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In this paper, we augment airborne gravity anomaly data from Antarctica, expanding the coverage area by 10.4% based on the existing data set. These data are combined with a gravity field model to establish a more comprehensive gravity anomaly database for Antarctica. Utilizing the Integral of Stokes Kernels' Derivatives (ISKD) method, we create the first 10 km resolution gravity gradient map in the Antarctic region. According to measured data in the McFaulds Lake (located in the James Bay lowlands of northern Ontario, Canada), the proposed method achieves a calculation accuracy with a standard deviation (Std.) of 3–7 E ( 1 E = 1 × 10 - 9 s - 2 ) in Txx , Tyy , Txy , Txz , Tyz , and 12.9 E in Tzz . The calculated gravity gradient effectively reveals density boundaries in Antarctica. This research lays the groundwork for future studies exploring the gravitational characteristics of Antarctica on a broader scale. [ABSTRACT FROM AUTHOR]

Background Tongue squamous cell carcinoma (TSCC) exhibits an aggressive biological behavior of lymph node and distant metastasis, which contributes to poorer prognosis and results in tongue function loss or death. In addition to known regulators and pathways of cell migration in TSCC, it is important to uncover pivotal switches governing tumor metastasis. Methods Cancer cell migration-associated transcriptional and epigenetic characteristics were profiled in TSCC, and the specific super-enhancers (SEs) were identified. Molecular function and mechanism studies were used to investigate the pivotal switches in TSCC metastasis. Results Ameboidal-type cell migration-related genes accompanied by transcriptional and epigenetic activity were enriched in TSCC. Meanwhile, the higher-ranked SE-related genes showed significant differences between 43 paired tumor and normal samples from the TCGA TSCC cohort. In addition, key motifs were detected in SE regions, and transcription factor-related expression levels were significantly associated with TSCC survival status. Notably, BATF and ATF3 regulated the expression of ameboidal-type cell migration-related MMP14 by switching the interaction with the SE region. Conclusion SEs and related key motifs transcriptional regulate tumor metastasis-associated MMP14 and might be potential therapeutic targets for TSCC. [ABSTRACT FROM AUTHOR]

Background: High-resolution magnetic resonance vessel wall imaging (HRMR-VWI) is a promising technique for identifying intracranial vulnerable plaques beyond lumen narrowing. However, the association between HRMR-VWI characteristics and recurrent stroke remains uncertain. Aims: This study aimed to investigate the association between HRMR-VWI characteristics and recurrent ipsilateral stroke in patients with symptomatic intracranial atherosclerotic steno-occlusive disease (ICAS). Methods: This multicenter, observational study recruited first-ever acute ischemic stroke patients attributed to ICAS (>50% stenosis or occlusion) within 7 days after onset. Participants were assessed by multiparametric magnetic resonance imaging (MRI) including diffusion-weighted imaging, three-dimension time-of-flight magnetic resonance angiography, and three-dimensional T1-weighted HRMR-VWI. The patients were recommended to receive best medical therapy and were systematically followed up for 12 months. The association between HRMR-VWI characteristics and the time to recurrent ipsilateral stroke was investigated by univariable and multivariable analysis. Results: Two hundred and fifty-five consecutive patients were enrolled from 15 centers. The cumulative 12 month ipsilateral recurrence incidence was 4.1% (95% confidence interval (CI): 1.6–6.6%). Patients with recurrent ipsilateral stroke exhibited higher rates of intraplaque hemorrhage (IPH) (30.0% vs 6.5%) and eccentric plaque (90.0% vs 48.2%), and lower occurrence of occlusive thrombus (10.0% vs 23.7%). Plaque length (5.69 ± 2.21 mm vs 6.67 ± 4.16 mm), plaque burden (78.40 ± 7.37% vs 78.22 ± 8.32%), degree of stenosis (60.25 ± 18.95% vs 67.50% ± 22.09%) and remodeling index (1.07 ± 0.27 vs 1.03 ± 0.35) on HRMR-VWI did not differ between patients with and without recurrent ipsilateral stroke. In the multivariable Cox regression analysis, IPH (hazard ratio: 6.64, 95% CI: 1.23–35.8, p = 0.028) was significantly associated with recurrent ipsilateral stroke after adjustment. Conclusions: Our results suggest intraplaque hemorrhage (IPH) is significantly associated with recurrent ipsilateral stroke and has potential value in the selection of patients for aggressive treatment strategies. Data access statement: Data from this study are available and can be accessed upon request. [ABSTRACT FROM AUTHOR]

