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Lyme spirochetes have coevolved with ticks to optimize transmission to hosts using tick salivary molecules (TSMs) to counteract host defenses. TSMs modulate various molecular events at the tick–host interface. Lymphotoxin-beta receptor (LTβR) is a vital immune receptor and plays protective roles in host immunity against microbial infections. We found that Ltbr knockout mice were more susceptible to Lyme disease spirochetes, suggesting the involvement of LTβR signaling in tick-borne Borrelia infection. Further investigation showed that a 15-kDa TSM protein from Ixodes persulcatus ( I. persulcatus salivary protein; IpSAP) functioned as an immunosuppressant to facilitate the transmission and infection of Lyme disease spirochetes. IpSAP directly interacts with LTβR to block its activation, thus inhibiting the downstream signaling and consequently suppressing immunity. IpSAP immunization provided mice with significant protection against I. persulcatus– mediated Borrelia garinii infection. Notably, the immunization showed considerable cross-protection against other Borrelia infections mediated by other ixodid ticks. One of the IpSAP homologs from other ixodid ticks showed similar effects on Lyme spirochete transmission. Together, our findings suggest that LTβR signaling plays an important role in blocking the transmission and pathogenesis of tick-borne Lyme disease spirochetes, and that IpSAP and its homologs are promising candidates for broad-spectrum vaccine development.

The feature endowing atomic Ni-N-C electrocatalysts with exceptional intrinsic alkaline hydrogen evolution activity is hitherto not well-documented and remains elusive. To this end, we rationally exploited the hierarchical porous carbon microstructures as scaffolds to construct unique Ni-N

Glycolaldehyde, a C2 compound, is the simplest sugar molecule, but whether it inherently exists in plants remains unclear due to its complicated existence form in different reaction conditions.

Supplementary Figure 5. FTY720 could efficiently prohibit lymphocytes from exiting the lymphoid organ.

Supplementary Figure 4. The therapeutic function of anti-CD20 is NK cell-independent.

Supplementary Figure 1. The therapeutic effect of anti-CD20 is not CD4+ T cell-dependent.

Supplementary Figure 7. Model for generation of anti-tumor T-cell response induced by anti-CD20 treatment.

Supplementary Figure 6. The percentage of CTLA4+ CD8+ T cells is much lower than that of CTLA-4+ Treg cells in the large established B-cell lymphoma.

Supplementary Figure 3. Clophosome could deplete macrophage efficiently, without depleting DCs.

Supplementary Figure 2. DT could deplete DCs efficiently in CD11c-DTR mice, without affecting macrophages so much.

Purpose: The inhibition of tumor growth by anti-CD20 antibody (Ab) treatment is mediated by Ab- and complement-dependent cytotoxicity in xenograft tumor models. In addition, anti-CD20 therapy for B-cell lymphoma can result in intrinsic and extrinsic tumor resistance to further Ab treatment. However, adaptive immune response–related resistance has not been well studied in anti-CD20–mediated tumor control, and adaptive immunity has long been underestimated. The purpose of this study was to explore whether T cells are involved in mediating the effects of anti-CD20 therapy and what factors contribute to adaptive immune response–related resistance.Experimental Design: Using a syngeneic mouse B-cell lymphoma model, we investigated the role of CD8+ T cells in anti-CD20–mediated tumor regression. Furthermore, we revealed how the tumor-specific T-cell response was initiated by anti-CD20. Finally, we studied adaptive immune response–related resistance in advanced B-cell lymphoma.Results: CD8+ T cells played an essential role in anti-CD20–mediated tumor regression. Mechanistically, anti-CD20 therapy promoted dendritic cell (DC)-mediated cross-presentation. Importantly, macrophages were also necessary for the increase in the tumor-specific CTL response after anti-CD20 treatment, via the production of type I IFN to activate DC function. Furthermore, adaptive resistance is gradually developed through the CTLA-4 pathway in Treg cells in larger lymphomas. Further blockade of CTLA-4 can synergize with anti-CD20 treatment in antitumor activities.Conclusions: The therapeutic function of anti-CD20 depends on tumor-specific CD8+ T-cell responses initiated by anti-CD20 through macrophages and DCs. CTLA-4 blockade can synergize with anti-CD20 to overcome adaptive immune response–related resistance in advanced B-cell lymphoma. Clin Cancer Res; 23(1); 193–203. ©2016 AACR.

