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Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by binding of the viral Spike protein to host receptor angiotensin-converting enzyme 2 (ACE2), followed by fusion of viral and host membranes. Although antibodies that block this interaction are in emergency use as early coronavirus disease 2019 (COVID-19) therapies, the precise determinants of neutralization potency remain unknown. We discovered a series of antibodies that potently block ACE2 binding but exhibit divergent neutralization efficacy against the live virus. Strikingly, these neutralizing antibodies can inhibit or enhance Spike-mediated membrane fusion and formation of syncytia, which are associated with chronic tissue damage in individuals with COVID-19. As revealed by cryoelectron microscopy, multiple structures of Spike-antibody complexes have distinct binding modes that not only block ACE2 binding but also alter the Spike protein conformational cycle triggered by ACE2 binding. We show that stabilization of different Spike conformations leads to modulation of Spike-mediated membrane fusion with profound implications for COVID-19 pathology and immunity.

BackgroundNeurovascular unit restoration is crucial for nerve regeneration, especially in critical gaps of injured peripheral nerve. Multipotent vascular stem cells (MVSCs) harvested from an adult blood vessel are involved in vascular remodeling; however, the therapeutic benefit for nerve regeneration is not clear.MethodsMVSCs were isolated from rats expressing green fluorescence protein (GFP), expanded, mixed with Matrigel matrix, and loaded into the nerve conduits. A nerve autograft or a nerve conduit (with acellular matrigel or MVSCs in matrigel) was used to bridge a transected sciatic nerve (10-mm critical gap) in rats. The functional motor recovery and cell fate in the regenerated nerve were investigated to understand the therapeutic benefit.ResultsMVSCs expressed markers such as Sox 17 and Sox10 and could differentiate into neural cells in vitro. One month following MVSC transplantation, the compound muscle action potential (CMAP) significantly increased as compared to the acellular group. MVSCs facilitated the recruitment of Schwann cell to regenerated axons. The transplanted cells, traced by GFP, differentiated into perineurial cells around the bundles of regenerated myelinated axons. In addition, MVSCs enhanced tight junction formation as a part of the blood-nerve barrier (BNB). Furthermore, MVSCs differentiated into perivascular cells and enhanced microvessel formation within regenerated neurovascular bundles.ConclusionsIn rats with peripheral nerve injuries, the transplantation of MVSCs into the nerve conduits improved the recovery of neuromuscular function; MVSCs differentiated into perineural cells and perivascular cells and enhanced the formation of tight junctions in perineural BNB. This study demonstrates the in vivo therapeutic benefit of adult MVSCs for peripheral nerve regeneration and provides insight into the role of MVSCs in BNB regeneration.

Background: The pTNM staging system is widely recognized as the most effective prognostic indicator for cancer. The latest update of this staging system introduced a new pathological staging system (ypTNM) for patients receiving neoadjuvant chemoradiotherapy (NACRT). However, whether the prognostic value of the ypTNM staging system for rectal cancer is similar to that of the pTNM staging system remains unclear. This study was conducted to compare the ypTNM and pTNM staging systems in terms of their prognostic value for patients with nonmetastatic rectal cancer undergoing proctectomy. Material and Methods: This study was conducted at a large teaching hospital. Between January 2014 and December 2022, 542 patients with rectal cancer were analyzed (median follow-up period, 60 months; range, 6–105 months). Of them, 258 and 284 were included in the pTNM and ypTNM groups, respectively. Inverse probability of treatment weighting (IPTW) was performed to account for the effects of confounders. Cox proportional-hazards regression was performed for the between-group comparison of overall survival (OS). Results: The crude model revealed that OS was similar between the two groups (p = 0.607). After performing IPTW, we found that patients with the same ypTNM- and pTNM-classified stages had similar overall survival (hazard ratio = 1.15; 95% CI = 0.76–1.73; p = 0.5074). Conclusions: For patients with rectal cancer who have received preoperative NACRT, the prognostic value of ypTNM staging appears to be similar to that of pTNM staging, mostly because of the downstaging effect of neoadjuvant chemoradiotherapy. [ABSTRACT FROM AUTHOR]

In regenerative medicine applications, the differentiation stage of implanted stem cells must be optimized to control cell fate and enhance therapeutic efficacy. We investigated the therapeutic potential of human induced pluripotent stem cell (iPSC)-derived cells at two differentiation stages on peripheral nerve regeneration. Neural crest stem cells (NCSCs) and Schwann cells (NCSC-SCs) derived from iPSCs were used to construct a tissue-engineered nerve conduit that was applied to bridge injured nerves in a rat sciatic nerve transection model. Upon nerve conduit implantation, the NCSC group showed significantly higher electrophysiological recovery at 1 month as well as better gastrocnemius muscle recovery at 5 months than the acellular group, but the NCSC-SC group didn't. Both transplanted NCSCs and NCSC-SCs interacted with newly-growing host axons, while NCSCs showed better survival rate and distribution. The transplanted NCSCs mainly differentiated into Schwann cells with no teratoma formation, and they secreted higher concentrations of brain-derived neurotrophic factor and nerve growth factor than NCSC-SCs. In conclusion, transplantation of iPSC-NCSCs accelerated functional nerve recovery with the involvement of stem cell differentiation and paracrine signaling. This study unravels the in vivo performance of stem cells during tissue regeneration, and provides a rationale of using appropriate stem cells for regenerative medicine.

Summary: The aim of this study was to create gluten‐free chiffon cakes by replacing wheat flour with rice flour (100%, 90% and 70% w/w) and adding yam (0%–30%). The effect of yam's water‐soluble fibre on cake batter properties was studied, including batter density, specific volume, colour, texture, moisture content, water activity and volatile compounds. Results revealed that yam addition decreased crumb lightness value, crust brown index and batter density. Batter viscosity and cake specific volume increased with yam levels, with the optimal amount being 10%. Specific volume decreased at a yam addition of 30%. Twenty‐four compounds were identified in gluten‐free chiffon cake with 10% yam addition (10Y). 1‐Octen‐3‐ol was the primary contributor, accounting for 89.9% odour activity value (OAV) of the aroma with a fruity, buttery, and mushroom odour, attributed to its low threshold. In addition, aldehyde compounds including hexanal, 3‐methylbutanal, 2‐methylbutanal, pentanal, 2‐methylpropanal, nonanal, octanal and heptanal, accounting for 9% of OAV, had high perception thresholds. [ABSTRACT FROM AUTHOR]