Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity

Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced cancers. However, the tumor microenvironment (TME) functions as a formidable barrier that severely impairs the efficacy of ICIs. While the crosstalk between tumor vessels and immune cells determines the nature of anti-tumor immunity, it is skewed toward a destructive cycle in growing tumors. First, the disorganized tumor vessels hinder CD8⁺ T cell trafficking into the TME, disable effector functions, and even kill T cells. Moreover, VEGF, the key driver of angiogenesis, interferes with the maturation of dendritic cells, thereby suppressing T cell priming, and VEGF also induces TOX-mediated exhaustion of CD8⁺ T cells. Meanwhile, a variety of innate and adaptive immune cells contribute to the malformation of tumor vessels. Protumoral M2-like macrophages as well as T_H2 and Treg cells secrete pro-angiogenic factors that accelerate uncontrolled angiogenesis and promote vascular immaturity. While CD8⁺ T and CD4⁺ T_H1 cells suppress angiogenesis and induce vascular maturation by secreting IFN-γ, they are unable to infiltrate the TME due to malformed tumor vessels. These findings led to preclinical studies that demonstrated that simultaneous targeting of tumor vessels and immunity is a viable strategy to normalize aberrant vascular-immune crosstalk and potentiate cancer immunotherapy. Furthermore, this combination strategy has been evidently demonstrated through recent pivotal clinical trials, granted approval from FDA, and is now being used in patients with kidney, liver, lung, or uterine cancer. Overall, combining anti-angiogenic therapy and ICI is a valid therapeutic strategy that can enhance cancer immunity and will further expand the landscape of cancer treatment.Subject terms: Cancer immunotherapy, Cancer microenvironment, Tumour angiogenesis, Tumour immunology, Targeted therapies     

On an extension of Fekete's lemma

We show that if a real n × n non-singular matrix (n m) has all its minors of order m – 1 non-negative and has all its minors of order m which come from consecutive rows non-negative, then all mth order minors are non-negative, which may be considered an extension of Fekete's lemma.     

Comprehensive Mechanism for CO Electroreduction on Dual-Atom-Catalyst-Anchored N-Doped Graphene

Carbon neutrality has drawn increasing attention for realizing the carbon cyclization and reducing the greenhouse effect. Although the C1 products, such as CO, can be achieved with a high Faraday efficiency, the targeted production of C2 fuels as well as the mechanism have not been systematically investigated. In this work, we carry out a first-principles study to screen dual-atom catalysts (DACs) for producing C2 fuels through the electrocatalytic carbon monoxide reduction reaction (e-CORR). We find that methanol, ethanol and ethylene can be produced on both DAC−Co and DAC−Cu, while acetate can be achieved on DAC−Cu only. Importantly, methanol and ethylene are preferred on DAC−Co, while acetate and ethylene on DAC−Cu. Furthermore, we show that the explicit solvent can enhance the adsorption and influence the protonation steps, which subsequently affects the protonation and dimerization behavior as well as the performance and selectivity of e-CORR on DACs. We further demonstrate that the C−C coupling is easy to be formed and stabilized if the Integrated Crystal Orbital Hamilton Population (ICOHP) is low because of the low energy barrier. Our findings provide not only guidance on the design of novel catalysts for e-CORR, but an insightful understanding on the reduction mechanism.     

Counting bacteria on a microfluidic chip

This paper reports a lab-on-a-chip device that counts the number of bacteria flowing through a microchannel. The bacteria number counting is realized by a microfluidic differential Resistive Pulse Sensor (RPS). By using a single microfluidic channel with two detecting arm channels placed at the two ends of the sensing section, the microfluidic differential RPS can achieve a high signal-to-noise ratio. This method is applied to detect and count bacteria in aqueous solution. The detected RPS signals amplitude for Pseudomonas aeruginosa ranges from 0.05 V to 0.17 V and the signal-to-noise ratio is 5-17. The number rate of the bacteria flowing through the sensing gate per minute is a linear function of the sample concentration. Using this experimentally obtained correlation curve, the concentration of bacteria in the sample solution can be evaluated within several minutes by measuring the number rate of the bacteria flowing through the sensing gate of this microfluidic differential RPS chip. The method described in this paper is simple and automatic, and have wide applications in determining the bacteria and cell concentrations for microbiological and other biological applications.     

