494 AUF-1-bound mRNAs enriched in their 3'-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif. AUF-1 association with selected transcripts and with a synthetic GC-rich motif were validated by biotin pulldown. AUF-1-targets' steady-state levels were equally affected by partial or near-total AUF-1 loss induced by cytomix (TNFα/IL1β/IFNγ/10 nM each) and siRNA, respectively, with differential transcript decay rates. Cytomix-mediated decrease in AUF-1 levels in BEAS-2B and primary human small-airways epithelium (HSAEC) was replicated by treatment with the senescence- inducer compound etoposide and associated with readouts of cell-cycle arrest, increase in lysosomal damage and senescence-associated secretory phenotype (SASP) factors, and with AUF-1 transfer in extracellular vesicles, detected by transmission electron microscopy and immunoblotting. Extensive in-silico and genome ontology analysis found, consistent with AUF-1 functions, enriched RIP-Seq-derived AUF-1-targets in COPD-related pathways involved in inflammation, senescence, gene regulation and also in the public SASP proteome atlas; AUF-1 target signature was also significantly represented in multiple transcriptomic COPD databases generated from primary HSAEC, from lung tissue and from single-cell RNA-sequencing, displaying a predominant downregulation of expression. DISCUSSION: Loss of intracellular AUF-1 may alter posttranscriptional regulation of targets particularly relevant for protection of genomic integrity and gene regulation, thus concurring to airway epithelial inflammatory responses related to oxidative stress and accelerated aging. Exosomal-associated AUF-1 may in turn preserve bound RNA targets and sustain their function, participating to spreading of inflammation and senescence to neighbouring cells

Infraspinatus scapular retraction test: a reliable and practical method to assess infraspinatus strength in overhead athletes with scapular dyskinesis

Background Alteration of normal scapulohumeral rhythm due to the fatigue of scapular-stabilizing muscles induces decrease of rotator cuff strength. In this study we analyzed the interobserver and intraobserver realibility of the infraspinatus strength test (IST) and infraspinatus scapular retraction test (ISRT) in 29 overhead athletes with scapular dykinesis, before and after 6 months of scapular musculature rehabilitation. Materials and methods Subjects with magnetic resonance imaging (MRI) findings of labral injuries (2 cases, 5%) and cuff tears (4 cases, 11%) were excluded. Scapular dyskinesis patterns were evaluated according to Kibler et al. (J Shoulder Elbow Surg 11:550-556, 2002). We found a type I dyskinesis in 24 cases (83%) and a type II in 5 cases (17%). Patients were tested by using IST and ISRT and the maximum infraspinatus strength (kg) was registered by a handheld dynamometer. Changes in shoulder IR were measured by using a standard goniometry. Rehabilitation continued for 6 months and was focused on the restoration of scapular muscular control and balance. We used a paired Student t test for the significance of the force values (alpha = 0.01). Intraclass correlation coefficient (ICC) and standard error (SE) were applied to determine the realibility of repeated values collected within testers and between testers. Results Values of ICC close to 1 at baseline and at 6 months indicated a higher interexaminer and intraexaminer realibility. IST force values registered a significant increase at 6 months for both examiners (P&lt;0.01). The mean difference between IST and ISRT values were not significant at 6 months (P&gt;0.01). The increase of glenohumeral internal rotation was significant at 6 months (P&lt;0.01). Conclusion The good realibility and the easy reproducibility make the ISRT an excellent test to assess patients with infraspinatus weakness due to scapular dyskinesis and address them toward an appropriate program of rehabilitation aimed to restore scapular musculature balance and control. \ua9 The Author(s) 2010

Genome-wide association studies and genetic architecture of common human diseases

Genome-wide association scans provide the first successful method to identify genetic variation contributing to risk for common complex disease. Progress in identifying genes associated with melanoma show complex relationships between genes for pigmentation and the development of melanoma. Novel risk loci account for only a small fraction of the genetic variation contributing to this and many other diseases. Large meta-analyses find additional variants, but there is current debate about the contribution of common polymorphisms, rare polymorphisms or mutations to disease risk