Demonstration of Physicochemical and Functional Similarity of the Biosimilar BAT1806/BIIB800 to Reference Tocilizumab.

BACKGROUND AND OBJECTIVE: Tocilizumab is an immunoglobulin G1 monoclonal antibody targeting the interleukin-6 receptor (IL-6R). BAT1806/BIIB800 (tocilizumab-bavi) has been developed as a biosimilar to the reference product tocilizumab (TCZ). The objective of this study was to demonstrate physicochemical and functional similarity between BAT1806/BIIB800 and TCZ in a comprehensive comparability exercise. METHODS: A comprehensive panel of over 20 methods was used to generate datasets comparing critical and non-critical product quality attributes for 10 BAT1806/BIIB800 lots and 44 TCZ lots (16 sourced from China, 16 from the EU, and 12 from the US). Primary structure, higher-order structure, and physicochemical properties were assessed using liquid chromatography, mass spectrometry, various spectroscopy techniques/methods, capillary electrophoresis, and thermoanalytical techniques. Fragment antigen-binding (Fab)- and fragment crystallizable (Fc)-mediated biological properties were assessed using cell-based assays, immunoassays, flow cytometry, and kinetic binding assays. RESULTS: BAT1806/BIIB800 and TCZ (irrespective of source) were shown to be similar in terms of structural and functional properties. No differences were observed in terms of the most critical quality attributes, that is, soluble-IL-6R binding and inhibition of IL-6-mediated cell proliferation. BAT1806/BIIB800 and TCZ demonstrated similarity in terms of Fab- and Fc-mediated binding and biological activity. Minor differences were observed in glycosylation (afucosylation and sialylation), glycation, aggregation, and charge variants, which were demonstrated to be not clinically relevant. CONCLUSION: BAT1806/BIIB800 and TCZ were highly similar for all critical quality attributes. Where differences were observed in less critical quality attributes, additional analytical assessments and clinical study results determined these to be not clinically meaningful.

Regulating the Critical Intermediates of Dual-Atom Catalysts for CO2 Electroreduction.

Electrocatalysis is a very attractive way to achieve a sustainable carbon cycle by converting CO2 into organic fuels and feedstocks. Therefore, it is crucial to design advanced electrocatalysts by understanding the reaction mechanism of electrochemical CO2 reduction reaction (eCO2RR) with multiple electron transfers. Among electrocatalysts, dual-atom catalysts (DACs) are promising candidates due to their distinct electronic structures and extremely high atomic utilization efficiency. Herein, the eCO2RR mechanism and the identification of intermediates using advanced characterization techniques, with a particular focus on regulating the critical intermediates are systematically summarized. Further, the insightful understanding of the functionality of DACs originates from the variable metrics of electronic structures including orbital structure, charge distribution, and electron spin state, which influences the active sites and critical intermediates in eCO2RR processes. Based on the intrinsic relationship between variable metrics and critical intermediates, the optimized strategies of DACs are summarized containing the participation of synergistic atoms, engineering of the atomic coordination environment, regulation of the diversity of central metal atoms, and modulation of metal-support interaction. Finally, the challenges and future opportunities of atomically dispersed catalysts for eCO2RR processes are discussed.

Constructing Symmetry-Mismatched RuxFe3-xO4 Heterointerface-Supported Ru Clusters for Efficient Hydrogen Evolution and Oxidation Reactions.

Ru-related catalysts have shown excellent performance for the hydrogen evolution reaction (HER) and hydrogen oxidation reaction (HOR); however, a deep understanding of Ru-active sites on a nanoscale heterogeneous support for hydrogen catalysis is still lacking. Herein, a click chemistry strategy is proposed to design Ru cluster-decorated nanometer RuxFe3-xO4 heterointerfaces (Ru/RuxFe3-xO4) as highly effective bifunctional hydrogen catalysts. It is found that introducing Ru into nanometric Fe3O4 species breaks the symmetry configuration and optimizes the active site in Ru/RuxFe3-xO4 for HER and HOR. As expected, the catalyst displays prominent alkaline HER and HOR performance with mass activity much higher than that of commercial Pt/C as well as robust stability during catalysis because of the strong interaction between the Ru cluster and the RuxFe3-xO4 support, and the optimized adsorption intermediate (Had and OHad). This work sheds light on a promsing approach to improving the electrocatalysis performance of catalysts by the breaking of atomic dimension symmetry.

