This study identifies mechanisms mediating responses to immune checkpoint inhibitors using mouse models of triple-negative breast cancer. By creating new mammary tumor models, we find that tumor mutation burden and specific immune cells are associated with response. Further, we developed a rich resource of single-cell RNA-seq and bulk mRNA-seq data of immunotherapy-treated and non-treated tumors from sensitive and resistant murine models. Using this, we uncover that immune checkpoint therapy induces T follicular helper cell activation of B cells to facilitate the anti-tumor response in these models. We also show that B cell activation of T cells and the generation of antibody are key to immunotherapy response and propose a new biomarker for immune checkpoint therapy. In total, this work presents resources of new preclinical models of breast cancer with large mRNA-seq and single-cell RNA-seq datasets annotated for sensitivity to therapy and uncovers new components of response to immune checkpoint inhibitors.

The separation of C 2 H 2 /CO 2 is an important process in industry but challenged by the trade-off of capacity and selectivity owning to their similar physical properties and identical kinetic molecular size. We report the first example of symmetrically interpenetrated dodecaborate pillared MOF, ZNU-1, for benchmark selective separation of C 2 H 2 from CO 2 with ahigh C 2 H 2 capacity of 76.3 cm 3 g À1 and recordC 2 H 2 /CO 2 selectivity of 56.6 (298 K, 1bar) among all the robust porous materials without open metal sites.S ingle crystal structure analysis and modeling indicated that the interpenetration shifting from asymmetric to symmetric mode provided optimal pore chemistry with ideal synergistic "2+ +2" dihydrogen bonding sites for tight C 2 H 2 trapping.The exceptional separation performance was further evidenced by simulated and experimental breakthroughs with excellent recyclability and high productivity (2.4 mol kg À1 )o f9 9.5 %p urity C 2 H 2 during stepped desorption process.

Endothelial-to-mesenchymal transition (EndMT) occurs during development and underlies the pathophysiology of multiple diseases. In tumors, unscheduled EndMT generates cancer-associated myofibroblasts that fuel inflammation and fibrosis, and may contribute to vascular dysfunction that promotes tumor progression. We report that freshly isolated subpopulations of tumor-specific endothelial cells (TEC) from a spontaneous mammary tumor model undergo distinct forms of EndMT in response to TGFβ stimulation. Whereas some TEC strikingly up-regulate alpha smooth muscle actin (SMA), a principal marker of EndMT and activated myofibroblasts, counterpart normal mammary gland endothelial cells (NEC) showed little change in SMA expression after TGFβ treatment. Compared with NEC, SMA+ TEC were 40 % less motile in wound healing assays and formed more stable vascular-like networks in vitro when challenged with TGFβ. Lineage tracing using ZsGreenCdh5-Cre reporter mice confirmed that only a fraction of vessels in breast tumors contain SMA+ TEC, suggesting that not all endothelial cells (EC) respond identically to TGFβ in vivo. Indeed, examination of 84 TGFβ-regulated target genes revealed entirely different genetic signatures in TGFβ-stimulated NEC and TEC cultures. Finally, we found that basic FGF (bFGF) exerts potent inhibitory effects on many TGFβ-regulated genes but operates in tandem with TGFβ to up-regulate others. EC challenged with TGFβ secrete bFGF which blocks SMA expression in secondary cultures suggesting a cell-autonomous or lateral-inhibitory mechanism for impeding mesenchymal differentiation. Together, our results suggest that TGFβ-driven EndMT produces a spectrum of EC phenotypes with different functions that could underlie the plasticity and heterogeneity of the tumor vasculature.

Magnesium-based batteries have received much attention as promising candidates to next-generation batteries because of high volumetric capacity, low price, and dendrite-free property of Mg metal. Herein, we reported HVO nanowire cathode with excellent electrochemical property in magnesium-based batteries. First, it shows a satisfactory magnesium storage ability with 304.2 mA h g capacity at 50 mA g. Second, it possesses a high-voltage platform of ∼2.0 V vs Mg/Mg. Furthermore, when evaluated as a cathode material for magnesium-based hybrid Mg/Li battery, it exhibits a high specific capacity of 305.4 mA h g at 25 mA g and can be performed in a wide working temperature range (-20 to 55 °C). Notably, the insertion-type ion storage mechanism of HVO nanowires in hybrid Mg/Li batteries are investigated by ex situ X-ray diffraction and Fourier transform infrared. This research demonstrates that the HVO nanowire cathode is a potential candidate for high-performance magnesium-based batteries.

