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CDK4/6 are important regulators of cell cycle and their inhibitors have been approved as anti-cancer drugs. Here, we report a STING-dependent anti-tumor immune mechanism responsible for tumor suppression by CDK4/6 blockade. Clinical datasets show that in human tissues, CDK4 and CDK6 are over-expressed and their expressions are negatively correlated with patients overall survival and T cell infiltration. Deletion of Cdk4 or Cdk6 in tumor cells significantly reduce tumor growth. Mechanistically, we find that Cdk4 or Cdk6 deficiency contributes to an increased level of endogenous DNA damage, which triggers the cGAS-STING signaling pathway to activate type I interferon response. Knockout of Sting is sufficient to reverse and partially reverse the anti-tumor effect of Cdk4 and Cdk6 deficiency respectively. Therefore, our findings suggest that CDK4/6 inhibitors may enhance anti-tumor immunity through the STING-dependent type I interferon response.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the global coronavirus disease 2019 (COVID-19) pandemic, contains a unique, four amino acid (aa) "PRRA" insertion in the spike (S) protein that creates a transmembrane protease serine 2 (TMPRSS2)/furin cleavage site and enhances viral infectivity. More research into immunogenic epitopes and protective antibodies against this SARS-CoV-2 furin cleavage site is needed.MethodsCombining computational and experimental methods, we identified and characterized an immunogenic epitope overlapping the furin cleavage site that detects antibodies in COVID-19 patients and elicits strong antibody responses in immunized mice. We also identified a high-affinity monoclonal antibody from COVID-19 patient peripheral blood mononuclear cells; the antibody directly binds the furin cleavage site and protects against SARS-CoV-2 infection in a mouse model.FindingsThe presence of "PRRA" amino acids in the S protein of SARS-CoV-2 not only creates a furin cleavage site but also generates an immunogenic epitope that elicits an antibody response in COVID-19 patients. An antibody against this epitope protected against SARS-CoV-2 infection in mice.InterpretationThe immunogenic epitope and protective antibody we have identified may augment our strategy in handling COVID-19 epidemic.FundingThe National Natural Science Foundation of China (82102371, 91542201, 81925025, 82073181, and 81802870), the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (2021-I2M-1-047 and 2022-I2M-2-004), the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2020-PT310-006, 2019XK310002, and 2018TX31001), the National Key Research and Development Project of China (2020YFC0841700), US National Institute of Health (NIH) funds grant AI158154, University of California Los Angeles (UCLA) AI and Charity Treks, and UCLA DGSOM BSCRC COVID-19 Award Program. H.Y. is supported by Natural Science Foundation of Jiangsu Province (BK20211554 andBE2022728).

BackgroundIn 2015, herpes simplex virus 1 (HSV-1)-derived talimogene laherparepvec (T-VEC) was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment. However, its antitumor application is limited to local treatment of melanoma, and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity. We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus.MethodsWe systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1. Then, we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1. Furthermore, we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models.ResultsWe identified eight IFN-stimulated genes (ISGs) controlling HSV-1 replication, among which BTB and CNC homology 1 (BACH1) suppressed HSV-1 replication by inhibiting the transcription of ICP4, ICP27, and UL39. Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis, HMGB1 secretion, and calreticulin exposure in tumor cells. More importantly, hemin, an FDA-approved drug known to downregulate BACH1, significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site.ConclusionsOur studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.

BackgroundZika virus (ZIKV) infection and ZIKV epidemic have been continuously spreading silently throughout the world and its associated microcephaly and other serious congenital neurological complications poses a significant global threat to public health. Type I interferon response to ZIKV infection in host cells suppresses viral replication by inducing the expression of interferon-stimulated genes (ISGs).MethodsThe study aims to demonstrate the anti-ZIKV mechanism of PARP11. PARP11 knock out and overexpressing A549 cell lines were constructed to evaluate the anti-ZIKV function of PARP11. PARP11-/-, PARP12-/- and PARP11-/-PARP12-/- HEK293T cell lines were constructed to explain the synergistic effect of PARP11 and PARP12 on NS1 and NS3 protein degradation. Western blotting, immunofluorescence and immunoprecipitation assay were performed to illustrate the interaction between PARP11 and PARP12.ResultsBoth mRNA and protein levels of PARP11 were induced in WT but not IFNAR1-/- cells in response to IFNα or IFNβ stimulation and ZIKV infection. ZIKV replication was suppressed in cells expressed PARP11 but was enhanced in PARP11-/- cells. PARP11 suppressed ZIKV independently on itself PARP enzyme activity. PARP11 interacted with PARP12 and promoted PARP12-mediated ZIKV NS1 and NS3 protein degradation.ConclusionWe identified ADP-ribosyltransferase PARP11 as an anti-ZIKV ISG and found that it cooperated with PARP12 to enhance ZIKV NS1 and NS3 protein degradation. Our findings have broadened the understanding of the anti-viral function of ADP-ribosyltransferase family members, and provided potential therapeutic targets against viral ZIKV infection.

The tumor microenvironment (TME), including infiltrated immune cells, is known to play an important role in tumor growth; however, the mechanisms underlying tumor immunogenicity have not been fully elucidated. Here, we discovered an unexpected role for the transcription factor SIX1 in regulating the tumor immune microenvironment. Based on analyses of patient datasets, we found that SIX1 was upregulated in human tumor tissues and that its expression levels were negatively correlated with immune cell infiltration in the TME and the overall survival rates of cancer patients. Deletion of Six1 in cancer cells significantly reduced tumor growth in an immune-dependent manner with enhanced antitumor immunity in the TME. Mechanistically, SIX1 was required for the expression of multiple collagen genes via the TGFBR2-dependent Smad2/3 activation pathway, and collagen deposition in the TME hampered immune cell infiltration and activation. Thus, our study uncovers a crucial role for SIX1 in modulating tumor immunogenicity and provides proof-of-concept evidence for targeting SIX1 in cancer immunotherapy.

