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This paper investigates the problem of adaptive synchronization for discrete-time complex dynamical networks with random delays. In such complex systems, there occurs two kinds of nonidentical probability delays, i.e. self-feedback delays and coupling delays, and these delays are assumed to take values in a given finite sets with probability distributions. By means of the Lyapunov theory, discrete-time Jensen inequality and reciprocal convex combination approach, several delay-probability-distribution-dependent conditions are derived in the linear matrix inequality (LMI) format such that the discrete-time complex dynamical networks with random delays are globally synchronization in mean square. In addition, we use Watts–Strogatz (WS) random complex networks and regular Rulkov networks as two numerical examples to illustrate the effectiveness of our theoretical analysis.

In spite of the successful development of effective countermeasures against Covid-19, variants have and will continue to emerge that could compromise the efficacy of currently approved neutralizing antibodies and vaccines. Consequently, novel and more efficacious agents are urgently needed. We have developed a bispecific antibody, 2022, consisting of two antibodies, 2F8 and VHH18. 2F8 was isolated from our proprietary fully synthetic human IDEAL (Intelligently Designed and Engineered Antibody Library)-VH/VL library and VHH18 is a single domain antibody isolated from IDEAL-nanobody library. 2022 was constructed by attaching VHH18 to the C-terminal of Fc of 2F8. 2022 binds two non-overlapping epitopes simultaneously on the RBD of the SARS-CoV-2 spike protein and blocks the binding of RBD to human angiotensin-converting enzyme 2 (ACE2). 2022 potently neutralizes SARS-CoV-2 and all of the variants tested in both pseudovirus and live virus assays, including variants carrying mutations known to resist neutralizing antibodies approved under EUA and that reduce the protection efficiency of current effective vaccines. The half-maximum inhibitory concentration (IC50) of 2022 is 270 pM, 30 pM, 20 pM, and 1 pM, for wild-type, alpha, beta, and delta pseudovirus, respectively. In the live virus assay, 2022 has an IC50 of 26.4 pM, 13.3 pM, and 88.6 pM, for wild-type, beta, and delta live virus, respectively. In a mouse model of SARS-CoV-2, 2022 showed strong prophylactic and therapeutic effects. A single administration of 2022 intranasal (i.n.) or intraperitoneal (i.p.) 24 hours before virus challenge completely protected all mice from bodyweight loss, as compared with up to 20% loss of bodyweight in placebo treated mice. In addition, the lung viral titers were undetectable (FRNT assay) in all mice treated with 2022 either prophylactically or therapeutically, as compared with around 1×105pfu/g lung tissue in placebo treated mice. In summary, bispecific antibody 2022 showed potent binding and neutralizing activity across a variety of SARS-CoV-2 variants and could be an attractive weapon to combat the ongoing waves of the COVID-19 pandemic propagated mainly by variants, especially, the much more contagious delta variant.

Background: To compare the pharmacokinetic (PK) profile, safety, and immunogenicity between golimumab and the biosimilar BAT2506 in healthy Chinese male subjects. Research design and methods: A tot...

This paper studied the adaptive pinning synchronization in complex networks with variable-delay coupling via periodically intermittent control. Theoretical analysis is included by means of Lyapunov functions and linear matrix inequalities (LMI) to make all nodes reach complete synchronization. Moreover, the synchronization criteria do not impose any restriction on the size of time delay. Numerical examples including the regular, Watts–Strogatz and scale-free BA random topological architecture are provided to illustrate the importance of our theoretical analysis.

A Pt/C/TiO2 nanotube composite catalyst was successfully prepared for enhanced methanol electro-oxidation. Pt nanoparticles with a particle size of 2 nm were synthesized by plasma sputtering in water, and anatase TiO2 nanotubes with an inner diameter of approximately 100 nm were prepared by a simple two-step anodization method and annealing process. Field-emission scanning electron microscopy images indicated that the different morphologies of TiO2 synthesized on the surface of Ti foils were dependent on the different anodization parameters. The electrochemical performance of Pt/C/TiO2 catalysts for methanol oxidation showed that TiO2 nanotubes were more suitable for use as Pt nanoparticle support materials than irregular TiO2 short nanorods due to their tubular morphology and better electronic conductivity. X-ray photoelectron spectroscopy characterization showed that the binding energies of the Pt 4f of the Pt/C/TiO2 nanotubes exhibited a slightly positive shift caused by the relatively strong interaction between Pt and the TiO2 nanotubes, which could mitigate the poisoning of the Pt catalyst by COads, and further enhance the electrocatalytic performance. Thus, the as-obtained Pt/C/TiO2 nanotubes composites may become a promising catalyst for methanol electro-oxidation.

