Nuclear VCP drives colorectal cancer progression by promoting fatty acid oxidation.

Fatty acid oxidation (FAO) fuels many cancers. However, knowledge of pathways that drive FAO in cancer remains unclear. Here, we revealed that valosin-containing protein (VCP) upregulates FAO to promote colorectal cancer growth. Mechanistically, nuclear VCP binds to histone deacetylase 1 (HDAC1) and facilitates its degradation, thus promoting the transcription of FAO genes, including the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). FAO is an alternative fuel for cancer cells in environments exhibiting limited glucose availability. We observed that a VCP inhibitor blocked the upregulation of FAO activity and CPT1A expression triggered by metformin in colorectal cancer (CRC) cells. Combined VCP inhibitor and metformin prove more effective than either agent alone in culture and in vivo. Our study illustrates the molecular mechanism underlying the regulation of FAO by nuclear VCP and demonstrates the potential therapeutic utility of VCP inhibitor and metformin combination treatment for colorectal cancer.

Macrophage hitchhiking for systematic suppression in postablative multifocal HCC.

BACKGROUND AND AIMS: HCC, particularly the multifocal HCC, features aggressive invasion and dismal prognosis. Locoregional treatments were often refractory to eliminate tumor tissue, resulting in residual tumor cells persisting and subsequent progression. Owing to problematic delivery to the tumor tissue, systemic therapies, such as lenvatinib (LEN) therapy, show limited clinical benefit in preventing residual tumor progression. Therefore, more advanced strategies for postablative multifocal HCC are urgently needed. APPROACH AND RESULTS: Motivated by the chemotaxis in tumor penetration of macrophages, we report a strategy named microinvasive ablation-guided macrophage hitchhiking for the targeted therapy toward HCC. In this study, the strategy leverages the natural inflammatory gradient induced by ablation to guide LEN-loaded macrophages toward tumor targeting, which increased by ~10-fold the delivery efficiency of LEN in postablative HCC in vivo. Microinvasive ablation-guided macrophage hitchhiking has demonstrated significant antitumor activity in various HCC models, including the hydrodynamic tail vein injection multifocal HCC mouse model and the orthotopic xenograft HCC rabbit model, systematically inhibiting residual tumor progression after ablation and prolonging the median survival of tumor-bearing mice. The potential antitumor mechanism was explored using techniques such as flow cytometry, ELISA, and immunohistochemistry. We found that the strategy significantly suppressed tumor cell proliferation and neovascularization, and such enhanced delivery of LEN stimulated systemic immune responses and induced durable immune memory. CONCLUSIONS: The macrophage hitchhiking strategy demonstrates exceptional therapeutic efficacy and biosafety across various species, offering promising prospects for clinical translation in controlling residual tumor progression and improving outcomes following HCC ablation.

The RNA polymerase of cytoplasmically replicating Zika virus binds with chromatin DNA in nuclei and regulates host gene transcription.

Zika virus (ZIKV) targets the neural progenitor cells (NPCs) in brain during intrauterine infections and consequently causes severe neurological disorders, such as microcephaly in neonates. Although replicating in the cytoplasm, ZIKV dysregulates the expression of thousands of host genes, yet the detailed mechanism remains elusive. Herein, we report that ZIKV encodes a unique DNA-binding protein to regulate host gene transcription in the nucleus. We found that ZIKV NS5, the viral RNA polymerase, associates tightly with host chromatin DNA through its methyltransferase domain and this interaction could be specifically blocked by GTP. Further study showed that expression of ZIKV NS5 in human NPCs markedly suppressed the transcription of its target genes, especially the genes involved in neurogenesis. Mechanistically, ZIKV NS5 binds onto the gene body of its target genes and then blocks their transcriptional elongation. The utero electroporation in pregnant mice showed that NS5 expression significantly disrupts the neurogenesis by reducing the number of Sox2- and Tbr2-positive cells in the fetal cortex. Together, our findings demonstrate a molecular clue linking to the abnormal neurodevelopment caused by ZIKV infection and also provide intriguing insights into the interaction between the host cell and the pathogenic RNA virus, where the cytoplasmic RNA virus encodes a DNA-binding protein to control the transcription of host cell in the nuclei.

