Identification of key mutations responsible for the enhancement of receptor-binding affinity and immune escape of SARS-CoV-2 Omicron variant.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised concerns worldwide due to its enhanced transmissibility and immune escapability. The first dominant Omicron BA.1 subvariant harbors more than 30 mutations in the spike protein from the prototype virus, of which 15 mutations are located at the receptor binding domain (RBD). These mutations in the RBD region attracted significant attention, which potentially enhance the binding of the receptor human angiotensin-converting enzyme 2 (hACE2) and decrease the potency of neutralizing antibodies/nanobodies. This study applied the molecular dynamics simulations combined with the molecular mechanics-generalized Born surface area (MMGBSA) method, to investigate the molecular mechanism behind the impact of the mutations acquired by Omicron on the binding affinity between RBD and hACE2. Our results indicate that five key mutations, i.e., N440K, T478K, E484A, Q493R, and G496S, contributed significantly to the enhancement of the binding affinity by increasing the electrostatic interactions of the RBD-hACE2 complex. Moreover, fourteen neutralizing antibodies/nanobodies complexed with RBD were used to explore the effects of the mutations in Omicron RBD on their binding affinities. The calculation results indicate that the key mutations E484A and Y505H reduce the binding affinities to RBD for most of the studied neutralizing antibodies/nanobodies, mainly attributed to the elimination of the original favorable gas-phase electrostatic and hydrophobic interactions between them, respectively. Our results provide valuable information for developing effective vaccines and antibody/nanobody drugs.

Identification of the Intrinsic Motions and Related Key Residues Responsible for the Twofold Channel Opening of Poliovirus Capsid by Using an Elastic Network Model Combined with an Internal Coordinate.

Poliovirus (PV) is an infectious virus that causes poliomyelitis, which seriously threatens the health of children. The release of viral RNA is a key step of PV in host cell infection, and multiple lines of evidence have demonstrated that RNA release is initiated by the opening of the twofold channels of the PV capsid. However, the mechanism that controls the twofold channel opening is still not well understood. In addition, the channel opening motion of the recombinant PV capsid leads to the destruction of predominant neutralizing epitopes and thus hinders the capsid as a vaccine immunogen. Therefore, it is important to identify the intrinsic motions and the related key residues controlling the twofold channel opening for understanding the virus infection mechanism and developing capsid-based vaccines. In the present work, the width of the channel was selected as an internal coordinate directly related to the channel opening, and then the elastic network model (ENM) combined with the group theory were employed to extract the intrinsic motion modes that mostly contribute to the opening of the twofold channels. Our results show that the channel opening predominately induced by the breathing motion and the overall rotation of each protomer in the capsid. Then, an internal coordinate-based perturbation method was used to identify the key residues regulating the twofold channel opening of PV. The calculation results showed that the predicted key residues are mainly located at the twofold axes, the bottom of the canyons and the quasi threefold axes. Our study is helpful for better understanding the twofold channel opening mechanism and provides a potential target for preventing the opening of the channels, which is of great significance for PV vaccine design. The source code of this study is available at https://github.com/SJGLAB/CapsidKeyRes.git.

Novel meta-diamide insecticide, broflanilide, suppresses the population of common cutworm Spodoptera litura through its lethal and sublethal effects.

BACKGROUND: Broflanilide has been registered in China for the control of Lepidoptera and Coleoptera pests, and is widely used to control the target pests at lethal and sublethal levels. The lethal and sublethal effects of broflanilide on the common cutworm (CCW) Spodoptera litura Fabricius, a representative Lepidopteran pest in agricultural crops, were examined to explore its ecological influence on pests. RESULTS: In F0 , broflanilide had little influence on the hatchability of eggs, but significantly reduced the neonate survival rate. The lethal activity of broflanilide towards third-instar larvae and adults was 0.13 mg kg-1 (LD50 ) and 3.59 mg L-1 (LC50 ) respectively at 48 h. After being treated with a sublethal dose (LD10 and LD30 ) of broflanilide, the duration of third- to sixth-instar larvae and the mean fecundity of reproductive females were significantly increased, but pupation rate, weight of pupae and life-cycle rate were significantly decreased. In F1 , the duration of F1 larvae and the doubling time were prolonged, whereas the rates of pupation and the life cycle were decreased by 14.92% and 18.00%, respectively. The intrinsic rate of increase, finite rate of increase and net reproductive rate in the sublethal group were lower than in the control group. The relative fitness of F1 treated by LD10 and LD30 was 0.81 and 0.66, respectively. CONSLUSION: Broflanilide not only has highly lethal activity, but also suppresses the population growth and progeny of CCW, as a critical factor for guidelines of its usage in the field.

Acute pancreatitis connected with hypercalcemia crisis in hyperparathyroidism: A case report.