Cedryl acetate (CA), also called acetyl cedrene, is approved by the FDA as a flavoring or adjuvant to be added to foods. In this study, we aimed to investigate the preventive benefits of CA on obesity and obesity-related metabolic syndrome caused by a high-fat diet (HFD). Three groups of C57BL/6J mice (ten-week-old) were fed Chow, an HFD, or an HFD with CA supplementation (100 mg/kg) for 19 weeks. We observed that CA supplementation significantly reduced weight gain induced by an HFD, decreased the weight of the visceral fat pads, and prevented adipocyte hypertrophy in mice. Moreover, mice in the CA group showed significant improvements in hepatic lipid accumulation, glucose intolerance, insulin resistance, and gluconeogenesis compared with the mice in the HFD group. Since 16S rRNA analysis revealed that the gut microbiota in the CA and HFD groups were of similar compositions at the phylum and family levels, CA may have limited effects on gut microbiota in HFD-fed mice. The beneficial effects on the metabolic parameters of CA were reflected by CA’s regulation of metabolism-related gene expression in the liver (including Pepck, G6Pase, and Fbp1) and the epididymal white adipose tissues (including PPARγ, C/EBPα, FABP4, FAS,Cytc, PGC-1α, PRDM16, Cidea, and COX4) of the mice. In summary, a potent preventive effect of CA on HFD-induced obesity and related metabolic syndrome was highlighted by our results, and CA could be a promising dietary component for obesity intervention.

IL-15 is a promising cytokine to expand NK and CD8(+) T cells for cancer immunotherapy, but its application is limited by dose-limiting, on-target off-tumor toxicity. Here, we have developed a next-generation IL-15 that is activated inside the tumor microenvironment (TME). This pro-IL-15 has the extracellular domain of IL-15Rβ fused to the N-terminus of sIL-15-Fc through a tumor-enriched Matrix Metalloproteinase (MMP) cleavable peptide linker to block its activity. Unlike sIL-15-Fc, pro-IL-15 does not activate the peripheral expansion of NK cells and T cells, thus reducing systemic toxicity, but it still preserves efficient anti-tumor abilities. In various mouse tumors, the anti-tumor effect of pro-IL-15 depends on intratumoral CD8(+) T cells and IFN-γ. Pro-IL-15 increases the stem-like TCF1(+)Tim-3(−)CD8(+) T cells within tumor tissue and helps overcome immune checkpoint blockade (ICB) resistance. Moreover, pro-IL-15 synergizes with current tyrosine kinase inhibitor (TKI) targeted-therapy in a poorly inflamed TUBO tumor model, suggesting that pro-IL-15 helps overcome targeted-therapy resistance. Our results demonstrate a next-generation IL-15 cytokine that can stimulate potent anti-tumor activity without severe toxicity.

Checkpoint blockade immunotherapy releases the inhibition of tumor-infiltrating lymphocytes (TILs) but weakly induces TIL proliferation. Exogenous IL-15 could further expand TILs and thus synergize with αPD-L1 therapy. However, systemic delivery of IL-15 extensively expands peripheral NK cells, causing severe toxicity. To redirect IL-15 to intratumoral PD-1+CD8+T effector cells instead of NK cells for better tumor control and lower toxicity, we engineered an anti–PD-1 fusion with IL-15-IL-15Rα, whose activity was geographically concealed by immunoglobulin Fc region with an engineered linker (αPD-1-IL-15-R) to bypass systemic NK cells. Systematic administration of αPD-1-IL-15-R elicited extraordinary antitumor efficacy with undetectable toxicity. Mechanistically, cis-delivery of αPD-1-IL-15-R vastly expands tumor-specific CD8+T cells for tumor rejection. Additionally, αPD-1-IL-15-R upregulated PD-1 and IL-15Rβ on T cells to create a feedforward activation loop, thus rejuvenating TILs, not only resulting in tumor control in situ, but also suppressing tumor metastasis. Collectively, renavigating IL-15 to tumor-specific PD-1+CD8+T cells, αPD-1-IL-15-R elicits effective systemic antitumor immunity.