Machine Learning-Based Integrated Multiomics Characterization of Colorectal Cancer Reveals Distinctive Metabolic Signatures.

The metabolic signature identification of colorectal cancer is critical for its early diagnosis and therapeutic approaches that will significantly block cancer progression and improve patient survival. Here, we combined an untargeted metabolic analysis strategy based on internal extractive electrospray ionization mass spectrometry and the machine learning approach to analyze metabolites in 173 pairs of cancer samples and matched normal tissue samples to build robust metabolic signature models for diagnostic purposes. Screening and independent validation of metabolic signatures from colorectal cancers via machine learning methods (Logistic Regression_L1 for feature selection and eXtreme Gradient Boosting for classification) was performed to generate a panel of seven signatures with good diagnostic performance (the accuracy of 87.74%, sensitivity of 85.82%, and specificity of 89.66%). Moreover, seven signatures were evaluated according to their ability to distinguish between cancer and normal tissues, with the metabolic molecule PC (30:0) showing good diagnostic performance. In addition, genes associated with PC (30:0) were identified by multiomics analysis (combining metabolic data with transcriptomic data analysis) and our results showed that PC (30:0) could promote the proliferation of colorectal cancer cell SW480, revealing the correlation between genetic changes and metabolic dysregulation in cancer. Overall, our results reveal potential determinants affecting metabolite dysregulation, paving the way for a mechanistic understanding of altered tissue metabolites in colorectal cancer and design interventions for manipulating the levels of circulating metabolites.

An unconventional role of an ASB family protein in NF-κB activation and inflammatory response during microbial infection and colitis.

Nuclear factor κB (NF-κB)-mediated signaling pathway plays a crucial role in the regulation of inflammatory process, innate and adaptive immune responses. The hyperactivation of inflammatory response causes host cell death, tissue damage, and autoinflammatory disorders, such as sepsis and inflammatory bowel disease. However, how these processes are precisely controlled is still poorly understood. In this study, we demonstrated that ankyrin repeat and suppressor of cytokine signaling box containing 1 (ASB1) is involved in the positive regulation of inflammatory responses by enhancing the stability of TAB2 and its downstream signaling pathways, including NF-κB and mitogen-activated protein kinase pathways. Mechanistically, unlike other members of the ASB family that induce ubiquitination-mediated degradation of their target proteins, ASB1 associates with TAB2 to inhibit K48-linked polyubiquitination and thereby promote the stability of TAB2 upon stimulation of cytokines and lipopolysaccharide (LPS), which indicates that ASB1 plays a noncanonical role to further stabilize the target protein rather than induce its degradation. The deficiency of Asb1 protects mice from Salmonella typhimurium- or LPS-induced septic shock and increases the survival of mice. Moreover, Asb1-deficient mice exhibited less severe colitis and intestinal inflammation induced by dextran sodium sulfate. Given the crucial role of ASB proteins in inflammatory signaling pathways, our study offers insights into the immune regulation in pathogen infection and inflammatory disorders with therapeutic implications.

Virulence and community dynamics of fungal species with vertical and horizontal transmission on a plant with multiple infections.

The virulence evolution of multiple infections of parasites from the same species has been modeled widely in evolution theory. However, experimental studies on this topic remain scarce, particularly regarding multiple infections by different parasite species. Here, we characterized the virulence and community dynamics of fungal pathogens on the invasive plant Ageratina adenophora to verify the predictions made by the model. We observed that A. adenophora was highly susceptible to diverse foliar pathogens with mixed vertical and horizontal transmission within leaf spots. The transmission mode mainly determined the pathogen community structure at the leaf spot level. Over time, the pathogen community within a leaf spot showed decreased Shannon diversity; moreover, the vertically transmitted pathogens exhibited decreased virulence to the host A. adenophora, but the horizontally transmitted pathogens exhibited increased virulence to the host. Our results demonstrate that the predictions of classical models for the virulence evolution of multiple infections are still valid in a complex realistic environment and highlight the impact of transmission mode on disease epidemics of foliar fungal pathogens. We also propose that seedborne fungi play an important role in structuring the foliar pathogen community from multiple infections within a leaf spot.

Treatment of maternal syphilis for preventing congenital syphilis: an observational study of adherence to treatment recommendation in Suzhou, China, 2019-2021.

