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The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax’s limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitroand in vivoinhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xLwithout obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

In the present paper, a scheme of path sampling is explored for stochastic diffusion processes. The core issue is the evaluation of the diffusion propagators (spatial–temporal Green functions) by solving the corresponding Kolmogorov forward equations with Dirac delta functions as initials. The technique can be further used in evaluating general functional of path integrals. The numerical experiments demonstrated that the simulation scheme based on this approach overwhelms the popular Euler scheme and Exact Algorithm in terms of accuracy and efficiency in fairly general settings. An example of likelihood inference for the diffusion driven Cox process is provided to show the scheme’s potential power in applications.

A novel polycyclic π-system (1) featuring both a pleiaheptalene framework (a three-fused heptagon system) and nitrogen–boron–nitrogen (NBN) unit was constructed by electrophilic borylation. A combined experimental and computational study demonstrated that 1has a highly twisted π-backbone with approximate C2symmetry, which can undergo conformational isomerization at room temperature in contrast to pleiaheptalene. It was also found that 1can bind the fluoride ion in the solution, which induces changes in the absorption and emission spectra.

Combining the advantages of riveting and laser welding methods, and the characteristics of stepped rivets, excellent QP980 steel/CFRP weld-rivet hybrid joint joints were obtained and the effects of different laser powers on the welded joints were investigated. It was found that this welding method can reduce the damage to CFRP by heat input and obtain joints with favorable mechanical properties with maximum tensile shear load over 10 kN. Three failure characteristics of joints with this hybrid joining process were found: failure of steel joint, failure of CFRP, and failure of both steel joint and CFRP. The stress distribution characteristics in case of CFRP failure were simulated with ABAQUS. Different heat inputs resulted in different melting amounts of steel and CFRP, and these melted materials entered the assembly gap due to thermal expansion, thus changing the load-bearing characteristics of the hybrid joint. This load-bearing structure is not just a simple riveted and welded structure, but also forms a mechanical interlocking effect.

The side chains on non‐fullerene acceptors (NFAs) can affect greatly the photovoltaic performances of the resulting organic solar cells (OSCs) by regulating the molecular packing and orientation of NFAs. To explore suitable side groups for asymmetric simple NFAs, in this work, we design and synthesize two A‐D1‐A′‐D2‐A type NFAs, NTC‐4Cl, and PhNTC‐4Cl, which own flexible alkyloxy and rigid aryloxy side chains on the A′ cores, respectively. Due to the same molecular backbone (A′: benzotriazole; D1: thiophene; D2: cyclopentadithiophene; A: dichlorodicyanoindanone), NTC‐4Cl and PhNTC‐4Cl have similar absorptions and energy levels. However, the PhNTC‐4Cl‐based OSC gives a higher power conversion efficiency than that of the NTC‐4Cl‐based one (11.09% vs. 10.82%) because PhNTC‐4Cl shows more compact π–π stacking and dominant face‐on orientation, enhancing charge transport and mitigating charge recombination. Therefore, this work provides a new insight into the molecular design of high‐performance NFAs, especially the rational choice of side groups on asymmetric simple NFAs.

•Sonrotoclax is a potent and selective BCL2 inhibitor that is also effective in venetoclax-resistant BCL2 mutants both in vitro and in vivo.•The crystal structure of BCL2 G101V:sonrotoclax elucidates the molecular basis of overcoming G101V–induced venetoclax resistance.

Ceramic materials are the most popular additives to regulate the reinless interfacial reaction between lithium and the electrolyte by strengthening the SEI layer or tuning lithium deposition. Here, we propose an exceptional material, MgNiO2, abbreviated as MN, which can improve the durability of lithium metal anode. Since it is undecomposed up to 0 V vs Li/Li+, the MN’s particles give some semiconductive characteristics to the SEI layer to tune the interfacial reactions. The addition of MgNiO2in the protective films lowers interfacial resistance, which is responsible for the improved durability of Li|Cu cells: ∼210 cycles, which is 4 times longer than that of the control. Furthermore, this ceramic is used to modify the carbon film woven with carbon nanofibers (CNF @ MN). The cells with this modified 3-D host present excellent operational lives, as high as ∼2400 h in Li|Li symmetric cells and ∼280 cycles in the Li|NCM811 cells. Our approaches demonstrate that MN is an effective ceramic for stabilizing the lithium anode. It also indicates that the inert nature of the semiconductor to lithium is worth exploring thoroughly.

Aberrant activation of Bruton’s tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111(31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.

The effect of a water layer on the precipitation process in a three-channel microreactor at low temperatures was investigated. Fourier-transform infrared spectroscopy, X-ray powder diffraction, thermal gravimetric analysis, X-ray photoelectron spectroscopy, temperature-programmed reduction, and Brunauer–Emmett–Teller analysis were employed for studying the structural evolution of the intermediate products during the preparation of both zincian georgeite-derived and zincian malachite-derived catalysts, and catalytic activities were measured for methanol synthesis from syngas. It is manifested that the effect of uniform precipitates acts consecutively on the subsequent aging process, Zn incorporation in precursors, thermal decomposition, reduction, and catalytic performance of the catalysts. Numerical simulation revealed the change of species properties, and reaction rates at varying temperatures can lead to different regulations of the water layer, denoting that disparate ratios of the water layer were required for obtaining uniform precipitates under different conditions, which further suggests the key role of uniformity of the precipitates in preparing high-activity Cu/ZnO catalysts.

