The neutralizing breadth of antibodies targeting diverse conserved epitopes between SARS-CoV and SARS-CoV-2.

Antibody therapeutics for the treatment of COVID-19 have been highly successful. However, the recent emergence of the Omicron variant has posed a challenge, as it evades detection by most existing SARS-CoV-2 neutralizing antibodies (nAbs). Here, we successfully generated a panel of SARS-CoV-2/SARS-CoV cross-neutralizing antibodies by sequential immunization of the two pseudoviruses. Of the potential candidates, we found that nAbs X01, X10, and X17 offer broad neutralizing potential against most variants of concern, with X17 further identified as a Class 5 nAb with undiminished neutralization against the Omicron variant. Cryo-electron microscopy structures of the three antibodies together in complex with each of the spike proteins of the prototypical SARS-CoV, SARS-CoV-2, and Delta and Omicron variants of SARS-CoV-2 defined three nonoverlapping conserved epitopes on the receptor-binding domain. The triple-antibody mixture exhibited enhanced resistance to viral evasion and effective protection against infection of the Beta variant in hamsters. Our findings will aid the development of antibody therapeutics and broad vaccines against SARS-CoV-2 and its emerging variants.

Standardized Ultrasound Diagnosis of Nuchal Cord.

OBJECTIVE: This study aims to investigate the formation factors that affect the angle of nuchal cord and explore the types of nuchal cord that exist and the process of standardized ultrasound diagnosis of nuchal cord. METHODS: Ultrasonography was performed on 707 fetuses with nuchal cord, to observe the direction of the coil, determine the type of coil, and analyze the correlation between the fetal position, placental location, and the direction of the coil with the angle of the umbilical cord. RESULTS: Among the 707 fetuses, those with 1 loop accounted for 89.67%, fetuses with 2 loops accounted for 6.08%, fetuses with 3 loops accounted for 0.28%, and fetuses with partial draping of the umbilical cord accounted for 3.96%. Nuchal cord mostly occurred in fetuses where the placenta was attached to the anterior wall of the uterus, and the α-shaped and C-shaped types were in the majority. The C-shaped type accounted for 43.14%, the α-shaped type for 40.88%, the O-shaped type for 12.02%, and the L-shaped type for 3.96%. CONCLUSION: The direction of the coil of the umbilical cord can be determined by blood flow vector observation. The fetal position, placental location, and the direction of the coil are the three factors affecting the coiling angle of the umbilical cord. Ultrasonic classification of nuchal cord can provide detailed information, which can be used by physicians when performing surgery on the fetus. The advances in the diagnosis procedure allow the diagnosis of nuchal cord to be carried out in an orderly manner, making it more accurate and standardized.

Mitochondrial redox-driven mitofusin 2 S-glutathionylation promotes neuronal necroptosis via disrupting ER-mitochondria crosstalk in cadmium-induced neurotoxicity.

Reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and mitochondrial dysfunction are known to affect the structural and functional damage in the neural system. Cadmium (Cd) is an environmental contaminant that is widely found in numerous environmental matrices and exhibits potential neurotoxic risk. However, it remains unclear how mitochondrial redox status induces, and whether Cd destabilizes, the ER-mitochondria crosstalk to have a toxic effect on the nervous system. Herein, in our present study, bioinformatics analysis revealed an important role of protein interaction and mitochondrial machinery in brain samples from Alzheimer's disease (AD) patients. Furthermore, we established a neurotoxicity model in vivo and in vitro induced by cadmium chloride (CdCl2). We demonstrated that CdCl2 exposure disrupts the balance in mitochondrial redox represented by enhanced mitochondrial ROS (mitoROS) levels, which enhance mitofusin 2 (Mfn2) S-glutathionylation and interrupt the mitochondria-associated ER membranes (MAMs) for crosstalk between the ER and mitochondria to induce neuronal necroptosis. Mechanistically, it was shown that CdCl2 exposure significantly enhances the mitochondria-associated degradation (MAD) of Mfn2 via S-glutathionylation, which inhibits Mfn2 localization to the MAMs and subsequently leads to the formation of the RIPK1-RIPK3-p-MLKL complex (a key component of the necrosome) at MAMs, to promote neuronal necroptosis. Furthermore, the glutaredoxin 1 (Grx1) catalyzed and Mfn2 overexpression restored S-glu-Mfn2, MAMs perturbation, necrosome formation, and necroptosis in neurons induced by CdCl2 exposure in vitro. Moreover, the intervention with antioxidants to reduce mitochondrial redox, such as N-acetyl-l-cysteine (NAC) and mitochondria-targeted antioxidant Mito-TEMPO, reduced the S-glutathionylation of Mfn2 involved in the antagonism of CdCl2-induced necroptosis and neurotoxicity in vivo and in vitro. Taken together, our results are the first time to demonstrate that S-glutathionylation of Mfn2 promotes neuronal necroptosis via disruption of ER-mitochondria crosstalk in CdCl2-induced neurotoxicity, providing the novel mechanistic insight into how hazardous chemical-induced adverse effects in various organs and tissues could be interpreted by intraorganellar pathways under the control of MAMs components in neurons.

Standardization of diagnosis for coiling of the umbilical cord around fetal neck by ultrasound.

OBJECTIVE: To elucidate classification of coiling of the umbilical cord around fetal neck (CUFN) by ultrasound and forming factors of entanglement angle of CUFN. METHODS: From January 2006 to December 2012, color Doppler ultrasonic was used to observe the blood flow vector of umbilical artery, and prospective descriptive observation was made for entanglement direction and type of 707 single fetuses taking prenatal examination in our hospital during the middle and late trimester of pregnancy and having umbilical cord echo around the neck. The relationship of position of fetus, position of placenta and entanglement direction of umbilical cord with the entanglement angle of umbilical cord is analyzed. RESULTS: Among the 707 fetuses, 634 had one circle of coiling, 43 had two circles of coiling, two had three circles of coiling, and 28 had CUFN. According to entanglement direction, 361 had entanglement from left to right and 318 had entanglement from right to left According to entanglement type, 305 were C-shaped type (43.14%), 85 were O-shaped type (12.02%), 289 were α-shaped type (40.88%), and 28 were L-shaped type (3.96%). CONCLUSION: Color Doppler ultrasound was used to detect the entanglement direction of umbilical cord and establish the five-type classification of umbilical cord around the neck, laying the foundation for the feasibility of establishing the normalization of diagnostic standard of umbilical cord around the neck.