Currently, pyrolysis as the most widely used method still has some key issues not well resolved for synthesis of carbon-supported single-atom catalysts (C-SACs), e.g., the sintering of metal atoms at high temperature as well as the high cost and complicated preparations of precursors. In this report, molten salts are demonstrated to be marvellous medium for preparation of C-SACs by pyrolysis of small molecular precursors (ionic liquid). The ultrastrong polarity on one hand establishes robust interaction with precursor and enables better carbonization, resulting in largely enhanced yield. On the other hand, the aggregation of metal atoms is effectively refrained while no nanoparticle or cluster is formed. By this strategy, a C-SAC with atomically dispersed Fe-N4 sites and a high specific area over 2000 m2 g−1 is obtained, which illustrates high ORR activity in both acid and alkaline media. Moreover, this SAC exhibits superior methanol tolerance and stability after acid soaking at 85 °C for 48 h. It is believed that the molten-salts-assisted pyrolysis can be developed into a routine strategy as it not only can largely simply the synthesis of C-SACs, but also can be extended to prepare other types of SACs.

The perovskite solar cell has emerged rapidly in the field of photovoltaics as it combines the merits of low cost, high efficiency, and excellent mechanical flexibility for versatile applications. However, there are significant concerns regarding its operational stability and mechanical robustness. Most of the previously reported approaches to address these concerns entail separate engineering of perovskite and charge-transporting layers. Herein we present a holistic design of perovskite and charge-transporting layers by synthesizing an interpenetrating perovskite/electron-transporting-layer interface. This interface is reaction-formed between a tin dioxide layer containing excess organic halide and a perovskite layer containing excess lead halide. Perovskite solar cells with such interfaces deliver efficiencies up to 22.2% and 20.1% for rigid and flexible versions, respectively. Long-term (1000 h) operational stability is demonstrated and the flexible devices show high endurance against mechanical-bending (2500 cycles) fatigue. Mechanistic insights into the relationship between the interpenetrating interface structure and performance enhancement are provided based on comprehensive, advanced, microscopic characterizations. This study highlights interface integrity as an important factor for designing efficient, operationally-stable, and mechanically-robust solar cells., Operational stability and mechanical robustness remain as engineering bottlenecks in perovskite solar cells technology. Here, Dong et al. introduce an interpenetrating perovskite at the electron-transporting-layer interface that enables a 1000-hour stable operation and high endurance against bending fatigue over 2500 cycles.

Carbon-based single-atom catalysts (C-SACs), featured with flexible, well-defined atomic geometry and superior electrical conductivity, have experienced a rapid development in the last decade and proved unique opportunities in selective oxygen reduction reaction (ORR) electrocatalysis via direct 4e- pathway or alternative 2e- pathway for sustainable energy conversion and chemical synthesis. This concise review summarizes recent experimental efforts aiming at tailored selectivity, activities and derived progressive guidelines for catalyst design. First, the current exploration and development of synthetic methodologies of diverse C-SACs for ORR is briefly outlined. Then we present a key overview on structure-dependent catalytic selectivity and activity properties, in particular emphasizing on the microenvironment modulation of single-atom active sites from the aspects of regulating the central metal atoms, coordination environment and support properties. Besides, the dual active sites enabled synergistic catalysis for breaking conventional scaling relation are also highlighted. Finally, the current remaining challenges in C-SACs for ORR and related perspectives are proposed to shed some light on the further developments toward industrialization in the future.

Immune checkpoint blockade therapies have shown clinical promise in a variety of cancers, but how tumor-infiltrating T cells are activated remains unclear. In this study, we explore the functions of PD-L1 on dendritic cells (DCs), which highly express PD-L1. We observe that PD-L1 on DC plays a critical role in limiting T cell responses. Type 1 conventional DCs are essential for PD-L1 blockade and they upregulate PD-L1 upon antigen uptake. Upregulation of PD-L1 on DC is mediated by type II interferon. While DCs are the major antigen presenting cells for cross-presenting tumor antigens to T cells, subsequent PD-L1 upregulation protects them from killing by cytotoxic T lymphocytes, yet dampens the antitumor responses. Blocking PD-L1 in established tumors promotes re-activation of tumor-infiltrating T cells for tumor control. Our study identifies a critical and dynamic role of PD-L1 on DC, which needs to be harnessed for better invigoration of antitumor immune responses., The role of PD-L1 expression on tumor-infiltrating immune cells in promoting tumor immune escape is not fully understood. Here, the authors show that PD-L1 expression by dendritic cells plays a crucial role in hindering anti-tumor T cell responses and is essential for the therapeutic efficacy of PD-L1 blockade.