Bruton’s tyrosine kinase (BTK) plays an essential role in B-cell receptor (BCR)-mediated signaling as well as the downstream signaling pathway for Fc receptors (FcRs). Targeting BTK for B-cell malignancies by interfering with BCR signaling has been clinically validated by some covalent inhibitors, but suboptimal kinase selectivity may lead to some adverse effects, which also makes the clinical development of autoimmune disease therapy more challenging. The structure–activity relationship (SAR) starting from zanubrutinib (BGB-3111) leads to a series of highly selective BTK inhibitors, in which BGB-8035is located in the ATP binding pocket and has similar hinge binding to ATP but exhibits high selectivity over other kinases (EGFR, Tec, etc.). With an excellent pharmacokinetic profile as well as demonstrated efficacy studies in oncology and autoimmune disease models, BGB-8035has been declared a preclinical candidate. However, BGB-8035showed an inferior toxicity profile compared to that of BGB-3111.

Uncontrolled lithium growth and the consequent interfacial reaction are obstacles to the practical application of lithium metal anode. Here, a multifunctional subassembly of carbon nanotube paper grafted with a thin layer of LiNO3(LNO@CP) is proposed. According to the results of experiments and theory calculation, the nucleation sites are enriched and the nuclei are tailored into spherical shape on LNO@CP. Consequently, the Li plating gradually fills the void of LNO@CP and then grows outward uniformly, resulting in an increased Li reversibility and a stable solid electrolyte interphase layer. The LNO@CP covering the Li backup source works as a protective layer to defense the electrolyte corrosion effectively. The lithium metal battery with this multifunctional subassembly delivers a remarkable capacity retention of 81.2% after 500 cycles. This work emphasizes that the a protective layer such as LNO@CP is crucial to the high performance lithium metal battery.

In Vehicle‐to‐Everything (V2X), cellular Device‐to‐Device (D2D) communication can not only enhance system capacity and spectral utilization but also reduce the traffic load and communication delay. However, due to the fast variations of the channel state information (CSI) caused by high mobility of vehicles, the accurate CSI is difficult to be obtained in real‐time. In this paper, different from other previous researches that are subject to the perfect CSI, a more realistic channel state model is adopted that only the partial CSI of the communication links is available. Then we study the joint power allocation and spectrum sharing problem to maximize the total weighted ergodic capacity of all vehicular links, namely, Vehicle‐to‐Infrastructure (V2I) links and Vehicle‐to‐Vehicle (V2V) links. Meanwhile, the transmission reliability guarantees the quality of service (QoS) requirements of V2I and V2V. Since the formulated problem is a nonconvex mixed integer nonlinear programming (MINLP) problem, we first derive the strategy for obtaining the optimal solution of power allocation under arbitrary weighted factor and quantify different cases of feasible regions. Then we propose a two‐stage algorithm to complete the optimal resource allocation in polynomial time. Moreover, we further propose a low‐complexity spectrum sharing method based on the principles of Gale‐Shapley mechanism. The simulation results show that the proposed algorithms outperform the other baseline schemes significantly, and the low‐complexity scheme can effectively achieve a tradeoff between performance and complexity. V2X, aided with cellular D2D communication, has a great potential in enhancing the road safety and transportation. However, due to the fast variations of channel state information (CSI) caused by high mobility of vehicles, the accurate CSI is difficult to be obtained in real time. Therefore, we consider a more realistic channel state model that only partial CSI is available and propose the corresponding resource allocation scheme.

Benefiting from the evolution of nanotechnology, the combination therapy by gene interference and reactive oxygen species (ROS) scavenging are expected, which holds great potential in inflammatory bowel disease (IBD) therapy. However, the functional integration of different therapeutic modules through interface modification of gene vectors for safe and efficient treatment is urgently needed. Herein, we present a catechol chemistry-mediated core–shell nanoplatform for ROS scavenging-mediated oxidative stress alleviation and siRNA-mediated gene interference in a dextran sulfate sodium (DSS)-induced colitis model. The nanoplatform is constructed by employing mesoporous polydopamine nanoparticles (MPDA NPs) with surface modification of amines as the porous core for TNF-α-siRNA loading (31 wt %) and exerts an antioxidant function, while PDA-induced biomineralization of the calcium phosphate (CaP) coating is used as the pH-sensitive protective shell to prevent siRNA from premature release. The CaP layer degraded under weakly acidic subcellular conditions (lysosomes); thus, the synergistic integration of catechol and cation moieties on the exposed surface of MPDA resulted in an efficient lysosomal escape. Subsequently, effective ROS scavenging caused by the electron-donating ability of MPDA and efficient knocking down (40.5%) of tumor necrosis factor-α (TNF-α) viasufficient cytosolic gene delivery resulted in a synergistic anti-inflammation therapeutic effect both in vitroand in vivo. This work establishes the first paradigm of synergistic therapy in IBD by ROS scavenging and gene interference.

This paper describes the reversible phase transition behavior of a thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) shell at the surface of a hydrophilic core. Reversible addition-fragmentation transfer (RAFT) polymerization of N-isopropylacrylamide was conducted using a hydrophilic hyperbranched poly(glycidol) (HPG)-based macroRAFT agent. At lower temperatures (<30?°C), the resultant multiarm star block copolymer (HPG–PNIPAM) exists as unimolecular micelles, with hydrophilic HPG as the core and a densely grafted PNIPAM brush as the shell. In laser light scattering (LLS) studies, the concentration used for HPG–PNIPAM is 5 × 10-6?g?ml-1, to avoid any possible aggregation between dendritic unimolecular micelles above the lower critical solution temperature (~32?°C) of PNIPAM. What we observe for the phase transition of HPG–PNIPAM involves only unimolecular process. A combination of dynamic and static LLS studies of HPG–PNIPAM in aqueous solution reveals a reversible phase transition on heating and cooling.