In this paper, a Kaldor–Kalecki model of business cycle with both discrete and distributed delays is considered. With the corresponding characteristic equation analyzed, the local stability of the positive equilibrium is investigated. It is found that there exist Hopf bifurcations when the discrete time delay passes a sequence of critical values. By applying the method of multiple scales, the explicit formulae which determine the direction of Hopf bifurcation and the stability of bifurcating periodic solutions are derived. Finally, numerical simulations are carried out to illustrate our main results.

In this paper, local Hopf bifurcation of a gene expression model with three delays is investigated by applying the frequency domain approach. It is shown that Hopf bifurcation will occur as the bifurcation parameter, the sum of all delays, passes through a sequence of critical values. The direction and the stability of bifurcating periodic solutions are determined by the Nyquist criterion and the graphical Hopf bifurcation theorem. By using the Bendixson’s criterion for high-dimensional ordinary differential equations and global Hopf bifurcation theorem for functional differential equations, the global existence of periodic solutions is established. Numerical results are also included to give a verification test of the theoretical analysis.

There is an urgent need for developing advanced purification techniques with the merits of low cost and satisfactory capacity in order to meet the challenges in the current downstream purification of monoclonal antibodies (mAbs). Herein, a simple and inexpensive nitrogen heterocycle molecule, 1-vinylimidazole (VIM), was proposed as the capture ligand of antibodies for the first time. The corresponding VIM-based non-affinity polymeric material (polyVIM) was then fabricated via a one-step polymerization for use in the highly selective purification of antibodies. Compared to the previously reported materials, this novel material exhibited many advantages without clearly sacrificing selectivity, such as a simpler and faster fabrication (within 1.5 h), comparable or even higher binding capacity (saturated static adsorption capacity > 190 mg/g polymer, dynamic binding capacity about 31.62 mg/g polymer), lower non-specific protein adsorption, and much lower cost. Notably, the polyVIM can effectively purify the antibodies from multiple biological sources with high purity (95.4% for mAbs in the cell culture medium, 93.3% for hIgG in the human serum), with an acceptable recovery (91.6% for mAbs, 77.0% for hIgG), and good reusability (> 10 times). Moreover, the target ELISA binding assay and NFAT-luc reporter gene assay demonstrated that the enriched antibodies can well maintain their binding activity and bioactivity during the whole purification process. The excellent performance of the polyVIM material may be attributed to the high recognition ability of VIM for antibodies, as well as the biocompatible and antifouling properties of the porous polymer. This study provides a promising alternative material for the purification of mAbs in downstream processes and the enrichment of hIgG in human serum.

In this paper, we give a detailed study of the stable region in discrete-time FitzHugh–Nagumo delayed excitable Systems, which can be divided into two parts: one is independent of delay and the other is dependent on delay. Two different new states are to be observed, which are new steady states (equilibria-the excitable FitzHugh–Nagumo) or limit cycles/higher periodic orbits (the FitzHugh–Nagumo oscillators) as the origin loses its stability, and usually, one is synchronized and the other asynchronized. We also find out that there exist critical curves through which there occur fold bifurcations, flip bifurcations, Neimark–Sacker bifurcations and even higher-codimensional bifurcations etc. It is also shown that delay can play an important role in rich dynamics, such as the occurrence of chaos or not, by means of Lyapunov exponents, Lyapunov dimensions, and the sensitivity to the initial conditions. Multistability phenomena are also discussed including the coexistence of synchronized and asynchronized oscillators, or synchronized/asynchronized oscillators and multiple stable nontrivial equilibria etc.