Morchella esculenta is a precious edible and medicinal fungus rich in protein, polysaccharides, polyphenols, amino acids, triterpenes, and other active components. In this study, MS-1 was isolated from the fruiting body of M. esculenta. Through conducting single-factor experiments and the response surface analysis of the culture conditions, the optimal culture components of an M. esculenta fermentation broth for extracellular polysaccharide production were determined, namely, 3.7% glucose, 2% yeast extract, and 0.15% sodium chloride. The polysaccharides MSF and MSL were extracted from the fruiting body of M. esculenta and the fermentation broth, respectively, and analyzed with gel permeation chromatography (GPC), monosaccharide composition, scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and in vivo and in vitro antioxidant and anti-inflammatory activity analyses. The research results show that the calculated MW of MSF is 2.34 × 105 Da, and the calculated MW of MSL is 1.40 × 105 Da. MSF is composed of three monosaccharides: D-galactose, D-glucose, and D-mannose (molar ratio of 4.34:90.22:5.45). MSL consists of five monosaccharides: D-arabinose, D-galactose, D-glucose, D-mannose, and glucuronic acid (molar ratio of 0.31:14.71:13.03:71.43:0.53). The in vitro antioxidant test results show that MSF and MSL both have significant antioxidant activities. Activity experiments on MSF and MSL in zebrafish showed that MSF and MSL have significant repair effects on the oxidative damage caused by metronidazole in zebrafish embryos, and there were significant changes in the transcriptional activity levels of the oxidative stress-related genes SOD, Keap1, and Nrf2. Therefore, the polysaccharides MSF and MSL from MS-1 can be used as important raw materials for functional foods and drugs. [ABSTRACT FROM AUTHOR]

Signaling pathways play a crucial role in regulating cellulase production. The pathway mediated by signaling proteins plays a crucial role in understanding how cellulase expression is regulated. In this study, using affinity purification of ClrB, we have identified sixteen proteins that potentially interact with ClrB. One of the proteins, the catalytic subunit of cAMP-dependent protein kinase A (PoPKA-C), is an important component of the cAMP/PKA signaling pathway. Knocking out PoPKA-C resulted in significant decreases in the growth, glucose utilization, and cellulose hydrolysis ability of the mutant strain. Furthermore, the cellulase activity and gene transcription levels were significantly reduced in the ΔPoPKA-C mutant, while the expression activity of CreA, a transcriptional regulator of carbon metabolism repression, was notably increased. Additionally, deletion of PoPKA-C also led to earlier timing of conidia production. The expression levels of key transcription factor genes stuA and brlA, which are involved in the production of the conidia, showed significant enhancement in the ΔPoPKA-C mutant. These findings highlight the involvement of PoPKA-C in mycelial development, conidiation, and the regulation of cellulase expression. The functional analysis of PoPKA-C provides insights into the mechanism of the cAMP/PKA signaling pathway in cellulase expression in filamentous fungi and has significant implications for the development of high-yielding cellulase strains. [ABSTRACT FROM AUTHOR]

With the continuous advancement of target detection technology in remote sensing, target detection technology in images captured by drones has performed well. However, object detection in drone imagery is still a challenge under rainy conditions. Rain is a common severe weather condition, and rain streaks often degrade the image quality of sensors. The main issue of rain streaks removal from a single image is to prevent over smoothing (or underclearing) phenomena. Aiming at the above problems, this paper proposes a deep learning (DL)-based rain streaks removal framework called GSDerainNet, which properly formulates the single image rain streaks removal problem; rain streaks removal is aptly described as a Gaussian Shannon (GS) filter-based image decomposition problem. The GS filter is a novel filter proposed by us, which consists of a parameterized Gaussian function and a scaled Shannon function. Two-dimensional GS filters exhibit high stability and effectiveness in dividing an image into low- and high-frequency parts. In our framework, an input image is first decomposed into a low-frequency part and a high-frequency part by using the GS filter. Rain streaks are located in the high-frequency part. We extract and separate the rain features of the high-frequency part through a deep convolutional neural network (CNN). The experimental results obtained on synthetic data and real data show that the proposed method can better suppress the morphological artifacts caused by filtering. Compared with state-of-the-art single image rain streaks removal methods, the proposed method retains finer image object structures while removing rain streaks. [ABSTRACT FROM AUTHOR]