Symmetry-Broken Ru Nanoparticles with Parasitic Ru-Co Dual-Single Atoms Overcome the Volmer Step of Alkaline Hydrogen Oxidation.

Efficient dual-single-atom catalysts are crucial for enhancing atomic efficiency and promoting the commercialization of fuel cells, but addressing the sluggish kinetics of hydrogen oxidation reaction (HOR) in alkaline media and the facile dual-single-atom site generation remains formidable challenges. Here, we break the local symmetry of ultra-small ruthenium (Ru) nanoparticles by embedding cobalt (Co) single atoms, which results in the release of Ru single atoms from Ru nanoparticles on reduced graphene oxide (Co1 Ru1,n /rGO). In situ operando spectroscopy and theoretical calculations reveal that the oxygen-affine Co atom disrupts the symmetry of ultra-small Ru nanoparticles, resulting in parasitic Ru and Co dual-single-atom within Ru nanoparticles. The interaction between Ru single atoms and nanoparticles forms effective active centers. The parasitism of Co atoms modulates the adsorption of OH intermediates on Ru active sites, accelerating HOR kinetics through faster formation of *H2 O. As anticipated, Co1 Ru1,n /rGO exhibits ultrahigh mass activity (7.68 A mgRu -1 ) at 50 mV and exchange current density (0.68 mA cm-2 ), which are 6 and 7 times higher than those of Ru/rGO, respectively. Notably, it also displays exceptional durability surpassing that of commercial Pt catalysts. This investigation provides valuable insights into hybrid multi-single-atom and metal nanoparticle catalysis.

Stability and Hopf bifurcation in an eco-epidemiological system with the cost of anti-predator behaviors.

The fear effect is a powerful force in prey-predator interaction, eliciting a variety of anti-predator responses which lead to a reduction of prey growth rate. To study the impact of the fear effect on population dynamics of the eco-epidemiological system, we develop a predator-prey interaction model that incorporates infectious disease in predator population as well as the cost of anti-predator behaviors. Detailed mathematical results, including well-posedness of solutions, stability of equilibria and the occurrence of Hopf bifurcation are provided. It turns out that population density diminishes with increasing fear, and the fear effect can either destabilize the stability or induce the occurrence of periodic behavior. The theoretical results here provide a sound foundation for understanding the effect of the anti-predator behaviors on the eco-epidemiological interaction.

Flower-Like Amorphous MoO3- x Stabilized Ru Single Atoms for Efficient Overall Water/Seawater Splitting.

Benefitting from the maximum atom utilization efficiency, special size quantum effects and tailored active sites, single-atom catalysts (SACs) have been promising candidates for bifunctional catalysts toward water splitting. Besides, due to the unique structure and properties, some amorphous materials have been found to possess better performance than their crystalline counterparts in electrocatalytic water splitting. Herein, by combining the advantages of ruthenium (Ru) single atoms and amorphous substrates, amorphous molybdenum-based oxide stabilized single-atomic-site Ru (Ru SAs-MoO3- x /NF) catalysts are conceived as a self-supported electrode. By virtue of the large surface area, enhanced intrinsic activity and fast reaction kinetics, the as-prepared Ru SAs-MoO3- x /NF electrode effectively drives both oxygen evolution reaction (209 mV @ 10 mA cm-2 ) and hydrogen evolution reaction (36 mV @ 10 mA cm-2 ) in alkaline media. Impressively, the assembled electrolyzer merely requires an ultralow cell voltage of 1.487 V to deliver the current density of 10 mA cm-2 . Furthermore, such an electrode also exhibits a great application potential in alkaline seawater electrolysis, achieving a current density of 100 mA cm-2 at a low cell voltage of 1.759 V. In addition, Ru SAs-MoO3- x /NF only has very small current density decay in the long-term constant current water splitting test.

