Prophylactic efficacy of an intranasal spray with 2 synergetic antibodies neutralizing Omicron.

BACKGROUNDAs Omicron is prompted to replicate in the upper airway, neutralizing antibodies (NAbs) delivered through inhalation might inhibit early-stage infection in the respiratory tract. Thus, elucidating the prophylactic efficacy of NAbs via nasal spray addresses an important clinical need.METHODSThe applicable potential of a nasal spray cocktail containing 2 NAbs was characterized by testing its neutralizing potency, synergetic neutralizing mechanism, emergency protective and therapeutic efficacy in a hamster model, and pharmacokinetics/pharmacodynamic (PK/PD) in human nasal cavity.RESULTSThe 2 NAbs displayed broad neutralizing efficacy against Omicron, and they could structurally compensate each other in blocking the Spike-ACE2 interaction. When administrated through the intranasal mucosal route, this cocktail demonstrated profound efficacy in the emergency prevention in hamsters challenged with authentic Omicron BA.1. The investigator-initiated trial in healthy volunteers confirmed the safety and the PK/PD of the NAb cocktail delivered via nasal spray. Nasal samples from the participants receiving 4 administrations over a course of 16 hours demonstrated potent neutralization against Omicron BA.5 in an ex vivo pseudovirus neutralization assay.CONCLUSIONThese results demonstrate that the NAb cocktail nasal spray provides a good basis for clinical prophylactic efficacy against Omicron infections.TRIAL REGISTRATIONwww.chictr.org.cn, ChiCTR2200066525.FUNDINGThe National Science and Technology Major Project (2017ZX10202203), the National Key Research and Development Program of China (2018YFA0507100), Guangzhou National Laboratory (SRPG22-015), Lingang Laboratory (LG202101-01-07), Science and Technology Commission of Shanghai Municipality (YDZX20213100001556), and the Emergency Project from the Science & Technology Commission of Chongqing (cstc2021jscx-fyzxX0001).

Potent human neutralizing antibodies against Nipah virus derived from two ancestral antibody heavy chains.

Nipah virus (NiV) is a World Health Organization priority pathogen and there are currently no approved drugs for clinical immunotherapy. Through the use of a naïve human phage-displayed Fab library, two neutralizing antibodies (NiV41 and NiV42) targeting the NiV receptor binding protein (RBP) were identified. Following affinity maturation, antibodies derived from NiV41 display cross-reactivity against both NiV and Hendra virus (HeV), whereas the antibody based on NiV42 is only specific to NiV. Results of immunogenetic analysis reveal a correlation between the maturation of antibodies and their antiviral activity. In vivo testing of NiV41 and its mature form (41-6) show protective efficacy against a lethal NiV challenge in hamsters. Furthermore, a 2.88 Å Cryo-EM structure of the tetrameric RBP and antibody complex demonstrates that 41-6 blocks the receptor binding interface. These findings can be beneficial for the development of antiviral drugs and the design of vaccines with broad spectrum against henipaviruses.

Enhancing View Synthesis with Depth-Guided Neural Radiance Fields and Improved Depth Completion.

Neural radiance fields (NeRFs) leverage a neural representation to encode scenes, obtaining photorealistic rendering of novel views. However, NeRF has notable limitations. A significant drawback is that it does not capture surface geometry and only renders the object surface colors. Furthermore, the training of NeRF is exceedingly time-consuming. We propose Depth-NeRF as a solution to these issues. Specifically, our approach employs a fast depth completion algorithm to denoise and complete the depth maps generated by RGB-D cameras. These improved depth maps guide the sampling points of NeRF to be distributed closer to the scene's surface, benefiting from dense depth information. Furthermore, we have optimized the network structure of NeRF and integrated depth information to constrain the optimization process, ensuring that the termination distribution of the ray is consistent with the scene's geometry. Compared to NeRF, our method accelerates the training speed by 18%, and the rendered images achieve a higher PSNR than those obtained by mainstream methods. Additionally, there is a significant reduction in RMSE between the rendered scene depth and the ground truth depth, which indicates that our method can better capture the geometric information of the scene. With these improvements, we can train the NeRF model more efficiently and achieve more accurate rendering results.