It is a challenge to effectively reactivate preexisting tumor-infiltrating lymphocytes (TILs) without causing severe toxicity. IL-12 can potently activate lymphocytes, but its clinical use is limited by its short half-life and dose-related toxicity. In this study, we developed a tumor-conditional IL-12 (pro-IL-12), which masked IL-12 with selective extracellular receptor binding domains of the IL-12 receptor, while preferentially and persistently activating TILs after being unmasking by matrix metalloproteases expressed by tumors. Systemic delivery of pro-IL-12 demonstrated reduced toxicity but better control of established tumors compared to IL-12-Fc. Mechanistically, antitumor responses induced by pro-IL-12 were dependent on TILs and IFNγ. Furthermore, direct binding of IL-12 to IL12R on CD8(+), not CD4(+), T cells was essential for maximal effectiveness. Pro-IL-12 improved the efficacy of both immune checkpoint blockade and targeted therapy when used in combination. Therefore, our study demonstrated that pro-IL-12 could rejuvenate TILs, which then combined with current treatment modalities while limiting adverse effects for treating established tumors.

Perovskite solar cells (PSCs) as an emerging photovoltaic technique have achieved exceptional power conversion efficiency (PCE) up to 25.7% after fast development over the past decade. But currently some critical issues are still not well addressed in terms of realizing large-scale fabrication, for example, fast fabrication of high-quality perovskite film with good stability. Here, we demonstrate the use of stable and fast-crystallizing low-dimensional (LD) perovskite thin films as the light absorber with only a 10 s annealing time at 250 degrees C, delivering a PCE of 18.16%. The crystallization and photoelectric properties of LD perovskite are well illustrated. The reduction in the annealing time will dramatically increase the productivity of PSCs. The PSCs based on rapidly annealed LD perovskite thin films exhibit excellent stability, with only 12% loss of PCE after 1000 h storage at 85 degrees C and 40-70% relative humidity.

A hostile microenvironment in tumor tissues disrupts endoplasmic reticulum homeostasis and induces the unfolded protein response (UPR). A chronic UPR in both cancer cells and tumor-infiltrating leukocytes could facilitate the evasion of immune surveillance. However, how the UPR in cancer cells cripples the anti-tumor immune response is unclear. Here, we demonstrate that, in cancer cells, the UPR component X-box binding protein 1 (XBP1) favors the synthesis and secretion of cholesterol, which activates myeloid-derived suppressor cells (MDSCs) and causes immunosuppression. Cholesterol is delivered in the form of small extracellular vesicles and internalized by MDSCs through macropinocytosis. Genetic or pharmacological depletion of XBP1 or reducing the tumor cholesterol content remarkably decreases MDSC abundance and triggers robust anti-tumor responses. Thus, our data unravel the cell-non-autonomous role of XBP1/cholesterol signaling in the regulation of tumor growth and suggest its inhibition as a useful strategy for improving the efficacy of cancer immunotherapy.

While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies., Interleukin-2 (IL-2) based cancer therapy is limited by severe toxicity and strong Treg amplification at the therapeutic dosage. Here, the authors develop a recombinant IL-2 immunocytokine which is comprised of a tumor-targeting antibody fused to a super mutant IL-2 and show in mouse models that this next-generation IL2 has reduced toxicity and enhanced antitumor activity.

Metal-organic frameworks have attracted extensively attentions due to their unique structural properties such as high porosity, good crystallinity, and three-dimensional networking. However, to the best of our knowledge, there is no report concerning the application of partially decomposed metal-organic frameworks based catalyst for sodium borohydride hydrolysis for H2 generation. Herein, the partially decomposed cobalt-based zeolitic imidazolate frameworks supported Pd nanoclusters are fabricated by evaporation solvent assisted method followed by subsequent annealing under H2 atmosphere. Our results show that catalytic performance of the designed catalyst can be largely improved by optimizing the Pd loading and the annealing temperatures. The optimized catalyst exhibits a high catalytic activity towards hydrolysis of alkalized sodium borohydride with a specific H2 generation rate of 20.6 l min−1 mgPd−1 and turnover frequency of 495.0 mol min−1 molPd−1 at 25 °C, which is the highest reported so far among the similar catalysts. Moreover, the resulted catalyst also demonstrates a high level of stability. Based on structural characterization and experimental optimization, the extraordinary performance of the fabricated catalyst is mainly contributed to the synergetic effect of highly dispersed Pd nanoclusters with partially decomposed cobalt-based zeolitic imidazolate frameworks.