Layered perovskites with giant spontaneous polarizations for nonvolatile memories

A series of titanate-based layered perovskites having large values of the spontaneous polarization P(s) were developed for their applcations to nonvolatile ferroelectric random access memories. Among these, the Nd-modified bismuth titanate [Bi(4-x)Nd(x)Ti(3)O(12) (BNdT)] system exhibited the most remarkable ferroelectric properties. The c-axis oriented BNdT capacitor was characterized by a switchable remanent polarization 2P(r) of over 100 microC/cm(2) and imprinting and fatigue-free behavior. The active Ti site responsible for the giant P(s) was identified with the help of Rietveld analysis, x-ray absorption near-edge structure study, and ab initio quantum computations.     

In situ measurement of biaxial modulus of Si anode for Li-ion batteries

We report in situ measurement of biaxial moduli of a Si thin-film electrode as a function of its lithium concentration. During lithiation, biaxial compressive stress is induced in the Si film and it undergoes plastic flow. At any state-of-charge (SOC), a relatively small delithiation–relithiation sequence unloads and reloads the film elastically. From the stress and strain changes during a delithiation–relithiation cycle, the biaxial modulus of the film is calculated. Stress change is obtained by measuring the change in substrate curvature using a Multi-beam Optical Sensor; the elastic strain change is obtained from the change in SOC. By repeating these measurements at several different values of SOC, the biaxial modulus was seen to decrease from ca. 70 GPa for Li_0.32Si to ca. 35 GPa for Li_3.0Si. Such a significant reduction in elastic modulus has important implications for modeling stress evolution and mechanical degradation in Si-based anodes.     

Real-time measurement of stress and damage evolution during initial lithiation of crystalline silicon

Crystalline to amorphous phase transformation during initial lithiation in (100) Si wafers is studied in an electrochemical cell with Li metal as the counter and reference electrode. During initial lithiation, a moving phase boundary advances into the wafer starting from the surface facing the lithium electrode, transforming crystalline Si into amorphous Li(x)Si. The resulting biaxial compressive stress in the amorphous layer is measured in situ, and it was observed to be ca. 0.5 GPa. High-resolution TEM images reveal a very sharp crystalline-amorphous phase boundary, with a thickness of ～1 nm. Upon delithiation, the stress rapidly reverses and becomes tensile, and the amorphous layer begins to deform plastically at around 0.5 GPa. With continued delithiation, the yield stress increases in magnitude, culminating in a sudden fracture of the amorphous layer into microfragments, and the cracks extend into the underlying crystalline Si.     

An improved error bound for a finite element approximation of a model for phase separation of a multi-component alloy

Using the approach of Rulla (1996 SIAM J. Numer. Anal. 33, 68-87)for analysing the time discretization error and assuming moreregularity on the initial data, we improve on the error boundderived by Barrett and Blowey (1996 IMA J. Numer. Anal. 16,257-287) for a fully practical piecewise linear finite elementapproximation with a backward Euler time discretization of amodel for phase separation of a multi-component alloy.     

Time-Temperature-Transformation (TTT) Diagram of Battery-Grade Li-Garnet Electrolytes for Low-Temperature Sustainable Synthesis

Efficient and affordable synthesis of Li⁺ functional ceramics is crucial for the scalable production of solid electrolytes for batteries. Li-garnet Li₇La₃Zr₂O_12−d (LLZO), especially its cubic phase (cLLZO), attracts attention due to its high Li⁺ conductivity and wide electrochemical stability window. However, high sintering temperatures raise concerns about the cathode interface stability, production costs, and energy consumption for scalable manufacture. We show an alternative “sinter-free” route to stabilize cLLZO as films at half of its sinter temperature. Specifically, we establish a time-temperature-transformation (TTT) diagram which captures the amorphous-to-crystalline LLZO transformation based on crystallization enthalpy analysis and confirm stabilization of thin-film cLLZO at record low temperatures of 500 °C. Our findings pave the way for low-temperature processing via TTT diagrams, which can be used for battery cell design targeting reduced carbon footprints in manufacturing.