Microglia orchestrate synaptic and neuronal stripping: Implication in neuropsychiatric lupus.

Systemic lupus erythematosus (SLE), a multifactorial autoimmune disease, can affect the brain and cause neuropsychiatric dysfunction, also named neuropsychiatric lupus (NPSLE). Microglial activation is observed in NPSLE patients. However, the mechanisms regulating microglia-mediated neurotoxicity in NPSLE remain elusive. Here, we showed that M1-like proinflammatory cytokine levels were increased in the cerebrospinal fluid (CSF) of SLE patients, especially those with neuropsychiatric symptoms. We also demonstrated that MRL/lpr lupus mice developed anxiety-like behaviours and cognitive deficits in the early and active phases of lupus, respectively. An increase in microglial number was associated with upregulation of proinflammatory cytokines in the MRL/lpr mouse brain. RNA sequencing revealed that genes associated with phagocytosis and M1 polarization were upregulated in microglia from lupus mice. Functionally, activated microglia induced synaptic stripping in vivo and promoted neuronal death in vitro. Finally, tofacitinib ameliorated neuropsychiatric disorders in MRL/lpr mice, as evidenced by reductions in microglial number and synaptic/neuronal loss and alleviation of behavioural abnormalities. Thus, our results indicated that classically activated (M1) microglia play a crucial role in NPSLE pathogenesis. Minocycline and tofacitinib were found to alleviate NPSLE by inhibiting micrglial activation, providing a promising therapeutic strategy.

Clinical analysis of acute poisoning in children.

OBJECTIVE: The clinical characteristics of hospitalized children with acute poisoning were analyzed to provide a reference for preventing poisoning and seeking effective prevention and treatment. METHODS: The clinical data of 112 children with acute poisoning admitted to Qilu Hospital of Shandong University from January 1, 2018, to December 31, 2021, were collected and analyzed from different perspectives. RESULTS: The majority of acute poisoning cases that occurred in children were in early childhood and preschool age (89 cases, accounting for 79.4%). The most common types of poisoning were pesticide poisoning and drug poisoning, and the main ways of poisoning were accidental administration via the digestive tract and accidental ingestion. Poisoning occurred slightly more in spring and summer all year round, and most children had a good prognosis after timely treatment. CONCLUSION: Acute poisoning often occurs in children. Parental education and intensified child supervision are needed to prevent the incidence of unintentional poisoning.

Reliable prognostic definition and immunotherapy response prediction in bladder cancer, based on a novel aging-associated 5-gene signature model.

Background: Bladder cancer (BC) is a urological tumor which can be associated with a poor prognosis. Aging is a crucial factor in cancer development, but the role and prognostic value of aging-related genes (ARGs) in BC are unclear. Methods: In this study, with reference to The Cancer Genome Atlas (TCGA) database, a 5-gene signature model was constructed for the analysis of BC prognosis, immune microenvironment, and immunotherapy response. Least absolute shrinkage and selection operator (LASSO) and univariate Cox regression analyses were applied. Results: There was significant heterogeneity in the genetic variation and expression profiles of ARGs in BC. Striking variations were revealed in survival outcomes between high- and low-risk groups by Kaplan-Meier curves. The majority of samples of cases in the high-risk group belonged to the middle and late stage of the tumor and had a higher abundance of immune infiltration and immune checkpoint expression, and better immunotherapeutic effects. Conclusions: The risk score model of ARGs achieved more satisfactory results in the prediction of prognosis, clinical characteristics, immune infiltration, tumor mutational load, and immunotherapy in BC patients with good stability and reproducibility, offering innovative approaches and orientations for the diagnosis and treatment of patients with BC in the future.

An authentic assessment method for cordyceps sinensis.

