The sheer ubiquity of Gioblastoma (GBM) cases would lead you to believe that there should have been many opportunities for the discovery of treatments to successfully render it into remission. ...Unfortunately, its persistent commonality is due in large part to the fact that it is the most treatment-resistant tumors in adults. That completely changes the treatment plan of attack. Long established and accepted treatment therapies such as surgical resection, radiation, and aggressive chemotherapy, (and any combination thereof) have only confirmed that the disease lives up to its treatment-resistant reputation. To add to the seemingly insurmountable task of finding a cure, GBM has also proven to be a very stubborn and formidable opponent to newer immunotherapies. Across the board, regardless of the therapy combination, the five-year survival rate of GBM patients is still very poor at a heartbreaking 5.6%. Obviously, the present situation cannot be tolerated or deemed acceptable. The grave situation calls for researchers to be more innovative and find more efficient strategies to discover new and successful strategies to treat GBM. Inspired by researchers worldwide attempting to control GBM, we provide in this review a comprehensive overview of the many diverse cell therapies currently being used to treat GBM. An overview of the treatments include: CAR T cells, CAR NK cells, gamma-delta T cells, NKT cells, dendritic cells, macrophages, as well stem cell-based strategies. To give you the complete picture, we will discuss the efficacy, safety, and developmental stages, the mechanisms of action and the challenges of each of these therapies and detail their potential to be the next-generation immunotherapeutic to eliminate this dreadful disease.
Influenza A virus (IAV) coopts numerous host factors to complete its replication cycle. Here, we identify free fatty acid receptor 2 (FFAR2) as a cofactor for IAV entry into host cells. We found that ...downregulation of FFAR2 or Ffar2 expression significantly reduced the replication of IAV in A549 or RAW 264.7 cells. The treatment of A549 cells with small interfering RNA (siRNA) targeting
or the FFAR2 pathway agonists 2-(4-chlorophenyl)-3-methyl-
-(thiazol-2-yl)butanamide (4-CMTB) and compound 58 (Cmp58) (
)-2-(4-chlorophenyl)-3,3-dimethyl-
-(5-phenylthiazol-2-yl)butanamide dramatically inhibited the nuclear accumulation of viral nucleoprotein (NP) at early time points postinfection, indicating that FFAR2 functions in the early stage of the IAV replication cycle. FFAR2 downregulation had no effect on the expression of sialic acid (SA) receptors on the cell membrane, the attachment of IAV to the SA receptors, or the activity of the viral ribonucleoprotein (vRNP) complex. Rather, the amount of internalized IAVs was significantly reduced in FFAR2-knocked-down or 4-CMTB- or Cmp58-treated A549 cells. Further studies showed that FFAR2 associated with β-arrestin1 and that β-arrestin1 interacted with the β2-subunit of the AP-2 complex (AP2B1), the essential adaptor of the clathrin-mediated endocytosis pathway. Notably, siRNA knockdown of either β-arrestin1 or AP2B1 dramatically impaired IAV replication, and AP2B1 knockdown or treatment with Barbadin, an inhibitor targeting the β-arrestin1/AP2B1 complex, remarkably decreased the amount of internalized IAVs. Moreover, we found that FFAR2 interacted with three G protein-coupled receptor (GPCR) kinases (i.e., GRK2, GRK5, and GRK6) whose downregulation inhibited IAV replication. Together, our findings demonstrate that the FFAR2 signaling cascade is important for the efficient endocytosis of IAV into host cells.
To complete its replication cycle, IAV hijacks the host endocytosis machinery to invade cells. However, the underlying mechanisms of how IAV is internalized into host cells remain poorly understood, emphasizing the need to elucidate the role of host factors in IAV entry into cells. In this study, we identified FFAR2 as an important host factor for the efficient replication of both low-pathogenic and highly pathogenic IAV. We revealed that FFAR2 facilitates the internalization of IAV into target cells during the early stage of infection. Upon further characterization of the role of FFAR2-associated proteins in virus replication, we found that the FFAR2-β-arrestin1-AP2B1 signaling cascade is important for the efficient endocytosis of IAV. Our findings thus further our understanding of the biological details of IAV entry into host cells and establish FFAR2 as a potential target for antiviral drug development.