BACKGROUND: China is one of the countries that set the goal to eliminate mother-to-child transmission (EMTCT) of syphilis by a target date. Active screening for syphilis among pregnant women, followed by effective treatment of maternal syphilis, is critical for achieving the goal. The China health authority issued national implementation protocols to guide EMTCT practice in health facilities. METHODS: Within a cohort of infants born to mothers infected with syphilis, we obtained the data of regimens used for treatment of maternal syphilis from the National Information System of Prevention of Mother-to-Child Transmission of HIV, Syphilis and Hepatitis B, and analysed the physician's treatment behaviour and its associated factors in a public hospital in Suzhou of China. RESULTS: A total of 450 pregnant women who were positive for treponemal or non-treponemal antibody, or had previous infection with syphilis were included into the study for analysis. Of them, 260 (57.8%) were positive for both treponemal and non-treponemal antibodies (syphilis seropositivity), and 353 (78.4%) were treated for syphilis according to the protocol in which 123 (34.8%) were treated with two courses. Non-adherence to treatment recommended by the protocol for maternal syphilis was significantly associated with antenatal visits in the third trimester (AOR 6.65, 95% CI 2.20-20.07, P =0.001), being positive only for a treponemal test (AOR 5.34, 95% CI 3.07-9.29, P <0.001) or having a syphilis infection before the pregnancy (AOR 2.05, 95% CI 1.14-3.69, P =0.017), whereas the uptake of treatment for two treatment courses was associated with attending antenatal care in 2020 or before (AOR 3.49, 95% CI 1.89-6.42, P <0.001), being positive for treponemal and non-treponemal tests (AOR 5.28, 95% CI 2.78-10.06, P <0.001) or having non-treponemal antibody titre of ≥1:8 (AOR 3.71, 95% CI 1.77-7.78, P =0.001). CONCLUSIONS: Implementation of the current recommendation to offer a universal treatment for syphilis among all pregnant women who are shown to be positive for a treponemal test alone is challenging in some clinical settings in China.

Metabolic-Dysregulation-Based iEESI-MS Reveals Potential Biomarkers Associated with Early-Stage and Progressive Colorectal Cancer.

The application of rapid and accurate diagnostic methods can improve colorectal cancer (CRC) survival rates dramatically. Here, we used a non-targeted metabolic analysis strategy based on internal extractive electrospray ionization mass spectrometry (iEESI-MS) to detect metabolite ions associated with the progression of CRC from 172 tissues (45 stage I/II CRC, 41 stage III/IV CRC, and 86 well-matched normal tissues). A support vector machine (SVM) model based on 10 differential metabolite ions for differentiating early-stage CRC from normal tissues was built with a good prediction accuracy of 92.6%. The biomarker panel consisting of lysophosphatidylcholine (LPC) (18:0) has good diagnostic potential in differentiating early-stage CRC from advanced-stage CRC. We showed that the down-regulation of LPC (18:0) in tumor tissues is associated with CRC progression and related to the regulation of the epidermal growth factor receptor. Pathway analysis showed that metabolic pathways in CRC are related to glycerophospholipid metabolism and purine metabolism. In conclusion, we built an SVM model with good performance to distinguish between early-stage CRC and normal groups based on iEESI-MS and found that LPC (18:0) is associated with the progression of CRC.

Quantum correlation propagation in a waveguide-QED system with long-range interaction.

We investigate the excitation and correlation propagations among a one-dimensional atom chain with exponentially decaying, ideal long-range, and power-law decaying interactions. We show that although a clear light-cone-like structure can appear in both the excitation and correlation propagation patterns under the exponentially decaying interaction, only an obscure light-cone-like structure appears with multi-power-law decaying interaction and surprisingly an inverse light-cone-like structure appears in the ideal long-range interaction case. The extracted excitation and correlation propagation velocities in the ideal long-range interaction case are about one order of magnitude larger than those in the multi-power-law interaction case and about two orders of magnitude larger than those in the short-range interaction case. These results indicate that the waveguide-quantum electrodynamics system with long-range interaction can boost the quantum information transfer speed and is beneficial for building fast quantum network and scalable quantum computer.

Meta-Transcriptomic Analysis Reveals the Virome and Viral Genomic Evolution of Medically Important Mites.