Cordyceps Sinensis, renowned for its diverse pharmacological properties and the rarity of its natural species, faces significant challenges due to rampant adulteration by counterfeit products. Consequently, there is a crucial need to reliably identify Cordyceps species to ensure their quality and efficacy. While current analytical techniques predominantly rely on LC-MS, there remains a notable deficiency and substantial demand for the development of a unified, reproducible, and fast method suitable for commercial applications. In this study, we employed a cost-effective and straightforward approach utilizing headspace GC-MS to authenticate Cordyceps sinensis. This method enables the comprehensive analysis of the chemical profile, facilitating the identification of quality and authenticity in Cordyceps samples. Through a comparative analysis of the chemical profiles of seven authentic Cordyceps samples with seven other Cordyceps samples, we propose a Quality Assessment System for Authentic Cordyceps, encompassing the following criteria: 1) the presence of 29 compounds commonly found in authentic Cordyceps within the chemical profile, and 2) the area ratio of 3-methylbutanal to 2-methylbutanal falling within the range of 2.09-3.01. This method exhibits considerable promise as a standardized, reproducible, and expeditious technique for the quality assessment and authentication of Cordyceps.

Retrospective study of single-use digital flexible ureteroscopic lithotripsy versus miniaturized percutaneous nephrolithotomy for 1.5-2.5cm lower pole renal stones.

PURPOSE: Retrospective analysis was performed on the clinical information of patients with 1.5-2.5 cm lower pole renal stones treated by single-use digital flexible ureteroscopic lithotripsy (fURS) and miniaturized percutaneous nephrolithotomy (MPCNL) in affiliated hospital of the Nantong University from January 2020 to December 2022. To compare the safety and efficacy of single-use fURS and MPCNL in the treatment from 1.5cm to 2.5cm lower pole renal stones. METHODS: Clinical information of 141 patients were collected and divided into single-use fURS group and MPCNL group according to their treatment methods, including 83 patients in the single-use fURS group and 58 patients in the MPCNL group. Baseline data, data on the clinical characteristics of stones, laboratory examination data, operation time, and postoperative data of the two groups were collected. Statistical analysis was made on the collected data to analyze the differences and causes between the two groups of patients. RESULTS: There was no significant difference in the baseline data and preoperative clinical features of 141 patients between the two groups (P > 0.05). In comparison of postoperative serum indexes, the drop values of hemoglobin and creatinine in single-use fURS group were lower than those in MPCNL group, and the difference was statistically significant (P < 0.05). The stone free rate was higher in the MPCNL group than in the single-use fURS group on the first day after surgery. At the 1st month after surgery, the two groups were similar. At 3rd month after surgery, the single-use fURS group was slightly higher than the MPCNL group, with no statistical significance (P > 0.05). The total complication rate in single-use fURS group was slightly lower than that in MPCNL group, but there was no statistical significance (P > 0.05). CONCLUSIONS: Single-use fURS has similar safety and efficacy to MPCNL in the treatment of 1.5-2.5cm lower pole renal stones. Single-use fURS may be a new option for the treatment of these stones.

Structural insight into the macrocyclic inhibitor TPX-0022 of c-Met and c-Src.

c-Met has been an attractive target of prognostic and therapeutic studies in various cancers. TPX-0022 is a macrocyclic inhibitor of c-Met, c-Src and CSF1R kinases and is currently in phase I/II clinical trials in patients with advanced solid tumors harboring MET gene alterations. In this study, we determined the co-crystal structures of the c-Met/TPX-0022 and c-Src/TPX-0022 complexes to help elucidate the binding mechanism. TPX-0022 binds to the ATP pocket of c-Met and c-Src in a local minimum energy conformation and is stabilized by hydrophobic and hydrogen bond interactions. In addition, TPX-0022 exhibited potent activity against the resistance-relevant c-Met L1195F mutant and moderate activity against the c-Met G1163R, F1200I and Y1230H mutants but weak activity against the c-Met D1228N and Y1230C mutants. Overall, our study reveals the structural mechanism underlying the potency and selectivity of TPX-0022 and the ability to overcome acquire resistance mutations and provides insight into the development of selective c-Met macrocyclic inhibitors.

Risk factor analysis and prediction model for papillary thyroid carcinoma with lymph node metastasis.

