Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors

Small molecular PD‐1 inhibitors are lacking in current immuno‐oncology clinic. PD‐1/PD‐L1 antibody inhibitors currently approved for clinical usage block interaction between PD‐L1 and PD‐1 to enhance cytotoxicity of CD8+ cytotoxic T lymphocyte (CTL). Whether other steps along the PD‐1 signaling pathway can be targeted remains to be determined. Here, we report that methylene blue (MB), an FDA‐approved chemical for treating methemoglobinemia, potently inhibits PD‐1 signaling. MB enhances the cytotoxicity, activation, cell proliferation, and cytokine‐secreting activity of CTL inhibited by PD‐1. Mechanistically, MB blocks interaction between Y248‐phosphorylated immunoreceptor tyrosine‐based switch motif (ITSM) of human PD‐1 and SHP2. MB enables activated CTL to shrink PD‐L1 expressing tumor allografts and autochthonous lung cancers in a transgenic mouse model. MB also effectively counteracts the PD‐1 signaling on human T cells isolated from peripheral blood of healthy donors. Thus, we identify an FDA‐approved chemical capable of potently inhibiting the function of PD‐1. Equally important, our work sheds light on a novel strategy to develop inhibitors targeting PD‐1 signaling axis

Human cytomegalovirus in cancer: the mechanism of HCMV-induced carcinogenesis and its therapeutic potential

Cancer is one of the leading causes of death worldwide. Human cytomegalovirus (HCMV), a well-studied herpesvirus, has been implicated in malignancies derived from breast, colorectal muscle, brain, and other cancers. Intricate host-virus interactions are responsible for the cascade of events that have the potential to result in the transformed phenotype of normal cells. The HCMV genome contains oncogenes that may initiate these types of cancers, and although the primary HCMV infection is usually asymptomatic, the virus remains in the body in a latent or persistent form. Viral reactivation causes severe health issues in immune-compromised individuals, including cancer patients, organ transplants, and AIDS patients. This review focuses on the immunologic mechanisms and molecular mechanisms of HCMV-induced carcinogenesis, methods of HCMV treatment, and other studies. Studies show that HCMV DNA and virus-specific antibodies are present in many types of cancers, implicating HCMV as an important player in cancer progression. Importantly, many clinical trials have been initiated to exploit HCMV as a therapeutic target for the treatment of cancer, particularly in immunotherapy strategies in the treatment of breast cancer and glioblastoma patients. Taken together, these findings support a link between HCMV infections and cellular growth that develops into cancer. More importantly, HCMV is the leading cause of birth defects in newborns, and infection with HCMV is responsible for abortions in pregnant women

13C-Metabolic Flux Analysis Reveals the Metabolic Flux Redistribution for Enhanced Production of Poly-γ-Glutamic Acid in dlt Over-Expressed Bacillus licheniformis

Poly-γ-glutamic acid (γ-PGA) is an anionic polymer with various applications. Teichoic acid (TA) is a special component of cell wall in gram-positive bacteria, and its D-alanylation modification can change the net negative charge of cell surface, autolysin activity and cationic binding efficiency, and might further affect metabolic production. In this research, four genes (dltA, dltB, dltC, and dltD) of dlt operon were, respectively, deleted and overexpressed in the γ-PGA producing strain Bacillus licheniformis WX-02. Our results implied that overexpression of these genes could all significantly increase γ-PGA synthetic capabilities, among these strains, the dltB overexpression strain WX-02/pHY-dltB owned the highest γ-PGA yield (2.54 g/L), which was 93.42% higher than that of the control strain WX-02/pHY300 (1.31 g/L). While, the gene deletion strains produced lower γ-PGA titers. Furthermore, 13C-Metabolic flux analysis was conducted to investigate the influence of dltB overexpression on metabolic flux redistribution during γ-PGA synthesis. The simulation data demonstrated that fluxes of pentose phosphate pathway and tricarboxylic acid cycle in WX-02/pHY-dltB were 36.41 and 19.18 mmol/g DCW/h, increased by 7.82 and 38.38% compared to WX-02/pHY300 (33.77 and 13.86 mmol/g DCW/h), respectively. The synthetic capabilities of ATP and NADPH were also increased slightly. Meanwhile, the fluxes of glycolytic and by-product synthetic pathways were all reduced in WX-02/pHY-dltB. All these above phenomenons were beneficial for γ-PGA synthesis. Collectively, this study clarified that overexpression of dltB strengthened the fluxes of PPP pathway, TCA cycle and energy metabolism for γ-PGA synthesis, and provided an effective strategy for enhanced production of γ-PGA

Towards prediction of ordered phases in rechargeable battery chemistry via group–subgroup transformation

Abstract: The electrochemical thermodynamic and kinetic characteristics of rechargeable batteries are critically influenced by the ordering of mobile ions in electrodes or solid electrolytes. However, because of the experimental difficulty of capturing the lighter migration ion coupled with the theoretical limitation of searching for ordered phases in a constrained cell, predicting stable ordered phases involving cell transformations or at extremely dilute concentrations remains challenging. Here, a group-subgroup transformation method based on lattice transformation and Wyckoff-position splitting is employed to predict the ordered ground states. We reproduce the previously reported Li0.75CoO2, Li0.8333CoO2, and Li0.8571CoO2 phases and report a new Li0.875CoO2 ground state. Taking the advantage of Wyckoff-position splitting in reducing the number of configurations, we identify the stablest Li0.0625C6 dilute phase in Li-ion intercalated graphite. We also resolve the Li/La/vacancy ordering in Li3xLa2/3−xTiO3 (0 < x < 0.167), which explains the observed Li-ion diffusion anisotropy. These findings provide important insight towards understanding the rechargeable battery chemistry