Mites are notorious for being vectors transmitting infectious pathogens and source of allergens causing allergic conditions in animals and humans. However, despite their huge impact on public health, the virome of mites remains unknown. Here we characterized the virus diversity and abundance of 14 species of medically important mites based on total RNA sequencing data sets generated in this study as well as those deposited in the Sequence Read Archive (SRA) database. A total of 47 genetically distinct viruses were identified and classified into 17 virus families or virus super-groups, and the viral sequences accounted for as much as 29.67% of total non-rRNA transcriptome in one mite library. The most commonly identified viruses are members of Picornavirales, among which we revealed more than one type of viruses that are evolutionarily related to dicistronic viruses but contain a single open reading frame, thus likely representing a recent example of host (i.e., mite)-related parallel evolution from dicistronic to monocistronic genomic form within the family Dicistroviridae To our best knowledge, this is the first time to perform comprehensive and systematic screening of RNA virome in medically important mites including house dust mites (HDM). Overall, the RNA virome identified here provides not only significant insights into the diversity and evolution of RNA viruses in mites, but also a solid knowledge base for studying their roles in human diseases.IMPORTANCE Mites are important group of arthropods that are associated with a variety of human diseases including scrub typhus and asthma. However, it remains unclear whether or not mites carry viruses that might play a role in human infections or allergic disease. In this study, we used a total transcriptomics approach to characterize and compare the complete RNA virome within mites that are relevant to human health and diseases. Specifically, our data revealed a large diversity, a high abundance, and a flexible genomic evolution for these viruses. Although most of the viruses identified here are unknown to associate with human infectious disease, the abundant presence of viral RNAs may play an immunomodulatory role in the development of allergic reactions such as asthma during environmental exposure to mite allergens, and therefore provide important insights into the mite-induced allergy and preparation of mite allergen vaccines.

Fast size estimation of single-levitated nanoparticles in a vacuum optomechanical system.

Optical trapping of single nanoparticles in vacuum has various applications in both precise measurements and fundamental physics. However, to date, the number and size of randomly loaded nanoparticles in an optical trap is difficult to determine unless in vacuum. In this Letter, an efficient method for nanoparticle size estimation in an optical tweezer system before the evacuation of air was proposed and demonstrated experimentally, using scattering light from levitated particles. The particle radii deduced from the scattering light power in our proposal and from the kinetic theory of particles in gas match well (with the differences of less than 10%). For sample particles with radii ranging within 50-100 nm, we also provide a preselection rule based on this method, where over half of the trapped particles are verified as single particles. Such a particle analysis method is applicable also for the size estimation of levitated diamond particles, gold particles, and other plasmonic particles and can be applied to discovering novel scattering effects.

Remotididymella ageratinae sp. nov. and Remotididymella anemophila sp. nov., two novel species isolated from the invasive weed Ageratina adenophora in PR China.

To determine if Ageratina adenophora can accumulate diverse pathogens from surrounding native plants, we intensively sampled fungal communities, including endophytes, leaf spot pathogens and canopy air fungi, associated with Ag. adenophora as well as native plants in its invasive range. In total, we collected 4542 foliar fungal strains from 10 geographic sites, including 1340 from healthy leaves of Ag. adenophora, 2051 from leaf spots of Ag. adenophora and 1151 from leaf spots of 56 species of native plants and crops. Taxonomically, the common fungal genera included Colletotrichum, Diaporthe, Alternaria, Nemania, Xylaria, Neofusicoccum, Nigrospora, Epicoccum, Gibberella, Pestalotiopsis, Irpex, Schizophyllum and Clonostachys. We also isolated the cultivable fungi from 12 air samples collected from six areas in Yunnan Province, PR China. Among the total of 1255 air fungal isolates, the most common genera were Cladosporium, Trichoderma and Epicoccum. Among them, two new Remotididymella species, Remotididymella ageratinae from leaf spot of Ag. adenophora and Remotididymella anemophila from canopy air of Ag. adenophora were found. The two species showed both asexual and sexual reproductive structures. The conidia of R. ageratinae and R. anemophila are larger than those of R. anthropophila and R. destructiva. The size of ascospores of R. ageratinae and R. anemophila also differ from R. bauhiniae. Phylogenetic analysis of the combined ITS, LSU rRNA, rpb2 and tub2 sequences showed that R. ageratinae and R. anemophila each formed a distinct clade, separated from all species previously described in Remotididymella and confirmed them as new species belonging to Remotididymella. Full descriptions of R. ageratinae and R. anemophila are provided in this study.

