ABSTRACT
The clinical performance and failure issues are significantly influenced by prosthetic malposition in unicompartmental knee arthroplasty (UKA). Uncertainty exists about the impact of the prosthetic joint line height in UKA on tibial insert wear. In this study, we combined the UKA musculoskeletal multibody dynamics model, finite element model and wear model to investigate the effects of seven joint line height cases of fixed UKA implant on postoperative insert contact mechanics, cumulative sliding distance, linear wear depth and volumetric wear. As the elevation of the joint line height in UKA, the medial contact force and the joint anterior-posterior translation during swing phase were increased, and further the maximum von Mises stress, contact stress, linear wear depth, cumulative sliding distance, and the volumetric wear also were increased. Furthermore, the wear area of the insert gradually shifted from the middle region to the rear. Compared to 0 mm joint line height, the maximum linear wear depth and volumetric wear were decreased by 7.9% and 6.8% at -2 mm joint line height, and by 23.7% and 20.6% at -6 mm joint line height, the maximum linear wear depth and volumetric wear increased by 10.7% and 5.9% at +2 mm joint line height, and by 24.1% and 35.7% at +6 mm joint line height, respectively. UKA prosthetic joint line installation errors can significantly affect the wear life of the polyethylene inserted articular surfaces. Therefore, it is conservatively recommended that clinicians limit intraoperative UKA joint line height errors to -2-+2 mm.
Subject(s)
Humans , Arthroplasty, Replacement, Knee , Knee Joint , Knee Prosthesis , Mechanical Phenomena , Polyethylene , Osteoarthritis, Knee/surgery , Tibia/surgery , Biomechanical PhenomenaABSTRACT
SARS-CoV-2 is the causative agent for the COVID-19 pandemic and there is an urgent need to understand the cellular response to SARS-CoV-2 infection. Beclin-1 is an essential scaffold autophagy protein that forms two distinct subcomplexes with modulators Atg14 and UVRAG, responsible for autophagosome formation and maturation, respectively. In the present study, we found that SARS-CoV-2 infection triggers an incomplete autophagy response, elevated autophagosome formation but impaired autophagosome maturation, and declined autophagy by genetic knockout of essential autophagic genes reduces SARS-CoV-2 replication efficiency. By screening 28 viral proteins of SARS-CoV-2, we demonstrated that expression of ORF3a alone is sufficient to induce incomplete autophagy. Mechanistically, SARS-CoV-2 ORF3a interacts with autophagy regulator UVRAG to facilitate Beclin-1-Vps34-Atg14 complex but selectively inhibit Beclin-1-Vps34-UVRAG complex. Interestingly, although SARS-CoV ORF3a shares 72.7% amino acid identity with the SARS-CoV-2 ORF3a, the former had no effect on cellular autophagy response. Thus, our findings provide the mechanistic evidence of possible takeover of host autophagy machinery by ORF3a to facilitate SARS-CoV-2 replication and raises the possibility of targeting the autophagic pathway for the treatment of COVID-19.
ABSTRACT
The ongoing coronavirus disease (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a global public health concern due to relatively easy person-to-person transmission and the current lack of effective antiviral therapy. However, the exact molecular mechanisms of SARS-CoV-2 pathogenesis remain largely unknown. We exploited an integrated proteomics approach to systematically investigate intra-viral and virus-host interactomes for the identification of unrealized SARS-CoV-2 host targets and participation of cellular proteins in the response to viral infection using peripheral blood mononuclear cells (PBMCs) isolated from COVID-19 patients. Using this approach, we elucidated 251 host proteins targeted by SARS-CoV-2 and more than 200 host proteins that are significantly perturbed in COVID-19 derived PBMCs. From the interactome, we further identified that non-structural protein nsp9 and nsp10 interact with NKRF, a NF-[Kcy]B repressor, and may precipitate the strong IL-8/IL-6 mediated chemotaxis of neutrophils and overexuberant host inflammatory response observed in COVID-19 patients. Our integrative study not only presents a systematic examination of SARS-CoV-2-induced perturbation of host targets and cellular networks to reflect disease etiology, but also reveals insights into the mechanisms by which SARS-CoV-2 triggers cytokine storms and represents a powerful resource in the quest for therapeutic intervention.