Host defense systems employ posttranslational modifications to protect against invading pathogens. Here, we found that protein inhibitor of activated STAT 1 (PIAS1) interacts with the nucleoprotein ...(NP), polymerase basic protein 1 (PB1), and polymerase basic protein 2 (PB2) of influenza A virus (IAV). Lentiviral-mediated stable overexpression of PIAS1 dramatically suppressed the replication of IAV, whereas siRNA knockdown or CRISPR/Cas9 knockout of PIAS1 expression significantly increased virus growth. The expression of PIAS1 was significantly induced upon IAV infection in both cell culture and mice, and PIAS1 was involved in the overall increase in cellular SUMOylation induced by IAV infection. We found that PIAS1 inhibited the activity of the viral RNP complex, whereas the C351S or W372A mutant of PIAS1, which lacks the SUMO E3 ligase activity, lost the ability to suppress the activity of the viral RNP complex. Notably, the SUMO E3 ligase activity of PIAS1 catalyzed robust SUMOylation of PB2, but had no role in PB1 SUMOylation and a minimal role in NP SUMOylation. Moreover, PIAS1-mediated SUMOylation remarkably reduced the stability of IAV PB2. When tested in vivo, we found that the downregulation of Pias1 expression in mice enhanced the growth and virulence of IAV. Together, our findings define PIAS1 as a restriction factor for the replication and pathogenesis of IAV.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tripartite motif (TRIM) family proteins are important effectors of innate immunity against viral infections. Here we identified TRIM35 as a regulator of TRAF3 activation. Deficiency in or inhibition ...of TRIM35 suppressed the production of type I interferon (IFN) in response to viral infection. Trim35-deficient mice were more susceptible to influenza A virus (IAV) infection than were wild-type mice. TRIM35 promoted the RIG-Imediated signaling by catalyzing Lys63-linked polyubiquitination of TRAF3 and the subsequent formation of a signaling complex with VISA and TBK1. IAV PB2 polymerase countered the innate antiviral immune response by impeding the Lys63-linked polyubiquitination and activation of TRAF3. TRIM35 mediated Lys48-linked polyubiquitination and proteasomal degradation of IAV PB2, thereby antagonizing its suppression of TRAF3 activation. Our in vitro and in vivo findings thus reveal novel roles of TRIM35, through catalyzing Lys63-or Lys48-linked polyubiquitination, in RIG-I antiviral immunity and mechanism of defense against IAV infection.
Indoor air quality monitoring is of great importance to human health as people typically spend more than 90% of their time in indoor environments. An indoor air quality detector (IAQD) enabling ...measurement of CO 2 , PM2.5, temperature, humidity, has been designed and tested in residential buildings based on Internet of Things (IoT). The hardware and software design of IAQD are described in detail, and seven IAQDs with Zigbee wireless module embedded were deployed in the target building for a continuous period of one month in winter. The gateway collects sensor data from each IAQD in turn at an interval of two minutes, and transmits data to server in the cloud via GPRS/4G. The authorized users can access cloud platform via mobile apps or the Web browser. Monitoring data analysis results reveal that the maximum PM2.5 concentrations is 10 times than usual during cooking period, and CO 2 concentrations with the door closed will rise to 2500 ppm compared to the door opened at night, which threatens the health of occupants.
The Xiaojiang Fault Zone (XJF) is an important boundary fault on the southeast border of the Tibetan Plateau, with a complex subterranean structure and strong tectonic activity. In the present study, ...252 seismograph stations were deployed in the northern section of the XJF to collect ambient noise data in a span of 35 days. The minimum resolution attained was 2 km × 2 km to develop a high-precision underground velocity structure model. The velocity model helped in revealing that the low-velocity distribution originated below the XJF. It was also found that the fault, which is the primary channel for magma to rise, might be the cause of the upper crustal deformation of the XJF. The Dongchuan mining area is located to the west of the XJF, which has a low-velocity structure. However, the high-velocity structure appeared on both sides of the ore body. It is speculated that the ore was formed by magma intrusion. The intrusion serves as a heat source for the mining area and promotes deposit formation.
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•A short-period dense array based ambient noise tomography for Xiaojiang fault.•High and low velocity 3D structure under Xiaojiang fault.•Deep ore metallogenesis constraints beneath the Dongchuan ore field.