Quantifying the sharing of foliar fungal pathogens by the invasive plant Ageratina adenophora and its neighbours.

Local pathogens can accumulate as asymptomatic endophytes, making it difficult to detect the impacts of invasive species as propagators of disease in the invaded range. We used the invasive plant Ageratina adenophora to assess such accumulation. We intensively collected foliar fungal endophytes and leaf spot pathogens of A. adenophora and co-occurring neighbours and performed an inoculation experiment to evaluate their pathogenicity and host range. Ageratina adenophora harboured diverse necrotrophic pathogens; its communities of endophytes and leaf spot pathogens were different in composition and shared only a small number of fungal species. In the pathogen communities of local plant hosts, 21% of the operational taxonomic units (OTUs), representing 50% of strains, also occurred as leaf spot pathogens and/or endophytes of A. adenophora. The local pathogen community was more similar to the endophytes than to the pathogens of A. adenophora. The inoculation experiment showed that local pathogens could infect A. adenophora leaves asymptomatically and that local plant hosts were susceptible to both A. adenophora endophytes and pathogens. Ageratina adenophora is a highly competent host for local pathogens, and its asymptomatic latent pathogens are fungi primarily shared with local neighbours. This poses challenges for understanding the long-term ecological consequences of plant invasion.

High index of suspicion for brucellosis in a highly cosmopolitan city in southern China.

BACKGROUND: Brucellosis is one of the most widespread zoonosis in the world. In China, 90% of human brucellosis occurs in six northern agricultural provinces. However, there is a recent increase in the trend of human brucellosis in southern provinces with limited cases reported in the literature. Our study aims to describe the clinical features and epidemiology of brucellosis in a tertiary hospital in southern China. METHODS: A retrospective case series of brucellosis was conducted between January 1, 2014 and October 31. 2018. Cases were identified based on positive Brucella serology by tube agglutination test, or positive culture from clinical specimen identified by Vitek 2 and MALDL-TOF MS. Clinical details of brucellosis including patients' occupation, risk factors, and complications were analyzed. Clinical characteristics between patients from Guangdong and other provinces were also compared. RESULTS: A total of 13 cases of laboratory-confirmed brucellosis were identified. 7 (53.8%) of the patients were male, 6 (46.2%) were female, with age ranging from 29 to 73 years old (median age: 51 years). 5 patients (38.5%) were from Guangdong province, while the remaining patients (61.5%) were from other provinces. The commonest risk factors of acquisition were consumption of undercooked meat and goat placenta. Patients from Guangdong province were found to be more likely to have prior placenta consumption. The commonest clinical presentations were fever, osteoarticular pain, urinary symptoms, splenomegaly, and lymphadenopathy. Spondylodiscitis/ peripheral joint arthritis (5 patients, 38.5%) was the most prevalent complication, while extra-osteoarticular complications including abdominal aortitis, hepatosplenic abscess, chest wall abscess, and epididymo-orchitis were observed in 4 other patients. Furthermore, it was demonstrated that MALDI-TOF MS is reliable in Brucella identification after additional of reference spectra with standard Brucella strain. CONCLUSIONS: Brucellosis, previously thought to be only found in northern China, is now increasingly seen in highly cosmopolitan part of southern China. MALDI-TOF MS in hospitals in China should include reference spectra with standard Brucella strain to aid bacterial identification in routine clinical practice. In addition to tuberculosis, typhoid fever and typhus, brucellosis should be considered in patients with fever of unknown origin in this locality.

Plant-soil-foliage feedbacks on seed germination and seedling growth of the invasive plant Ageratina adenophora.