Activatable near-infrared probes for the detection of specific populations of tumour-infiltrating leukocytes in vivo and in urine

Tracking the immune microenvironment of tumours is essential for understanding the mechanisms behind the effectiveness of cancer immunotherapies. Molecular imaging of tumour-infiltrating leukocytes (TILs) can be used to non-invasively monitor the tumour immune microenvironment, but current imaging agents do not distinguish TILs from leukocytes resident in other tissues. Here we report a library of activatable molecular probes for the imaging, via near-infrared fluorescence, of specific TILs (including M1 macrophages, cytotoxic T lymphocytes and neutrophils) in vivo in real time and also via excreted urine, owing to the probes' renal clearance. The fluorescence of the probes is activated only in the presence of both tumour and leukocyte biomarkers, which allows for the imaging of populations of specific TILs in mouse models of cancers with sensitivities and specificities similar to those achieved via flow-cytometric analyses of biopsied tumour tissues. We also show that the probes enable the non-invasive evaluation of the immunogenicity of different tumours, the dynamic monitoring of responses to immunotherapies and the accurate prediction of tumour growth under various treatments.Ministry of Education (MOE)National Research Foundation (NRF)K.P. thanks the Singapore Ministry of Education, Academic Research Fund Tier 1 (RG125/19; RT05/20), Academic Research Fund Tier 2 (MOE2018-T2-2-042; MOE-T2EP30220-0010) and the Singapore National Research Foundation (NRF-NRFI07-2021-0005) for financial support

A dual-locked tandem fluorescent probe for imaging of pyroptosis in cancer chemo-immunotherapy

Real-time imaging of programmed cancer cell death (PCD) is imperative to monitor cancer therapeutic efficacy and tailor therapeutic regimens; however, specific in vivo detection of intratumoral pyroptosis remains challenging. Herein, a dual-locked and tandem activatable probe (DTAP) is reported for near-infrared fluorescence (NIRF) imaging of intratumoral pyroptosis during cancer chemo-immunotherapy in living mice. The probe comprises a hemicyanine dye dual-locked with an enzyme-responsive moiety that can be tandemly cleaved by pyroptosis-related biomarker (Caspase-1) and cancer biomarker (GGT) to turn on its NIRF signal. As pyroptosis plays a vital role in triggering anti-tumor immune responses, the activated signal of DTAP correlates well with the population of tumor-infiltrating cytotoxic T lymphocytes and tumor growth inhibition, consequently permitting the prediction of cancer therapeutic efficacy. This study also provides a non-invasive technique to study the regulatory mechanism of pyroptosis in cancer therapy and to optimize cancer chemo-immunotherapies for precision medicine.Ministry of Education (MOE)National Research Foundation (NRF)Submitted/Accepted versionK.P. thanks Singapore National Research Foundation (NRF) (NRF-NRFI07-2021-0005), and Singapore Ministry of Education, Academic Research Fund Tier 1 (2019-T1-002-045, RG125/19, and RT05/20), and Academic Research Fund Tier 2 (MOE-T2EP30220-0010; MOE-T2EP30221-0004), for the financial support

Analysis on the Status Quo of the Public Space in Dashiyuan Community in Nanchang City and Its Renewal Strategies: An Analysis Based on Multiple Perspectives

From the perspective of big data such as Baidu heat map and GIS kernel density analysis, this paper analyzed the gathering situation of residents of Dashiyuan at different times and the use of public service facilities, as well as problems existing in the old community of Dashiyuan in Nanchang City, and put forward targeted recommendations

Daliao River unique molecular formulae obtained from FT-ICR MS

The 8889 unique molecular formulae of six Daliao River samples (DL1 to DL6) obtained from FT-ICR MS. For more information, please contact D. He ([email protected])

Data from: Optical and molecular signatures of dissolved organic matter reflect anthropogenic influence in a coastal river, Northeast China

Sources and molecular composition of dissolved organic matter (DOM) in coastal rivers have been tightly linked with its reactivity and fate, thus influencing element and nutrient cycling. The DOM in coastal rivers is usually sourced from both terrestrial and marine inputs, with further complication by anthropogenic activities, which is less understood in coastal rivers located near populated industrial regions. In this study, DOM in a typical anthropogenically influenced coastal river, Daliao River, was analyzed for optical analyses and for molecular composition via Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) to give a better scope of composition and sources of DOM. The DOM was enriched in autochthonous and anthropogenic inputs at upstream sites according to high chlorophyll a concentrations, strong protein-like fluorescence, and nonoxygen heteroatomic CHOS formulae (19–24% by relative peak intensity) detected by FT-ICR MS analysis. A series of surfactant-like formulae, indicative of wastewater inputs, were identified and showed a decreasing trend from upstream to the river mouth. Compared with large world rivers, the DOM of Daliao River is characterized by higher abundances of heteroatomic (excluding O) formulae and molecular lability, which is likely caused by strong autochthonous and anthropogenic inputs. In general, we demonstrate that in addition to optical properties, the molecular composition can assess the specific anthropogenic imprints and molecular lability of DOM, which is essential for constraining sources and identifying processes during the transit of DOM from the river to estuary with increasing urbanization and industrialization