Deep reflection seismic data contain abundant surface wave information for which the velocity structure in the near-surface shallow underground can be obtained using multichannel analysis of surface ...waves (MASW). This paper uses the MASW method to process deep reflection data in the Yuanmou area in Yunnan province, China. The MASW method uses the phase velocity spectral transformation of Rayleigh waves to obtain its dispersion curve. The initial model for different lithology classifications is established to invert the underground velocity structure. This study obtains a two-dimensional shear wave velocity structure profile to investigate the shear wave velocity structure. Generally, the study results have shown that the shear wave velocity structure obtained by the MASW method corresponds well with the surface conditions and accurately reflects faults' changes, folds, and lithology. Moreover, the formation sand content calculation shows a large difference in Dongshan sag's formation sand content. The sand contents of Cretaceous and Middle Jurassic strata are over 30% similar, and the sandstone content of underlying Early Jurassic strata is mostly 30% lower. The stratum buried depth of Early Jurassic strata is between 0– 800 m. The dip angle of LZJF at this location is 90°. The west side of the LZJF is based on Proterozoic uplift, and the Quaternary sedimentary thickness exceeds 300 m above the uplift stratum. Whereas on the east side of the LZJF, the stratum of the Dongshan sag section is mainly a synclinal structure.
•Multichannel analysis of surface waves method is applicable to surface wave data in deep reflection profile.•The interlayer velocity difference method can be used to distinguish strata by shear wave velocity.•Shallow velocity structure can distinguish shallow geological structure with high resolution.
Urban structure imaging using noise-based techniques has rapidly developed in recent years. Given the complexity of the cross-correlation function in high-frequency signals, here, the beamforming ...(BF) method was used to analyze one data set taken from a dense array in the Jizhong Depression and obtain multi-mode dispersion curves. Multi-mode surface waves improved inversion stability, reduced non-uniqueness, and yielded a one-dimensional shear wave (S-wave) velocity model. Interpolation yielded a high-resolution three-dimensional (3D) S-wave velocity model for the study area. The model shows that velocity gradually changed in the horizontal direction and greatly increased in the vertical direction, which is largely consistent with changes in the sedimentary environment related to the continuous subsidence of the Jizhong Depression since the Quaternary. A low-velocity anomaly at a depth of ~300–400 m was revealed and determined to be caused by either a deep-buried ancient river course or low-lying area. This study demonstrates the potential of the BF method for processing dense array data sets of urban exploration. The high-resolution 3D S-wave velocity model provides a new reference for studying the Quaternary structure of the Jizhong Depression, as well as groundwater resources, urban infrastructure, and underground spaces.
Transcription and replication of the influenza A virus (IAV) genome occur in the nucleus of infected cells and are carried out by the viral ribonucleoprotein complex (vRNP). As a major component of ...the vRNP complex, the viral nucleoprotein (NP) mediates the nuclear import of the vRNP complex via its nuclear localization signals (NLSs). Clearly, an effective way for the host to antagonize IAV infection would be by targeting vRNP nuclear import. Here, we identified phospholipid scramblase 1 (PLSCR1) as a binding partner of NP by using a yeast two-hybrid (Y2H) screen. The interaction between NP and PLSCR1 in mammalian cells was demonstrated by using co-immunoprecipitation and pull-down assays. We found that the stable overexpression of PLSCR1 suppressed the nuclear import of NP, hindered the virus life cycle, and significantly inhibited the replication of various influenza subtypes. In contrast, siRNA knockdown or CRISPR/Cas9 knockout of PLSCR1 increased virus propagation. Further analysis indicated that the inhibitory effect of PLSCR1 on the nuclear import of NP was not caused by affecting the phosphorylation status of NP or by stimulating the interferon (IFN) pathways. Instead, PLSCR1 was found to form a trimeric complex with NP and members of the importin α family, which inhibited the incorporation of importin β, a key mediator of the classical nuclear import pathway, into the complex, thus impairing the nuclear import of NP and suppressing virus replication. Our results demonstrate that PLSCR1 negatively regulates virus replication by interacting with NP in the cytoplasm and preventing its nuclear import.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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