Some exotic plants become invasive because they partially release from soil-borne enemies and thus benefit from positive plant-soil feedbacks (PSFs) in the introduced range. However, reports that have focused only on PSFs may exaggerate the invader's competitiveness. Here, we conducted three experiments to characterize plant-soil-foliage feedbacks, including mature leaves (ML), leaf litter (LL), rhizosphere soil (RS) and leaves plus soil (LS), on the early growth stages of the invasive plant Ageratina adenophora. In general, the feedbacks from aboveground (ML, LL) adversely affected A. adenophora by delaying germination time, inhibiting germination rate and reducing seedling growth. The increased invasion history exacerbated the adverse effects of LL and LS feedbacks on seedling growth. These adverse effects were partially contributed by more abundant fungi (e.g. Didymella) or/and more virulent fungi (e.g. Fusarium) developed in the aboveground part of A. adenophora during the invasion. Interestingly, the aboveground adverse effects can be weakened by microbes from RSs. Our novel findings emphasize the important role of aboveground feedbacks in the evaluation of plant invasiveness, and their commonness and significance remain to be explored in other invasive systems.

Deficiency of the IRE1α-Autophagy Axis Enhances the Antitumor Effects of the Oncolytic Virus M1.

Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancer cells. M1 is a naturally occurring alphavirus (Togaviridae) which shows potent oncolytic activities against many cancers. Accumulation of unfolded proteins during virus replication leads to a transcriptional/translational response known as the unfolded protein response (UPR), which might counteract the antitumor effect of the oncolytic virus. In this report, we show that either pharmacological or biological inhibition of IRE1α or PERK, but not ATF6, substantially increases the oncolytic effects of the M1 virus. Moreover, inhibition of IRE1α blocks M1 virus-induced autophagy, which restricts the antitumor effects of the M1 virus through degradation of viral protein, in glioma cells. In addition, IRE1α suppression significantly increases the oncolytic effect of M1 virus in an orthotopic glioma model. From a molecular pathology study, we found that IRE1α is expressed at lower levels in higher-grade gliomas, suggesting greater antitumor efficacy of the oncolytic virus M1. Taken together, these findings illustrate a defensive mechanism of glioma cells against the oncolytic virus M1 and identify possible approaches to enhance the oncolytic viral protein accumulation and the subsequent lysis of tumor cells.IMPORTANCE Although oncolytic virotherapy is showing great promise in clinical applications, not all patients are benefiting. Identifying inhibitory signals in refractory cancer cells for each oncolytic virus would provide a good chance to increase the therapeutic effect. Here we describe that infection with the oncolytic virus M1 triggers the unfolded protein response (UPR) and subsequent autophagy, while blocking the UPR-autophagy axis significantly potentiates the antitumor efficacy of M1 in vitro and in vivo A survey of cancer tissue banks revealed that IRE1α, a key element in the UPR pathway, is commonly downregulated in higher-grade human gliomas, suggesting favorable prospects for the application of M1. Our work provides a potential predictor and target for enhancement of the therapeutic effectiveness of the M1 virus. We predict that the mechanism-based combination therapy will promote cancer virotherapy in the future.

Hexokinase 2-dependent hyperglycolysis driving microglial activation contributes to ischemic brain injury.

Hyperglycolysis, observed within the penumbra zone during brain ischemia, was shown to be detrimental for tissue survival because of lactate accumulation and reactive oxygen species overproduction in clinical and experimental settings. Recently, mounting evidence suggests that glycolytic reprogramming and induced metabolic enzymes can fuel the activation of peripheral immune cells. However, the possible roles and details regarding hyperglycolysis in neuroinflammation during ischemia are relatively poorly understood. Here, we investigated whether overactivated glycolysis could activate microglia and identified the crucial regulators of neuroinflammatory responses in vitro and in vivo. Using BV 2 and primary microglial cultures, we found hyperglycolysis and induction of the key glycolytic enzyme hexokinase 2 (HK2) were essential for microglia-mediated neuroinflammation under hypoxia. Mechanistically, HK2 up-regulation led to accumulated acetyl-coenzyme A, which accounted for the subsequent histone acetylation and transcriptional activation of interleukin (IL)-1ß. The inhibition and selective knockdown of HK2 in vivo significantly protected against ischemic brain injury by suppressing microglial activation and IL-1ß production in male Sprague-Dawley rats subjected to transient middle cerebral artery occlusion (MCAo) surgery. We provide novel insights for HK2 specifically serving as a neuroinflammatory determinant, thus explaining the neurotoxic effect of hyperglycolysis and indicating the possibility of selectively targeting HK2 as a therapeutic strategy in acute ischemic stroke.

