Mahlerfaber3555

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PROSPERO does not currently accept registrations for scoping reviews, literature reviews or mapping reviews.The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 28,000,000 infections and 900,000 deaths worldwide to date. Antibody development efforts mainly revolve around the extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates host cell entry by binding to the angiotensin-converting enzyme 2 (ACE2). Similar to many other viral fusion proteins, the SARS-CoV-2 spike utilizes a glycan shield to thwart the host immune response. Here, we built a full-length model of the glycosylated SARS-CoV-2 S protein, both in the open and closed states, augmenting the available structural and biological data. Multiple microsecond-long, all-atom molecular dynamics simulations were used to provide an atomistic perspective on the roles of glycans and on the protein structure and dynamics. We reveal an essential structural role of N-glycans at sites N165 and N234 in modulating the conformational dynamics of the spike's receptor binding domain (RBD), which is responsible for ACE2 recognition. This finding is corroborated by biolayer interferometry experiments, which show that deletion of these glycans through N165A and N234A mutations significantly reduces binding to ACE2 as a result of the RBD conformational shift toward the "down" state. Additionally, end-to-end accessibility analyses outline a complete overview of the vulnerabilities of the glycan shield of the SARS-CoV-2 S protein, which may be exploited in the therapeutic efforts targeting this molecular machine. Overall, this work presents hitherto unseen functional and structural insights into the SARS-CoV-2 S protein and its glycan coat, providing a strategy to control the conformational plasticity of the RBD that could be harnessed for vaccine development.COVID-19 is a global pandemic, thus requiring multiple strategies to develop modalities against it. Herein, we designed multiple bioactive small molecules that target a functional structure within the SARS-CoV-2's RNA genome, the causative agent of COVID-19. An analysis to characterize the structure of the RNA genome provided a revised model of the SARS-CoV-2 frameshifting element, in particular its attenuator hairpin. By studying an RNA-focused small molecule collection, we identified a drug-like small molecule (C5) that avidly binds to the revised attenuator hairpin structure with a Kd of 11 nM. The compound stabilizes the hairpin's folded state and impairs frameshifting in cells. The ligand was further elaborated into a ribonuclease targeting chimera (RIBOTAC) to recruit a cellular ribonuclease to destroy the viral genome (C5-RIBOTAC) and into a covalent molecule (C5-Chem-CLIP) that validated direct target engagement and demonstrated its specificity for the viral RNA, as compared to highly expressed host mRNAs. The RIBOTAC lead optimization strategy improved the bioactivity of the compound at least 10-fold. Collectively, these studies demonstrate that the SARS-CoV-2 RNA genome should be considered druggable.Background and study aims  Endoscopic ultrasound (EUS) has been used for portal vein sampling in patients with pancreaticobiliary cancers for enumerating circulating tumor cells but is not yet a standard procedure. Further evaluation is needed to refine the methodology. Therefore, we evaluated the feasibility and safety of 19-gauge (19G) versus a 22-gauge (22 G) EUS fine-needle aspiration needles for portal vein sampling in a swine model. Methods  Celiotomy was performed on two farm pigs. Portal vein sampling occurred transhepatically. We compared 19 G and 22 G needles coated interiorly with saline, heparin or ethylenediaminetetraacetic acid (EDTA). Small- (10 mL) and large- (25 mL) volume blood collections were evaluated. this website Two different collection methods were tested direct-to-vial and suction syringe. A bleeding risk trial for saline-coated 19 G and 22 G needles was performed by puncturing the portal vein 20 times. Persistent bleeding after 3 minutes was considered significant. Results  All small-volume collection trials were successful except for 22 G saline-coated needles with direct-to-vial method. All large-volume collection trials were successful when using suction syringe; direct-to-vial method for both 19 G and 22 G needles were unsuccessful. Collection times were shorter for 19 G vs. 22 G needles for both small and large-volume collections ( P   less then  0.05). Collection times for saline-coated 22 G needles were longer compared to heparin/EDTA-coated ( P   less then  0.05). Bleeding occurred in 10 % punctures with 19 G needles compared to 0 % with 22 G needles. Conclusion  The results of this animal study demonstrate the feasibility and the safety of using 22 G needles for portal vein sampling and can form the basis for a pilot study in patients.Background  The percutaneous approach allows for effective and safe treatment of liver lesions. But in case of subcapsular or left segments location, this approach seems to be less effective or unsafe. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a new technique used to treat pancreatic and neuroendocrine tumors in patients unfit for surgery. Methods  Hereby, we describe the case of a 70-year-old patient with cirrhosis with a large subcapsular hepatocellular carcinoma (HCC) in II-III-IVb segments, in which surgery or percutaneous therapies were not feasible, treated with EUS-RFA. The HCC was treated using an EUS-RFA (EUSRA) system, which consists of a 19G water-cooled monopolar RFA needle and a dedicated generator system. Results  After a multidisciplinary discussion, the lesion was ablated in two different sessions, which resulted in destruction of about 70 % of neoplastic tissue. A second step surgery was required but initially refused by the patient. Conclusions  EUS-RFA could be an effective way to treat left hepatic lesions not manageable with conventional percutaneous methods. This case report does not highlight concerns about safety of this approach and this observation needs to be validated in a larger cohort of patients with cirrhosis.