Objective: We aimed to identify the clinical factors associated with lymph node metastasis (LNM) based on ultrasound characteristics and clinical data, and develop a nomogram for personalized clinical decision-making. Methods: A retrospective analysis was performed on 252 patients with papillary thyroid carcinoma (PTC). The patient's information was subjected to univariate and multivariate logistic regression analyses to identify risk factors. A nomogram to predict LNM was established combining the risk factors. The performance of the nomogram was evaluated using receiver operating characteristic (ROC) curve, calibration curve, cross-validation, decision curve analysis (DCA), and clinical impact curve. Results: There are significant differences between LNM and non-LNM groups in terms of age, sex, tumor size, hypoechoic halo around the nodule, thyroid capsule invasion, lymph node microcalcification, lymph node hyperechoic area, peak intensity of contrast (PI), and area under the curve (AUC) of the time intensity curve of contrast (P<0.05). Age, sex, thyroid capsule invasion, lymph node microcalcification were independent predictors of LNM and were used to establish the predictive nomogram. The ROC was 0.800, with excellent discrimination and calibration. The predictive accuracy of 0.757 and the Kappa value was 0.508. The calibration curve, DCA and calibration curve demonstrated that the prediction model had excellent net benefits and clinical practicability. Conclusion: Age, sex, thyroid capsule invasion, and lymph node microcalcification were identified as significant risk factors for predicting LNM in patients with PTC. The visualized nomogram model may assist clinicians in predicting the likelihood of LNM in patients with PTC prior to surgery.

Characterization of the Hemolytic Activity of Mastoparan Family Peptides from Wasp Venoms.

Biologically active peptides have attracted increasing attention in research on the development of new drugs. Mastoparans, a group of wasp venom linear cationic α-helical peptides, have a variety of biological effects, including mast cell degranulation, activation of protein G, and antimicrobial and anticancer activities. However, the potential hemolytic activity of cationic α-helical peptides greatly limits the clinical applications of mastoparans. Here, we systematically and comprehensively studied the hemolytic activity of mastoparans based on our wasp venom mastoparan family peptide library. The results showed that among 55 mastoparans, 18 had strong hemolytic activity (EC50 ≤ 100 µM), 14 had modest hemolytic activity (100 µM < EC50 ≤ 400 µM) and 23 had little hemolytic activity (EC50 > 400 µM), suggesting functional variation in the molecular diversity of mastoparan family peptides from wasp venom. Based on these data, structure-function relationships were further explored, and, hydrophobicity, but not net charge and amphiphilicity, was found to play a critical role in the hemolytic activity of mastoparans. Combining the reported antimicrobial activity with the present hemolytic activity data, we found that four mastoparan peptides, Parapolybia-MP, Mastoparan-like peptide 12b, Dominulin A and Dominulin B, have promise for applications because of their high antimicrobial activity (MIC ≤ 10 µM) and low hemolytic activity (EC50 ≥ 400 µM). Our research not only identified new leads for the antimicrobial application of mastoparans but also provided a large chemical space to support the molecular design and optimization of mastoparan family peptides with low hemolytic activity regardless of net charge or amphiphilicity.

Association Between Monocyte-to-Lymphocyte Ratio and Hematoma Progression After Cerebral Contusion.

BACKGROUND: The objective of this research was to examine the impact of the monocyte-to-lymphocyte ratio (MLR) on the advancement of hematoma after cerebral contusion. METHODS: The clinical information and laboratory test findings of people with cerebral contusion were retrospectively analyzed. Using the tertiles of MLR, the study participants were categorized into three groups, enabling the evaluation of the correlation between MLR and the advancement of hematoma after cerebral contusion. RESULTS: Among the cohort of patients showing progression, MLR levels were significantly higher compared with the nonprogress group (P < 0.001). The high MLR group had a significantly higher proportion of patients with hematoma progression compared with the medium and low MLR groups. However, the medium MLR group had a lower proportion of patients with hematoma progression compared with the low MLR group. High MLR levels were independently linked to a higher risk of hematoma progression (Odds Ratio 3.546, 95% Confidence Interval 1.187-10.597, P = 0.024). By incorporating factors such as Glasgow Coma Scale score on admission, anticoagulant/antiplatelet therapy, white blood cell count, and MLR into the model, the predictive performance of the model significantly improved (area under the curve 0.754). CONCLUSIONS: Our study suggests that MLR may serve as a potential indicator for predicting the progression of hematoma after cerebral contusion. Further research is necessary to investigate the underlying pathological and physiological mechanisms that contribute to the association between MLR and the progression of hematoma after cerebral contusion and to explore its clinical implications.