Activation of Cyclic Adenosine Monophosphate Pathway Increases the Sensitivity of Cancer Cells to the Oncolytic Virus M1.

Oncolytic virotherapy is a novel and emerging treatment modality that uses replication-competent viruses to destroy cancer cells. Although diverse cancer cell types are sensitive to oncolytic viruses, one of the major challenges of oncolytic virotherapy is that the sensitivity to oncolysis ranges among different cancer cell types. Furthermore, the underlying mechanism of action is not fully understood. Here, we report that activation of cyclic adenosine monophosphate (cAMP) signaling significantly sensitizes refractory cancer cells to alphavirus M1 in vitro, in vivo, and ex vivo. We find that activation of the cAMP signaling pathway inhibits M1-induced expression of antiviral factors in refractory cancer cells, leading to prolonged and severe endoplasmic reticulum (ER) stress, and cell apoptosis. We also demonstrate that M1-mediated oncolysis, which is enhanced by cAMP signaling, involves the factor, exchange protein directly activated by cAMP 1 (Epac1), but not the classical cAMP-dependent protein kinase A (PKA). Taken together, cAMP/Epac1 signaling pathway activation inhibits antiviral factors and improves responsiveness of refractory cancer cells to M1-mediated virotherapy.

Rapid Detection of Atrazine at Workplace with Near-Infrared Spectroscopy.

As a wildly used herbicide, Atrazine is mainly produced in China. In order to strengthen the routine detection of Atrazine exposure concentration and protect the health of occupational contact workers, it's of great importance to develop on-site rapid detection method. A self-assembled near infrared spectrometer was used to record spectra of laboratory prepared atrazine solutions with concentration range from 10 to 1 000 mg·L-1. The influences of different pretreatment methods, such as multiplicative scatter correction, standard normal variate, first order derivative (D1), second order derivative and their combinations, different variable selection methods, such as competitive adaptive reweighted sampling (CARS) and genetic algorithm (GA), different regression methods, such as partial least square (PLS) and support vector regression(nu-SVR), on the model prediction accuracy were investigated. Results show that D1 is the best pretreatment method; GA obtain better results than CARS on selecting highly related spectral variables; nu-SVR model perform better than PLS model. The nu-SVR model constructed with 16 spectral variables selected by GA obtained the best results, whose coefficient of determination for calibration, the coefficient of determination for validation, root mean square error of calibration, root mean square error of validation (RMSEV) and residual validation deviation (defined as SD/RMSEV where SD denotes standard deviation) are 1, 0.99, 17.54 mg·L-1, 25.42 mg·L-1 and 11.43, respectively. These results indicate near infrared spectroscopy combined with chemometrics has great potential to quantify Atrazine concentration at workplace. This research explores the feasibility of quantification Atrazine at workplace with near infrared spectroscopy for the first time, which has great reference value for similar work in the future.

TRPM7 channel inhibition mediates midazolam-induced proliferation loss in human malignant glioma.

The melastatin-like transient receptor potential 7 (TRPM7) has been implicated in proliferation or apoptosis of some cancers, indicating the potential of TRPM7 as an anti-anaplastic target. Here, we identified the characteristic TRPM7 channel currents in human malignant glioma MGR2 cells, which could be blocked by a pharmacologic inhibitor Gd3+. We mined the clinical sample data from Oncomine Database and found that human malignant glioma tissues expressed higher TRPM7 mRNA than normal brain ones. Importantly, we identified a widely used clinical anesthetic midazolam as a TRPM7 inhibitor. Midazolam treatment for seconds suppressed the TRPM7 currents and calcium influx, and treatment for 48 h inhibited the TRPM7 expression. The inhibitory effect on TRPM7 accounts for the proliferation loss and G0/G1 phase cell cycle arrest induced by midazolam. Our data demonstrates that midazolam represses proliferation of human malignant glioma cells through inhibiting TRPM7 currents, which may be further potentiated by suppressing the expression of TRPM7. Our result indicates midazolam as a pharmacologic lead compound with brain-blood barrier permeability for targeting TRPM7 in the glioma.