The widespread prevalence of coronavirus disease-2019 (COVID-19) which is caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has resulted in a severe global public health emergency. However, there are no sensitive biomarkers to predict the disease prognosis of COVID-19 patients. Here, we have identified interleukin-8 (IL-8) as a biomarker candidate to predict different disease severity and prognosis of COVID-19 patients. While serum IL-6 become obviously elevated in severe COVID-19 patients, serum IL-8 was easily detectible in COVID-19 patients with mild syndromes. Furthermore, lL-8 levels correlated better than IL-6 levels with the overall clinical disease scores at different stages of the same COVID-19 patients. Thus, our studies suggest that IL-6 and IL-8 can be respectively used as biomarkers for severe COVID-19 patients and for COVID-19 disease prognosis.

With increasing competition in the food franchise industry, the success of a franchise operation depends on its ability to instigate franchisee patronage. This study focuses on franchisor characteristics that help in creating positive behavioural outcomes. Partial least squares structural equation modelling (PLS-SEM) using SmartPLS software is used to analyze 266 U.S. food franchisees. Findings show the relative impact of franchisee evaluation of information quality, service quality, rewards and recognition, and customization on perceived value. Also, positive perceived value in franchisees influences their willingness to pay a premium and their referrer intentions towards franchise brands. Multigroup analysis using demographic characteristics shows that the impacts of information quality and service quality on perceived value are higher in male and older franchisees than in female and younger franchisees. In contrast, the effect of customization on perceived value is greater in female and younger franchisees. This study provides insights to develop business strategies. [ABSTRACT FROM AUTHOR]

Due to the limitations inherent in satellite sensor capabilities, it remains a challenge to balance the temporal and spatial resolutions of current remote sensing observations. Spatiotemporal fusion has emerged as a viable approach to address this issue. Many spatiotemporal fusion models have been proposed to fuse surface reflectance initially; however, their adaption for land surface temperature (LST), particularly with the 'fusion-then-retrieval (FTR)' or 'retrieval-then-fusion (RTF)' strategy, has not yet been comprehensively explored. This paper describes a comparative study of the two strategies within the context of LST fusion using three classic fusion methods including the spatial and temporal adaptive reflectance fusion model (STARFM), the enhanced spatial and temporal adaptive reflectance fusion model (ESTARFM) and the flexible spatiotemporal data fusion model (FSDAF). The findings illuminate nuanced applicability across different models: (1) the FTR strategy is more suitable for STARFM; (2) the strategic applicability for ESTARFM and FSDAF is strongly related to the reference images; (3) the STARFM and FSDAF models are easily affected by the time interval between the predicted date and the reference date. This work is expected to provide practical guidance for synthesizing high spatiotemporal LST data with fusion models. [ABSTRACT FROM AUTHOR]

Three types of aggregate, including metallurgical slag aggregate (steel slag, copper slag, and iron sand), rare earth porcelain sand (REPS) aggregate as artificial aggregate, and recycled aggregate, were selected to produce concrete with the same basic mixture proportions in order to investigate the influence of aggregate types and aggregate replacement rates on their mechanical properties. Three levels of aggregate replacement rate—20%, 35%, and 50% for coarse aggregate (CA) and 20%, 30%, and 40% for fine aggregate (FA)—were employed in this study. The results indicate that replacing natural sand with metallurgical slag aggregate as FA enhances the mechanical properties of concrete. Among these, iron sand (IS) shows superior enhancement effects compared with copper slag (CS), and CS outperforms steel slag (SS). Specifically, at a 30% IS replacement rate, the compressive strength and splitting tensile strength of IS aggregate concrete are 32.8% and 35.6% higher than those of natural aggregate concrete, respectively. REPS used as CA demonstrates significant improvements in compressive strength, while REPS used as FA notably enhances splitting tensile strength. For recycled aggregate concrete with recycled coarse aggregate replacement rates of 35% and 50%, mechanical properties are effectively strengthened by incorporating CS as FA at a 30% replacement rate and REPS as CA at a 20% substitution ratio, respectively. Additionally, XRF and XRD techniques were employed to confirm aggregate composition and were combined with SEM and EDS techniques to analyze the concrete microstructure, clarifying the strengthening mechanisms of metallurgical and artificial aggregates on concrete. [ABSTRACT FROM AUTHOR]

CFG pile composite foundation is mainly used for multi-storey and high-rise buildings. In the past, researches and applications were mainly for the relatively deep foundation. For the independent foundation of backfill foundation, in general there is more pile foundation and less CFG pile composite foundations. This paper compares and analyzes the pile foundation and CFG pile composite foundation from the perspectives of stress mechanism, deformation characteristics and engineering cost. It also discusses the advantages of CFG pile composite foundation. Besides, relying on specific engineering examples, the settlement calculation of CFG pile composite foundation on the independent foundation of backfill foundation is compared and analyzed under different specification conditions. The following conclusions are drawn: for the independent foundation with low bearing capacity, compared with the pile foundation, CFG pile composite foundation can greatly save the engineering cost under the premise of meeting the bearing capacity and deformation control. The design of CFG pile composite foundation on the independent foundation of backfill foundation is mainly based on settlement control. The bearing capacity calculation and settlement calculation should consider the adverse effect of filling soil, and the settlement calculation should be calculated in accordance with the overall collaborative calculation. [ABSTRACT FROM AUTHOR]