T-DM1, an antibody drug conjugate (ADC), has been approved by FDA for patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane. DM1 is released because it is connected to the linker of T-DM1 by a thio-ether bond, which can be broken via retro-Michael addition. To improve the antibody-drug stability, we created an anti-HER2 ADC (BAT8001) which used a novel uncleavable linker to connect trastuzumab and a payload of maytansine derivative. BAT8001 exhibits similar level of potency against proliferation of HER2-overexpressed cells as T-DM1 and demonstrates strong inhibition activity on tumor growth in both cell-line and patient-derived xenograft models. Pharmacokinetics (PK) study in monkey reveals BAT8001 has similar level of exposure, half-life, and Cmax as T-DM1. BAT8001 Ph1 clinical trial in patients with HER2+ late-stage breast cancer recently was completed. The clinical study used standard “3+3” multiple-dose escalation method, evaluated BAT8001 safety, PK and explored the efficacy. Twenty-nine subjects were randomized and 27 subjects received the treatment with escalated dose 1.2mg/kg, 2.4mg/kg,3.6mg/kg, 4.8mg/kg and 6.0mg/kg. Two subjects died during the screening time without treatment due to disease progression. Nineteen (79.2%) subjects completed at least 4-cycle treatment. The PK parameter (Cmax and AUC(0-t)) values demonstrated dose-dependent linear relationship. In the safety evaluation, the incidences of AE and AE with CTCAE >=3 increased when dose escalated. The platelet count decrease and AST elevation were found to be the most common and severe AEs. Three subjects had serious adverse events (SAE) of bone destruction which were considered to be not investigated-drug related by the PI. Among those 3 subjects, 2 subjects withdrew from the study due to the SAE and 1 subject continued the treatment. The preliminary efficacy assessment after 10 months treatment found that 1 (3.7%) patient exhibited the complete response (CR), 5 (18.5%) patients exhibited the partial responses (PR), and 5(18.5%) patients exhibited the stable diseases. Based on the information above, the dose of 3.6mg/kg achieved target drug exposure and was found to be the effective and well-tolerated, which was selected to be the dose in the confirmatory clinical trial. Currently, a Phase 3, multicenter, randomized, open-label, controlled trial evaluating the efficacy and safety of BAT8001 has been initiated in patients with HER2+ metastatic breast cancer who previously received trastuzumab separately or in combination with taxanes. The trial is designed to compare BAT8001 versus lapatinib combined with capecitabine which is 2nd-line standard of care for metastatic breast cancer patients in China. This Phase 3 trial plans to recruit approximately 410 patients and by Jan 2019 more than 130 patients have received the treatment of BAT8001. The BAT8001 benefit-risk profile continues to support further development and the clinical results will be revealed by early 2020. Citation Format: Shusen Wang, Fei Xu, Ruoxi Hong, Wen Xia, Jin-Chen Yu, Weijia Tang, Jin Wei, ShuQiang Song, Zhaohe Wang, Li Zhang, Shengfeng Li. BAT8001, a potent anti-HER2 antibody drug conjugate with a novel uncleavable linker to reduce toxicity for patients with HER2-positive tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT053.

In this paper, some geometrical aspects of root distributions in a special polynomial of the form λ τ ( λ − ( 1 − α ) ) − β are discussed. Equivariant structures are explored in the corresponding systems. Some sufficient and necessary conditions for a pair of complex conjugate roots of the polynomial with τ = 3 lying on the unit circle. A comparison is made between two simple delayed discrete models, where one can be viewed as its perturbation of the other with delayed feedback. There exist rich dynamics in the perturbed system, such as chaotic, or even hyperchaotic behavior whereas only regular oscillation modes can be observed in the perturbed system. The introduction of delayed feedback can break or increase the special symmetrical/topological structure of the original system, which leads to complexity. Rich dynamics near equivariant bifurcations under the Z 4 / Z 8 cyclic group action is explored, including multiple bifurcations, multistability, chaos and hyperchaos etc. As the applications, one can find that there exist higher-codimensional bifurcations with 1:1 strong resonance and 1:2 strong resonance in those models with/without special equivariant systems, which were not discussed in Guo et al. (2008) [15] , Guo et al. (2008) [16] , Kuruklis (1994) [17] , Peng et al. (2008) [18] , Peng and Yang (2010) [19] , Peng and Yuan (2008) [20] , Peng and Yuan (2007) [21] , Wang and Peng (2009) [22] etc.

A new network of coupled maps is proposed in which the connections between units involve no delays but the intra-neural communication does, whereas in the work of Atay et al. [Phys. Rev. Lett. 92, 144101 (2004)], the focus is on information processing delayed by the inter-neural communication. We show that the synchronization of the network depends on not only the intrinsic dynamical features and inter-connection topology (characterized by the spectrum of the graph Laplacian) but also the delays and the coupling strength. There are two main findings: (i) the more neighbours, the easier to be synchronized; (ii) odd delays are easier to be synchronized than even ones. In addition, compared with those discussed by Atay et al. [Phys. Rev. Lett. 92, 144101 (2004)], our model has a better synchronizability for regular networks and small-world variants.

The hybrid projective synchronization (HPS) of a new hyperchaotic system is studied using a nonlinear feedback control. The nonlinear controller is designed according to Lyapunov’s direct method to guarantee HPS, which includes synchronization, anti-synchronization and projective synchronization. Numerical examples are presented in order to verify the effectiveness of the proposed scheme.