Sulfoglycodendron Antivirals with Scalable Architectures and Activities.

Many viruses initiate their cell-entry by binding their multi-protein receptors to human heparan sulfate proteoglycans (HSPG) and other molecular components present on cellular membranes. These viral interactions could be blocked and the whole viruses could be eliminated by suitable HSPG-mimetics providing multivalent binding to viral protein receptors. Here, large sulfoglyco-dendron HSPG-mimetics of different topologies, structures, and sizes were designed to this purpose. Atomistic molecular dynamics simulations were used to examine the ability of these broad-spectrum antivirals to block multi-protein HSPG-receptors in HIV, SARS-CoV-2, HPV, and dengue viruses. To characterize the inhibitory potential of these mimetics, their binding to individual and multiple protein receptors was examined. In particular, vectorial distributions of binding energies between the mimetics and viral protein receptors were introduced and calculated along the simulated trajectories. Space-dependent residual analysis of the mimetic-receptor binding was also performed. This analysis revealed detail nature of binding between these antivirals and viral protein receptors, and provided evidence that large inhibitors with multivalent binding might act like a molecular glue initiating the self-assembly of protein receptors in enveloped viruses.

Revision of Failed Short Stems in Total Hip Arthroplasty.

Background: The current literature lacks studies which evaluate the failure of short stems in total hip arthroplasty (THA). Therefore, the present clinical investigation reported our experience with the failure of short stems in THA, evaluating the causes of failure, survivorship, and the clinical outcomes of revision arthroplasty. Methods: The present study was performed according to the STROBE guidelines. This study was conducted at the Department of Orthopaedic Surgery of the Humanitas Clinical Institute, Milan, Italy, between 2017 and 2022. All patients who underwent revision surgery of a previously implanted THA using a short stem were prospectively included in the present study. Surgeries were performed with patients in lateral position, using a minimally invasive posterolateral approach. The outcomes of interest were to report information on the type and survivorship of implants used for the revision surgery and evaluate the clinical outcomes and the rate of complications. The following patient-reported outcome measures (PROMs) used for the clinical assessment were the Western Ontario McMaster Osteo-Arthritis Index (WOMAC) and related subscales of pain, stiffness, and function, and the visual analogue scale (VAS). Results: Data from 45 patients were retrieved. Of them, 31% (14 of 45 patients) were women. The mean age was 63.7 ± 13.9 years. The mean length of the implant survivorship was 6.2 ± 5.7 years. In total, 58% (26 of 45 patients) underwent revision of all components, 36% (16 of 45 patients) revised only the stem, and 1% (3 of 45 patients) received a two-stage revision. The mean length of the follow-up was 4.4 ± 1.5 years. The cup was revised in 58% (26 of 45) of patients. At 4.4 ± 1.5 years of follow-up, the WOMAC score was 3.5 ± 1.3 and the VAS was 1.2 ± 1.3. In total, 9% (4 of 45) of patients experienced minor complications. One patient used a walking aid because of reduced function. One patient evidenced muscular hypotrophy. Two patients experienced hip dislocations. All two dislocations were managed conservatively with repositioning in the emergency room under fluoroscopy. No patient needed additional revision surgery or experienced further dislocations. Conclusions: Revision surgery is effective and safe when a short stem THA fails. At approximately four years of follow-up, all patients were highly satisfied with their clinical outcomes. Despite the relatively high number (9%), complications were of a minor entity and were successfully managed conservatively.

Coupling of SARS-CoV-2 to Aß Amyloid Fibrils.

The COVID-19 infection has been more problematic for individuals with certain health predispositions. Coronaviruses could also interfere with neural diseases if the viruses succeed in entering the brain. Therefore, it might be of principal interest to examine a possible coupling of coronaviruses and amyloid fibrils. Here, molecular dynamics simulations were used to investigate direct coupling of SARS-CoV-2 and Aß fibrils, which play a central role in neural diseases. The simulations revealed several stable binding configurations and their dynamics of Aß42 fibrils attached to spike proteins of the Omicron and Alpha variants of SARS-CoV-2.

Antiviral fibrils of self-assembled peptides with tunable compositions.

The lasting threat of viral pandemics necessitates the development of tailorable first-response antivirals with specific but adaptive architectures for treatment of novel viral infections. Here, such an antiviral platform has been developed based on a mixture of hetero-peptides self-assembled into functionalized ß-sheets capable of specific multivalent binding to viral protein complexes. One domain of each hetero-peptide is designed to specifically bind to certain viral proteins, while another domain self-assembles into fibrils with epitope binding characteristics determined by the types of peptides and their molar fractions. The self-assembled fibrils maintain enhanced binding to viral protein complexes and retain high resilience to viral mutations. This method is experimentally and computationally tested using short peptides that specifically bind to Spike proteins of SARS-CoV-2. This platform is efficacious, inexpensive, and stable with excellent tolerability.