are important factors. More efforts are required to develop low-cost and efficient electrode materials. [4,5] As an important part of battery components, anode materials have been one of the most critical and extensively studied aspects in electrochemical research. [6][7][8][9][10] Among the many anode materials, transition metal-based compounds are characterized as a promising species due to their abundant reserves and multiple valence nature. Having more electrons involved in electrochemical reactions can provide higher capacity that meet the energy density requirements of modern electrochemical storage devices. [11,12] In this regard, many efforts have been made to discover new transition metal-based anode materials such as carbides, oxides, phosphides, or sulfides. [13][14][15] Due to its abundance and low prices, mineral-type nickel sulfide has gained much attention in photo-electrochemistry and is widely used in semiconductor, magnetic, photo-electrocatalytic, thermoelectric, phase-converting materials, and electrode materials for rechargeable lithium-ion batteries. [16][17][18][19][20] In prior research, the numerous nickel sulfides applied in rechargeable lithiumion batteries (NiS, NiS 2 , Ni 3 S 2 , and Ni 3 S 4 ) have all possessed high theoretical capacities (NiS/589, NiS 2 /870, Ni 3 S 2 /445, and Ni 3 S 4 /703 mAh g −1 ). [20] However, nickel sulfides are seldom regarded as excellent candidates for lithium-ion batteries, mainly due to the instability in the nickel-rich active material. As a result, during lithiation and delithiation the active materials tend to be more susceptible to pulverization and collapse, making it difficult to form a stable interface. The everexpanding interface area between active materials and electrolyte will continuously consume Li + to form the solid electrolyte interface (SEI), resulting in low coulombic efficiency. Meanwhile, the electrically insulated SEI layer will wrap the active materials to form "inactive island" which results in rapid capacity decay and poor cycle performance. [21,22] Numerous strategies have been developed to address this issue, such as controlling cutoff voltage, [20] constructing nanomaterials, [21] and compositing with graphene. [23,24] However, despite extensive research efforts, improving the performance of nickel sulfide to achieve high specific capacity and long cycle life is still a challenge. [21,25,26] Herein, a step-divided construction method was developed successfully to synthesize the NiS x @carbon (NiS x @C) yolk-shell microboxes via a template-assisted coating, thermal Nickel sulfides are regarded as promising anode materials for advanced rechargeable lithium-ion batteries due to their high theoretical capacity. However, capacity fade arising from significant volume changes during operation greatly limits their practical applications. Herein, confined NiS x @C yolk-shell microboxes are constructed to address volume changes and confine the active material in the internal void space. Having benefited from the yolk-shell structure de...

No abstract

CAR T therapy targeting solid tumors is restrained by limited infiltration and persistence of those cells in the tumor microenvironment (TME). Here, we developed approaches to enhance the activity of CAR T cells using an orthotopic model of locally advanced breast cancer. CAR T cells generated from Th/Tc17 cells given with the STING agonists DMXAA or cGAMP greatly enhanced tumor control, which was associated with enhanced CAR T cell persistence in the TME. Using single-cell RNA sequencing, we demonstrate that DMXAA promoted CAR T cell trafficking and persistence, supported by the generation of a chemokine milieu that promoted CAR T cell recruitment and modulation of the immunosuppressive TME through alterations in the balance of immune-stimulatory and suppressive myeloid cells. However, sustained tumor regression was accomplished only with the addition of anti–PD-1 and anti–GR-1 mAb to Th/Tc17 CAR T cell therapy given with STING agonists. This study provides new approaches to enhance adoptive T cell therapy in solid tumors.

Strokes are perhaps the most serious complications of sickle cell disease (SCD) and by the fifth decade occur in approximately 25% of patients. While most patients do not develop strokes, mounting evidence indicates that even without brain abnormalities on imaging studies, SCD patients can present profound neurocognitive dysfunction. We sought to evaluate the neurocognitive behavior profile of humanized SCD mice (Townes, BERK) and to identify hematologic and neuropathologic abnormalities associated with the behavioral alterations observed in these mice. Heterozygous and homozygous Townes mice displayed severe cognitive deficits shown by significant delays in spatial learning compared to controls. Homozygous Townes also had increased depression- and anxiety-like behaviors as well as reduced performance on voluntary wheel running compared to controls. Behavior deficits observed in Townes were also seen in BERKs. Interestingly, most deficits in homozygotes were observed in older mice and were associated with worsening anemia. Further, neuropathologic abnormalities including the presence of large bands of dark/pyknotic (shrunken) neurons in CA1 and CA3 fields of hippocampus and evidence of neuronal dropout in cerebellum were present in homozygotes but not control Townes. These observations suggest that cognitive and behavioral deficits in SCD mice mirror those described in SCD patients and that aging, anemia, and profound neuropathologic changes in hippocampus and cerebellum are possible biologic correlates of those deficits. These findings support using SCD mice for studies of cognitive deficits in SCD and point to vulnerable brain areas with susceptibility to neuronal injury in SCD and to mechanisms that potentially underlie those deficits.