Recent Progress in Framework Materials for High-Performance Lithium-Sulfur Batteries.

Lithium-Sulfur batteries (LSBs) have been considered as a promising candidate for the next generation of energy storage systems due to their high theoretical capacity. However, there are still lots of pending scientific and technological issues to be solved. Framework materials show great potential to address the above-mentioned issues due to the highly ordered distribution of pore sizes, effective catalytic activity, and periodically arranged aperture. In addition, good tunability gives framework materials unlimited possibilities to achieve satisfying performance for LSBs. In this review, the recent advances in pristine framework materials, their derivatives, and composites have been summarized. And a short conclusion and outlook regard to future prospects for guiding the development of framework materials and LSBs.

Plasma Meets MOFs: Synthesis, Modifications, and Functionalities.

As a porous and network materials consisting of metals and organic ligands, metal-organic frameworks (MOFs) have become one of excellent crystalline porous materials and play an important role in the era about materials science. Plasma, as a useful tool for stimulating efficient reactions under many conditions, and the plasma-assisted technology gets more attractions and endows MOFs more properties. Based on its feature, the research about the modifications and functionalities of MOFs have been developing a certain extent. This review contains a description of the methods for plasma-assisted modification and synthesis of MOFs, with specifically focusing on the plasma-assisted potential for modifications and functionalities of MOFs. The different applications of plasma-assisted MOFs were also presented.

Competitive Coordination-Pairing between Ru Clusters and Single-Atoms for Efficient Hydrogen Evolution Reaction in Alkaline Seawater.

The coordination environment of Ru centers determines their catalytic performance, however, much less attention is focused on cluster-induced charge transfer in a Ru single-atom system. Herein, by density functional theory (DFT) calculations, a competitive coordination-pairing between Ru clusters (RuRu bond) and single-atoms (RuO bond) is revealed leading to the charge redistribution between Ru and O atoms in ZnFe2 O4 units which share more free electrons to participate in the hydrogen desorption process, optimizing the proton adsorption and hydrogen desorption. Thus, a clicking confinement strategy for building a competitive coordination-pairing between Ru clusters and single-atoms anchored on ZnFe2 Ox nanosheets over carbon via RuO ligand (Ru1, n -ZnFe2 Ox -C) is proposed. Benefiting from the optimized coordination effect and the electronic synergy between Ru clusters and single-atoms, such a catalyst demonstrates the excellent activity and excellent stability in alkaline and seawater media, which has exceptional hydrogen evolution reaction activity with overpotentials as low as 10.1 and 15.9 mV to reach the current density of 10 mA cm-2 in alkaline and seawater media, respectively, higher than that of commercial Pt/C catalysts as a benchmark. Furthermore, it owns remarkably outstanding mass activity, approximately 2 and 8 times higher than that of Pt catalysts in alkaline and seawater media, respectively.

Prediction of lung cancer using gene expression and deep learning with KL divergence gene selection.