Distinct patterns of distribution, community assembly and cross-domain co-occurrence of planktonic archaea in four major estuaries of China.

BACKGROUND: Archaea are key mediators of estuarine biogeochemical cycles, but comprehensive studies comparing archaeal communities among multiple estuaries with unified experimental protocols during the same sampling periods are scarce. Here, we investigated the distribution, community assembly, and cross-domain microbial co-occurrence of archaea in surface waters across four major estuaries (Yellow River, Yangtze River, Qiantang River, and Pearl River) of China cross climatic zones (~ 1,800 km) during the winter and summer cruises. RESULTS: The relative abundance of archaea in the prokaryotic community and archaeal community composition varied with estuaries, seasons, and stations (reflecting local environmental changes such as salinity). Archaeal communities in four estuaries were overall predominated by ammonia-oxidizing archaea (AOA) (aka. Marine Group (MG) I; primarily Nitrosopumilus), while the genus Poseidonia of Poseidoniales (aka. MGII) was occasionally predominant in Pearl River estuary. The cross-estuary dispersal of archaea was largely limited and the assembly mechanism of archaea varied with estuaries in the winter cruise, while selection governed archaeal assembly in all estuaries in the summer cruise. Although the majority of archaea taxa in microbial networks were peripherals and/or connectors, extensive and distinct cross-domain associations of archaea with bacteria were found across the estuaries, with AOA as the most crucial archaeal group. Furthermore, the expanded associations of MGII taxa with heterotrophic bacteria were observed, speculatively indicating the endogenous demand for co-processing high amount and diversity of organic matters in the estuarine ecosystem highly impacted by terrestrial/anthropogenic input, which is worthy of further study. CONCLUSIONS: Our results highlight the lack of common patterns in the dynamics of estuarine archaeal communities along the geographic gradient, expanding the understanding of roles of archaea in microbial networks of this highly dynamic ecosystem.

Spatial intensity correlations of transmitted intensity patterns emerging from large particles.

Propagation of a coherent light beam through a random medium generates speckle patterns, in which some information of media and object is hidden. Speckles produced by particles smaller than wavelength are studied thoroughly, yet it is also essential to investigate speckles produced by larger particles. In this paper, the spatial intensity correlations of transmitted speckle patterns generated by large particles are studied theoretically and experimentally. A semi-empirical expression of spatial intensity correlation function of speckle patterns is derived based on Bethe-Salpeter equation, taking particle size and concentration into account. After performing experiments with various particle sizes and concentrations, we fit the theoretical expression to experimental results and determine the introduced parameters. We analyze the variation of spatial intensity correlation function with particle size and concentration. Theoretical analyses and experimental results given in this paper have potential applications in coherent imaging through random and disordered media.

Assessing the efficacy of bleaching powder in disinfecting marine water: Insights from the rapid recovery of microbiomes.

Single-bleaching powder disinfection is a highly prevalent practice to disinfect source water for marine aquaculture to prevent diseases. However, due to the decay of active chlorine and the presence of disinfectant resistance bacteria (DRB), the effects of bleaching powder on prokaryotic community compositions (PCCs) and function in marine water remain unknown. In the present study, the source water in a canvas pond was treated with the normal dose of bleaching powder, and the impact on PCCs and functional profiles was investigated using 16S rRNA gene amplicon sequencing. The bleaching powder strongly altered the PCCs within 0.5 h, but they began to recover at 16 h, eventually achieving 76% similarity with the initial time at 72 h. This extremely rapid recovery was primarily driven by the decay of Bacillus and the regrowth of Pseudoalteromonas, both of which are DRB. Abundant community not only help PCCs recover but also provide larger functional redundancy than rare community. During the recovery of PCCs, stochastic processes drove the community assembly. After 72 h, five out of seven identified disinfectant resistance genes related to efflux pump systems were highly enriched, primarily in Staphylococcus and Bacillus. However, 15 out of the 16 identified antibiotic resistance genes (ARGs) remained unchanged compared to the initial time, indicating that bleaching powder does not contribute to ARGs removal. Overall, the findings demonstrate that single-bleaching powder disinfection cannot successfully meet the objective of disease prevention in marine aquaculture water due to the extremely rapid recovery of PCCs. Hence, secondary disinfection or novel disinfection strategies should be explored for source water disinfection.

