Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules

Nature has evolved intricate machinery to target and degrade RNA, and some of these molecular mechanisms can be adapted for therapeutic use. Small interfering RNAs and RNase H-inducing oligonucleotides have yielded therapeutic agents against diseases that cannot be tackled using protein-centered approaches. Because these therapeutic agents are nucleic acid-based, they have several inherent drawbacks which include poor cellular uptake and stability. Here we report a new approach to target and degrade RNA using small molecules, proximity-induced nucleic acid degrader (PINAD). We have utilized this strategy to design two families of RNA degraders which target two different RNA structures within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. We demonstrate that these novel molecules degrade their targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy allows any RNA binding small molecule to be converted into a degrader, empowering RNA binders that are not potent enough to exert a phenotypic effect on their own. PINAD raises the possibility of targeting and destroying any disease-related RNA species, which can greatly expand the space of druggable targets and diseases.info:eu-repo/semantics/publishedVersio

Chest Wall Diseases Respiratory Pathophysiology

The chest wall consists of various structures that function in an integrated fashion to ventilate the lungs. Disorders affecting the bony structures or soft tissues of the chest wall may impose elastic loads by stiffening the chest wall and decreasing respiratory system compliance. These alterations increase the work of breathing and lead to hypoventilation and hypercapnia. Respiratory failure may occur acutely or after a variable period. This article focuses on the pathophysiology of respiratory function in specific diseases and disorders of the chest wall and highlights pathogenic mechanisms of respiratory failure

Association of the Shrinking Lung Syndrome in Systemic Lupus Erythematosus with Pleurisy: A Systematic Review

Objectives: To report 2 patients with systemic lupus erythematosus and typical shrinking lung syndrome (SLS) in which pleuritic chest pain was the predominant symptom. In addition, to record the prevalence of pleuritic chest pain in all reported cases of patients with SLS and diaphragmatic dysfunction. Methods: We conducted a comprehensive search of the English literature to record the association of pleurisy and SLS in an reported cases using the MEDLINE database from 1965 to present. Results: Of the 77 patients with SLS reported in the literature, 50 (65%) patients had pleuritic chest pain at the time of evaluation. Treatment with anti-inflammatory agents improved symptoms in the majority of cases. Conclusions: Pleuritic inflammation and pain may have an important role in the pathogenesis of SLS. A possible mechanism linking pleural inflammation and diaphragm dysfunction may be via a reflex inhibition of diaphragmatic activation. (C) 2008 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 39:30-3

Respiratory dysfunction in multiple sclerosis

Respiratory dysfunction frequently occurs in patients with advanced multiple sclerosis ( MS), and may manifest as acute or chronic respiratory failure, disordered control of breathing, respiratory muscle weakness, sleep disordered breathing, or neurogenic pulmonary edema. The underlying pathophysiology is related to demyelinating plaques involving the brain stem or spinal cord. Respiratory complications such as aspiration, lung infections and respiratory failure are typically seen in patients with long-standing MS. Acute respiratory failure is uncommon and due to newly appearing demyelinating plaques extensively involving areas of the brain stem or spinal cord. Early recognition of MS patients at risk for respiratory complications allows for the timely implementation of care and measures to decrease disease associated morbidity and mortality. (C) 2015 Elsevier Ltd. All rights reserved

Chest wall motion during speech production in patients with advanced ankylosing spondylitis

Purpose: To test the hypothesis that ankylosing spondylitis (AS) alters the pattern of chest wall motion during speech production. Method: The pattern of chest wall motion during speech was measured with respiratory inductive plethysmography in 6 participants with advanced AS (5 men, 1 woman, age 45 +/- 8 years, Schober test 1.45 +/- 1.5 cm, Bath Ankylosing Spondylitis Functional Index [BASFI] score 6 +/- 1.7) and 6 healthy volunteers, matched for age and gender. Measurements were made with participants in the upright seated and upright standing body position. Results: During reading in the seated and standing body positions, the rib cage wall volume displacements were smaller and abdominal wall volume displacements were larger in participants with AS than in healthy controls. There were no differences in the overall lung volume displacements recorded during the expiratory limb of, reading in either body position. In the participants with AS, the 66 cage remained near the end-expiratory level in both the seated and standing body position, differing from that for the control group. Conclusion: In individuals with advanced AS, the abdomen is the primary contributor to volume displacement. In the absence of speech impairment in participants with AS, the data show the capacity of the abdomen to compensate for the decreased compliance of the rib cage

Relative contributions of the ribcage and abdomen to lung volume displacement during speech production

We tested the hypothesis that the pattern of chest wall configuration during speech production correlates with the pattern of chest wall motion during resting breathing. Twenty-one men (age 40 +/- 8 years) with ankylosing spondylitis and varied degrees of ribcage involvement participated in the study. None of the patients had an obvious speech abnormality. Ribcage and abdominal displacements during quiet breathing and during reading were measured with a respiratory plethysmograph. Measurements were taken in the sitting and standing body positions. In each body position, ribcage or abdominal displacements during quiet breathing correlated with the corresponding chest wall displacements recorded during reading (P < 0.001). In addition, linear regression analysis showed that the slope of the chest wall motion loop during quiet breathing correlated with the ratio of ribcage to abdomen contribution to lung volume displacement during reading (r = 0.78, P < 0.001 for sitting and r = 0.64, P = 0.002 for standing position). The slopes of the regression lines did not differ between the sitting and standing body position (P > 0.05). We conclude that the relative contribution of the ribcage and abdomen to lung volume displacement during speech production correlates with the relative ribcage and abdomen contribution to tidal volume during quiet breathing; our data support the notion that the pattern of chest wall configuration during quiet breathing largely predicts the pattern of ribeage and abdomen displacement during speech