BACKGROUND: Lung cancer is one of the cancers with the highest mortality rate in China. With the rapid development of high-throughput sequencing technology and the research and application of deep learning methods in recent years, deep neural networks based on gene expression have become a hot research direction in lung cancer diagnosis in recent years, which provide an effective way of early diagnosis for lung cancer. Thus, building a deep neural network model is of great significance for the early diagnosis of lung cancer. However, the main challenges in mining gene expression datasets are the curse of dimensionality and imbalanced data. The existing methods proposed by some researchers can't address the problems of high-dimensionality and imbalanced data, because of the overwhelming number of variables measured (genes) versus the small number of samples, which result in poor performance in early diagnosis for lung cancer. METHOD: Given the disadvantages of gene expression data sets with small datasets, high-dimensionality and imbalanced data, this paper proposes a gene selection method based on KL divergence, which selects some genes with higher KL divergence as model features. Then build a deep neural network model using Focal Loss as loss function, at the same time, we use k-fold cross validation method to verify and select the best model, we set the value of k is five in this paper. RESULT: The deep learning model method based on KL divergence gene selection proposed in this paper has an AUC of 0.99 on the validation set. The generalization performance of model is high. CONCLUSION: The deep neural network model based on KL divergence gene selection proposed in this paper is proved to be an accurate and effective method for lung cancer prediction.

Cation/Anion Dual-Vacancy Pair Modulated Atomically-Thin Sex -Co3 S4 Nanosheets with Extremely High Water Oxidation Performance in Ultralow-Concentration Alkaline Solutions.

The density functional theory calculation results reveal that the adjacent defect concentration and electronic spin state can effectively activate the CoIII sites in the atomically thin nanosheets, facilitating the thermodynamic transformation of *O to *OOH, thus offering ultrahigh charge transfer properties and efficiently stabilizing the phase. This undoubtedly evidences that, for metal sulfides, the atom-scale cation/anion vacancy pair and surface electronic spin state can play a great role in enhancing the oxygen evolution reaction. Inspired by the theoretical prediction, interconnected selenium (Se) wired ultrathin Co3 S4 (Sex -Co3 S4 ) nanosheets with Co/S (Se) dual-vacancies (Se1.0 -Co3 S4 -VS/Se -VCo ) pairs are constructed by a simple approach. As an efficient sulfur host material, in an ultralow-concentration KOH solution (0.1 m), Se1.0 -Co3 S4 -VS/Se -VCo presents outstanding durability up to 165 h and a low overpotential of 289.5 mV at 10 mA cm-2 , which outperform the commercial Co3 S4 nanosheets (NSs) and RuO2 . Moreover, the turnover frequency of Se1.0 -Co3 S4 -VS/Se -VCo is 0.00965 s-1 at an overpotential of 0.39 V, which is 5.7 times that of Co3 S4 NSs, and 5.8 times that of commercial RuO2 . The finding offers a rational design strategy to create the multi-defect structure in catalysts toward high-efficiency water electrolysis.

Lanthanum Oxide Nickel Hydroxide Composite Triangle Nanosheets for Energy Density Asymmetric Supercapacitors.

Transition metal hydroxides are a kind of promising electrode material in electrochemical energy storage, but the poor conductivity limits their application. Lanthanides are good proton conductors and can usually improve the intrinsic conductivity of other materials. By integrating the merits of lanthanide elements and transition metal hydroxide, we designed lanthanum oxide nickel hydroxide composites (LONH) with unique ultrathin triangle nanosheet morphology via a controllable synthetic strategy for high-performance supercapacitors. When the LONH is used as positive electrode material in aqueous asymmetric supercapacitor, it reveals an energy density (107.8 W h kg-1 at 800 W kg-1), rate performance (86.9% retention at 4 kW kg-1) and outstanding cycle stability (more than 90% retention after 3,000 cycles). This work confirms that compositing La2O3 and Ni(OH)2 can significantly improve the supercapacitor performance of both pristine La2O3 and transition metal hydroxide composites. We hope this work would offer a good prospect for developing other lanthanide-transition metal hydroxide composites as an attractive class of electrode materials in electrochemical energy storage.

A Highly Sensitive LC-MS/MS Method for Targeted Quantitation of Lipase Host Cell Proteins in Biotherapeutics.