BACKGROUND: The association between primary hyperparathyroidism (PHPT) and acute pancreatitis is rarely reported. Here we describe the process of acute pancreatitis-mediated PHPT induced by hypercalcemia in a male patient. Hypercalcemia induced by undiagnosed PHPT may be the causative factor in recurrent acute pancreatitis. CASE SUMMARY: We report a case of hypercalcemia-induced acute pancreatitis caused by a functioning parathyroid adenoma in a 57-year-old man. The patient initially experienced a series of continuous gastrointestinal symptoms including abdominal distension, abdominal pain, nausea, vomiting, electrolyte disturbance, renal dysfunction, and acute pancreatitis. Due to prolonged hypercalcemia, the patient subsequently underwent surgical resection of the parathyroid adenoma. Two weeks after surgery, his serum calcium, amylase, and lipase concentrations were normal. The patient had a good recovery after a series of other relevant therapies. CONCLUSION: Acute pancreatitis as the first presentation is a rare clinical symptom caused by PHPT-induced hypercalcemia.

Uterine arteriovenous malformation combined with iliac arteriovenous malformation diagnosed by contrast-enhanced ultrasound: A case report and review of the literature.

 Uterine arteriovenous malformation (AVM) is an extremely rare condition characterized by abnormal connections between veins and arteries. The atypical clinical manifestations and relatively low morbidity of AVM are conducive to missed diagnosis. The present study describes a case of a 47-year-old female patient with congenital uterine AVM followed by iatrogenic AVM. The diagnosis was established by contrast-enhanced ultrasound combined with contrast-enhanced CT (CECT). Because the symptom of vaginal bleeding was severe, trophoblastic disease or neoplasia could be preferred. The manifestations on various imaging examinations were carefully assessed, and the relevant literature was also reviewed.

Thickness Calculation of Silicon Dioxide Nano-Film Based on GIXRR Reflectivity Curve.

To obtain nanometer thin film thickness fastly and accurately, a formula of linear fitting method based on the periodic Kiessig fringes for thickness determination is applied, and a series of SiO2 nanometer films on Si substrate with the film thickness ranging from 10 to 120 nm have been calculated with the formula. These samples are prepared with thermal atomic layer deposition (T-ALD) process and film thickness is measured with grazing incidence X-ray reflection (GIXRR) technique, in addition, the linear fitting procedure and several influencing factors among it are studied, all of the work is based on the reflectivity curve from GIXRR experiment. While at the same time, another fitting method based on a soft named Global Fit2.0 is brought into this study to compare the two obtained thicknesses from two kinds of analysis methods. In the end a novel method for film thickness determination-empirical curve is presented. The results show that: during the linear fitting process, the peak position series have a main effect on thickness determination, thickness will increase when the peak position adds up; Besides, any peak's corresponding reflection angle also has a significant effect on the thickness determination, it is expressed in the form of interference fringe period, thickness will decrease while the interference fringe period increases, however, the errors from either peak series or fringe period can be further weakened with trial and error method, calibration procedure of critical angle and interference fringe period individually. Choosing the same sample with random thickness, no matter using the linear fitting and soft fitting method, the two gained film thicknesses are consistent and the thickness deviation is less than 0.1 nm, which illustrates the accuracy of linear fitting method for thickness determination. An empirical relationship between film thickness and interference fringe period is then put forward on the foundation of the accurate thickness determination, according this curve, the target film thickness is directly got by putting an interference fringe period in the empirical curve. This novel method not only avoids the messy procedure of choosing peak position series or their corresponding angles during linear fitting process, but also avoids the complex task of building a correct structure for soft fitting process; it is of great significance in confirming thin film thickness with quick speed and high accuracy.

[Protection of Grateloupia filicina polysaccharide against hepatotoxicity induced by Dioscorea bulbifera L].

The present study was designed to observe the protection of Grateloupia filicina polysaccharide (GFP) against hepatotoxicity induced by Dioscorea bulbifera L in mice and its underlying mechanism. GFP was intragastrically (ig) given to mice at various doses. After 6 days, the mice were treated with ethyl acetate extract of Dioscorea bulbifera L (EF, ig). Serum levels of alanine/aspartate aminotransferase (ALT/AST), alkaline phosphatase (ALP), total bilirubin (TB) were measured, and liver histological evaluation was conducted. Furthermore, reductions of liver glutathione (GSH) amount and glutamate cysteine ligase (GCL) activity were tested. The expressions of GCL-c, GCL-m, and HO-1 (heme oxygenase-1) in liver were observed by Western-blot. The results showed that GFP (600 mg x kg(-1)) decreased EF-induced the increase of serum ALT, AST and TB, and GFP (400, 600 mg x kg(-1)) inhibited EF-induced the increase of serum ALP. Liver histological evaluation showed that the liver injury induced by EF was relieved after treated with GFP. GFP further increased liver GSH amount and reversed EF-induced the decrease of GCL activity. The Western-blot result showed that GFP augmented EF-induced the increase of HO-1, and reversed EF-induced the decrease of GCL-c. In conclusion, GFP can act against the oxidative stress liver injury induced by Dioscorea bulbifera L in mice.