Designing a highly active and stable catalyst for NaBH4 hydrolysis is a key step towards overcoming the challenges of hydrogen storage. Herein, we have developed a controllable strategy to fabricate a series of hierarchically structured cobalt-ruthenium-phosphide arrays on nickel foam (Co–Ru–P@NF) as a highly efficient and stable catalyst for hydrogen generation from NaBH4 hydrolysis in alkaline media. SEM and TEM analyses show that the interconnected rugae-like Co–Ru–P arrays are vertically grown on the surface of Ni foam, together with uniformly distributed RuP3 nanoclusters on the surface of CoP nanosheets. More importantly, the optimized Co–Ru–P@NF catalyst exhibits an outstanding catalytic performance on NaBH4 hydrolysis in alkaline media with a high turnover frequency (TOF) of 2123.6 molH2 min−1 molRu−1 at 25 °C, which is one of the highest known so far. Furthermore, the exceptional catalytic performance is in line with the outcome of low activation energy (40.3 kJ mol−1). Additionally, the catalyst also shows a high stability with less than 8.0% lost after 5 consecutive cycles. The superior catalytic performance is ascribed to the synergetic effect between RuP3 and CoP species resulting in a significant electron transfer effect, together with the unique morphologies associated with a large specific surface area and open-channels for effective solute transport/adsorption and H2 gas emissions.

Alerting customers on suspected online-payment fraud and persuade them to terminate transactions is increasingly requested with the rapid growth of digital finance worldwide. We explored the feasibility of using a conversational agent (CA) to fulfill this request. Shing, a voice-based CA, proactively initializes and repairs the conversation with empathetical communication skills in order to alert customers when a suspected online-payment fraud is detected, collects important information for fraud scrutiny and persuades customers to terminate the transaction once the fraud is confirmed. We evaluated our system by comparing it with a rule-based CA with regards to customer response and perceptions in a real-world context where our systems took 144,795 phone calls in total in which 83,019 (57.3%) natural breakdowns happened. Results showed that more customers stopped risky transactions after conversing with Shing. They seemed more willing to converse with Shing for more dialogue turns and provide transaction details. Our work presents practical implications for the design of proactive CA.

Xanthomonas campestris pv. campestris 8004 secretes several effector proteins that interfere with plant phosphorylation. Xanthomonas campestris pv. campestris (Xcc) can infect cruciferous plants and cause black rot. The strain Xcc8004 secretes effector proteins that interfere with plant cellular processes into host cells using a type III secretion (T3S) system. Several of the 24 predicted T3S effectors in the Xcc8004 genome have been implicated in the suppression of the Arabidopsis thaliana pattern-triggered immunity (PTI) response. We used an A. thaliana mesophyll protoplast-based assay to identify Xcc8004 T3S effectors that effectively interfere with PTI signalling induced by the bacterial peptide flg22. 11 of the 24 tested effector proteins (XopK, XopQ, HrpW, XopN, XopAC, XopD, XopZ1, XopAG, AvrBs2, XopL and XopX-1) inhibited expression of the flg22-inducible gene FRK1, and five effectors (XopK, XopG, XopQ, XopL and XopX-1) inhibited the expression of the flg22-inducible gene WRKY33. Therefore, there are 12 effector proteins that can inhibit the expression of relevant flg22-inducible genes. It was further investigated whether the 12 effector proteins affect the phosphorylation activation of mitogen-activated protein (MAP) kinases MPK3/MPK6, and four effector proteins (XopK, XopQ, XopZ1 and XopX-1) were found to markedly inhibit MPK3/MPK6 activation. Moreover, a subcellular localisation analysis revealed that the tested effectors were localised within various subcellular compartments. These results indicate that multiple T3S effectors in the Xcc8004 genome interfere with flg22-induced PTI signalling via various molecular mechanisms.

Endowing the transition-metal-nitrogen-carbon (M-N-Cs) electrocatalysts with high oxygen reduction activity for sustainable energy conversion, is a field of intense research while remains elusive. Here we exploit the variable configuration of atomically dispersed Cu1 centers on carbon support via rationally constructing prototypical CuN2+2 active sites to boost the kinetically sluggish electrochemical oxygen reduction. Density functional theory reveals the modified electronic structure of active Cu site and its derived orbital overlap through right symmetry with the degenerate π* orbital of O2 molecule, which more effectively facilitates O2 activation compared with CuN4 counterpart. The targeted electrocatalyst delivers superior alkaline ORR activity with a half-wave potential of 0.88 V and superior kinetics with Tafel slope of 48 mV dec−1, outperforming those of benchmark Pt/C. Remarkably, further demonstrated excellent peak power density and long-term durability in both primary liquid and flexible solid-state Zn-air battery assemblies signify the potential for practical applications.