Identification and accurate quantitation of host cell proteins (HCPs) in biotherapeutic drugs has become increasingly important due to the negative impact of certain HCPs on the safety, stability, and other product quality of biotherapeutics. Recently, several lipase HCPs have been identified to potentially cause the enzymatic degradation of polysorbate, a widely used excipient in the formulation of biotherapeutics, which can severely impact the stability and product quality of drug products. In this study, we identified three lipase HCPs that were frequently detected in Chinese hamster ovary (CHO) cell cultures using shotgun proteomics, including phospholipase B-like 2 (PLBL2), lipoprotein lipase (LPL), and lysosomal acid lipase (LIPA). A targeted quantitation method for these three lipase HCPs was developed utilizing liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) with high-resolution multiple-reaction-monitoring (MRMhr) quantitation. The method demonstrated good sensitivity with low limit of quantitation (LLOQ) around 1 ng/mL, and linear dynamic range of three orders of magnitude for the three lipase HCPs. It has been applied for the characterization of process intermediates from various in-house monoclonal antibody (mAb) production. In addition, the method has also been used to evaluate the robustness of clearance for one of the lipase HCPs, PLBL2, under different column purification process conditions.

"High-risk" host cell proteins (HCPs): A multi-company collaborative view.

Host cell proteins (HCPs) are process-related impurities that may copurify with biopharmaceutical drug products. Within this class of impurities there are some that are more problematic. These problematic HCPs can be considered high-risk and can include those that are immunogenic, biologically active, or enzymatically active with the potential to degrade either product molecules or excipients used in formulation. Some have been shown to be difficult to remove by purification. Why should the biopharmaceutical industry worry about these high-risk HCPs? What approach could be taken to understand the origin of its copurification and address these high-risk HCPs? To answer these questions, the BioPhorum Development Group HCP Workstream initiated a collaboration among its 26-company team with the goal of industry alignment around high-risk HCPs. The information gathered through literature searches, company experiences, and surveys were used to compile a list of frequently seen problematic/high-risk HCPs. These high-risk HCPs were further classified based on their potential impact into different risk categories. A step-by-step recommendation is provided for establishing a comprehensive control strategy based on risk assessments for monitoring and/or eliminating the known impurity from the process that would be beneficial to the biopharmaceutical industry.

Epidemic models with discrete state structures.

The state of an infectious disease can represent the degree of infectivity of infected individuals, or susceptibility of susceptible individuals, or immunity of recovered individuals, or a combination of these measures. When the disease progression is long such as for HIV, individuals often experience switches among different states. We derive an epidemic model in which infected individuals have a discrete set of states of infectivity and can switch among different states. The model also incorporates a general incidence form in which new infections are distributed among different disease states. We discuss the importance of the transmission-transfer network for infectious diseases. Under the assumption that the transmission-transfer network is strongly connected, we establish that the basic reproduction number R 0 is a sharp threshold parameter: if R 0 ≤ 1 , the disease-free equilibrium is globally asymptotically stable and the disease always dies out; if R 0 > 1 , the disease-free equilibrium is unstable, the system is uniformly persistent and initial outbreaks lead to persistent disease infection. For a restricted class of incidence functions, we prove that there is a unique endemic equilibrium and it is globally asymptotically stable when R 0 > 1 . Furthermore, we discuss the impact of different state structures on R 0 , on the distribution of the disease states at the unique endemic equilibrium, and on disease control and preventions. Implications to the COVID-19 pandemic are also discussed.

Modeling the Effects of Latency Reversing Drugs During HIV-1 and SIV Brain Infection with Implications for the "Shock and Kill" Strategy.