Characterization of the Molecular Diversity and Degranulation Activity of Mastoparan Family Peptides from Wasp Venoms.

Wasp stings have become an increasingly serious public health problem because of their high incidence and mortality rates in various countries and regions. Mastoparan family peptides are the most abundant natural peptides in hornet venoms and solitary wasp venom. However, there is a lack of systematic and comprehensive studies on mastoparan family peptides from wasp venoms. In our study, for the first time, we evaluated the molecular diversity of 55 wasp mastoparan family peptides from wasp venoms and divided them into four major subfamilies. Then, we established a wasp peptide library containing all 55 known mastoparan family peptides by chemical synthesis and C-terminal amidation modification, and we systematically evaluated their degranulation activities in two mast cell lines, namely the RBL-2H3 and P815 cell lines. The results showed that among the 55 mastoparans, 35 mastoparans could significantly induce mast cell degranulation, 7 mastoparans had modest mast cell degranulation activity, and 13 mastoparans had little mast cell degranulation activity, suggesting functional variation in mastoparan family peptides from wasp venoms. Structure-function relationship studies found that the composition of amino acids in the hydrophobic face and amidation in the C-terminal region are critical for the degranulation activity of mastoparan family peptides from wasp venoms. Our research will lay a theoretical foundation for studying the mechanism underlying the degranulation activity of wasp mastoparans and provide new evidence to support the molecular design and molecular optimization of natural mastoparan peptides from wasp venoms in the future.

Harringtonine: A more effective antagonist for Omicron variant.

Fusion with host cell membrane is the main mechanism of infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we propose that a new strategy to screen small-molecule antagonists blocking SARS-CoV-2 membrane fusion. Using cell membrane chromatography (CMC), we found that harringtonine (HT) simultaneously targeted SARS-CoV-2 S protein and host cell surface TMPRSS2 expressed by the host cell, and subsequently confirmed that HT can inhibit membrane fusion. HT effectively blocked SARS-CoV-2 original strain entry with the IC50 of 0.217 µM, while the IC50 in delta variant decreased to 0.101 µM, the IC50 in Omicron BA.1 variant was 0.042 µM. Due to high transmissibility and immune escape, Omicron subvariant BA.5 has become the dominant strain of the SARS-CoV-2 virus and led to escalating COVID-19 cases, however, against BA.5, HT showed a surprising effectiveness. The IC50 in Omicron BA.5 was even lower than 0.0019 µM. The above results revealed the effect of HT on Omicron is very significant. In summary, we characterize HT as a small-molecule antagonist by direct targeting on the Spike protein and TMPRSS2.

The role and regulation of Maf proteins in cancer.

The Maf proteins (Mafs) belong to basic leucine zipper transcription factors and are members of the activator protein-1 (AP-1) superfamily. There are two subgroups of Mafs: large Mafs and small Mafs, which are involved in a wide range of biological processes, such as the cell cycle, proliferation, oxidative stress, and inflammation. Therefore, dysregulation of Mafs can affect cell fate and is closely associated with diverse diseases. Accumulating evidence has established both large and small Mafs as mediators of tumor development. In this review, we first briefly describe the structure and physiological functions of Mafs. Then we summarize the upstream regulatory mechanisms that control the expression and activity of Mafs. Furthermore, we discuss recent studies on the critical role of Mafs in cancer progression, including cancer proliferation, apoptosis, metastasis, tumor/stroma interaction and angiogenesis. We also review the clinical implications of Mafs, namely their potential possibilities and limitations as biomarkers and therapeutic targets in cancer.