Combination antiretroviral therapy (cART) has greatly increased life expectancy for human immunodeficiency virus-1 (HIV-1)-infected patients. Even given the remarkable success of cART, the virus persists in many different cells and tissues. The presence of viral reservoirs represents a major obstacle to HIV-1 eradication. These viral reservoirs contain latently infected long-lived cells. The "Shock and Kill" therapeutic strategy aims to reactivate latently infected cells by latency reversing agents (LRAs) and kill these reactivated cells by strategies involving the host immune system. The brain is a natural anatomical reservoir for HIV-1 infection. Brain macrophages, including microglia and perivascular macrophages, display productive HIV-1 infection. A mathematical model was used to analyze the dynamics of latently and productively infected brain macrophages during viral infection and this mathematical model enabled prediction of the effects of LRAs applied to the "Shock and Kill" strategy in the brain. The model was calibrated using reported data from simian immunodeficiency virus (SIV) studies. Our model produces the overarching observation that effective cART can suppress productively infected brain macrophages but leaves a residual latent viral reservoir in brain macrophages. In addition, our model demonstrates that there exists a parameter regime wherein the "Shock and Kill" strategy can be safe and effective for SIV infection in the brain. The results indicate that the "Shock and Kill" strategy can restrict brain viral RNA burden associated with severe neuroinflammation and can lead to the eradication of the latent reservoir of brain macrophages.

RuRh Bimetallene Nanoring as High-efficiency pH-Universal Catalyst for Hydrogen Evolution Reaction.

Electrocatalysis of the hydrogen evolution reaction (HER) is a vital and demanding, yet challenging, task to produce clean energy applications. Here, the RuRh2 bimetallene nanoring with rich structural defects is designed and successfully synthesized by a mixed-solvent strategy, displaying ascendant HER performance with high mass activity at -0.05 and -0.07 V, separately higher than that of the commercial Pt catalyst. Also, it maintains steady hydrogen bubble evolution even after 30 000 potential cycles in acid media. Furthermore, the RuRh2 bimetallene nanoring shows an outstanding activity in both alkaline and neutral media, outperforming that of Pt catalysts and other reported HER catalysts. A combination of atomic-scale structure observation and density functional theory calculations demonstrates that both the grain boundaries and symmetry breaking of RuRh2 bimetallene cannot only weaken the adsorption strength of atomic hydrogen, but also facilitate the transfer of electrons and the adsorption of reactants, further boosting the HER electrocatalytic performance in all pH values.

Effects of interleukin-2 concentration and administration method on proliferation and function of cytokine-induced killer cells.

BACKGROUND: Cytokine-induced killer cells (CIKs) adoptive cell transfer (ACT) is a common malignant tumor treatment method. Interleukin-2 (IL-2) is one of the essential cytokines for CIKs cultures. In different phase of CIKs (quiescent and exponential growth), due to different active states and IL-2R expression of the CIKs surface, different doses of IL-2 are required. However, most studies, only addressed the effects of IL-2 concentrations on the function of CIKs, and the differences between varied administration methods of IL-2 have not been explored. METHODS: This study established a novel sequential administration methods for IL-2. Different concentrations of IL-2 were added during different CIKs induction phases. Then, the proliferation ability of CIKs was evaluated using cell proliferation curves. The immune phenotype was analyzed by flow cytometry (FCM), and IFN-γ secretion ability and cytotoxicity were detected using enzyme-linked immunosorbent assay (ELISA) kits and cell counting kit-8, respectively. Multiple comparisons were conducted between each group to compare the function of CIKs in 12 experimental groups. RESULTS: As the IL-2 concentration increased, the number of CIKs continued to increase in each group, but the function of CIKs was not positively related to its number: CD3+ CD56+ subpopulation ratio, INF-γ secretion ability, and cytotoxicity showed irregular changes. During the quiescent and exponential growth phases, adding 300 and 1,000 U/mL IL-2 respectively achieved powerful CIKs (cell numbers of day 16: (384.37±2.05)×106/mL, proliferation: 128.12, CD3+ CD56+ subpopulation ratio: 40.9%, INF-γ secretion ability: 542 pg/mL, cytotoxicity: 40:1, 74.22). CONCLUSIONS: Different concentrations of IL-2 had a greater influence on the biological function of CIKs in different growth phases, and it is better to add IL-2 sequentially during the quiescent and exponential growth phases of CIKs.