Background: Recent studies have discovered an emerging role of IL11 in various colitis-associated cancers, suggesting that IL11 mainly promotes tumor cell survival and proliferation in regulating tumorigenesis. Herein we aimed to reveal a novel function of IL-11 through STAT3 signaling in regulating tumor immune evasion. Methods: AOM/DSS model in Il11−/− and Apcmin/+/Il11−/− mice were used to detect tumor growth and CD8+ T infiltration. STAT1/3 phosphorylation and MHC-I, CXCL9, H2-K1 and H2-D1 expression were detected in MC38 cells and intestine organoids treated with/without recombinant IL11 to explore effect of IL11/STAT3 signaling, with IL11 mutein used to competitively inhibit IL11 and rescue inhibited STAT1 activation. Correlation between IL11 and CD8+ T infiltration was analyzed using TIMER2.0 website. IL11 expression and survival prognosis was analyzed in clinical data of patient cohort from Nanfang Hospital. Results: IL11 is highly expressed in CRC and indicates unfavorable prognosis. IL11 knockout increased CD8+ T cell infiltration and reduced intestinal and colon formation. Tumors were significantly suppressed while MHC-I and CXCL9 expression for CD8+ T infiltration were remarkably increased in the tumor tissues of Apcmin/+/Il11−/− mice or Il11−/− mice induced by AOM/DSS. IL11/STAT3 signaling downregulated MHC-I and CXCL9 by inhibiting IFNγ-induced STAT1 phosphorylation. IL11 mutein competitively inhibit IL11 to upregulate CXCL9 and MHC-I in tumor and attenuated tumor growth. Conclusions: This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer. [ABSTRACT FROM AUTHOR]

Sea level rise (SLR) increases the frequency of floods caused by forces such as spring tides or storm surges. However, with the continuous evolution of global ocean tides, future flooding may be driven only by astronomical tides. Therefore, we introduce an inaction method (IM) that can accurately extract the harmonic constant of tidal components from the time‐frequency spectrum of the tide, and obtain the precise long‐term trend and spatial evolution characteristics of the tides at 18 sites along the East Coast of the United States (ECUS). Except for some sites in the middle of the East Coast, M2 shows an average upward trend of more than 51 mm/century, which is most obvious at three sites in North Carolina, with an average upward trend of more than 80 mm/century. We simultaneously combine the IM with harmonic analysis into an IMHA method to estimate the historical and future "Tide‐only" inundation (TOI) frequency and quantify the effect of tidal evolution on the future TOI frequency. The results show that four stations in the Gulf of Maine have experienced relatively frequent TOI events in the past, with the highest frequency at the Eastport station. The most significant increasing and decreasing effects of tidal evolution on the future TOI frequency under the SLR scenario are at the Wilmington and Lewes stations, respectively. At the spatial scale, there are increases in the northeast and southeast and a decrease in the middle of the ECUS, which is consistent with the spatial characteristics of the long‐term tidal trend. Plain Language Summary: SLR increases the frequency of flood occurrence, and the evolution of ocean tide also promotes or reduces flood inundation to varying degrees. On the basis of SLR, floods may be caused by tides alone in the future, which is called "Tide‐only" inundation (TOI). It is different from high tide flood which is mainly driven by tide and can also be caused by other factors. We adopt a new water level decomposition method to calculate the long‐term trend of tide amplitude on the East Coast of the United States by generating accurate historical astronomical tides, and obtain the spatial evolution characteristics of tides. Furthermore, the frequency of TOI is estimated in past and future SLR scenarios. By considering and omitting the long‐term tidal trend, the influence of tidal evolution on the future TOI frequency is quantified. The area where the tidal evolution leads to an increase in TOI frequency is found to be much greater than the area where it decreases. Key Points: Using a method that can directly extract the tidal amplitude from the water level can generate more accurate historical astronomical tidesOn the basis of rising sea level, the continuous evolution of tides leads to increasing flood inundations that are driven by tides aloneConsidering the long‐term trend of tides can improve the prediction accuracy of future water levels and flood inundation frequencies [ABSTRACT FROM AUTHOR]

In this work, we study the potential of a lossless subwavelength high-index-contrast metastructure as a broadband active coherent polarization control element. A parametric optimization of the metastructure is performed to determine its robust working parameter space. Using rigorous coupled wave analysis, we show that there exist large sets of suitable designs in the geometric parameter space capable of supporting wide-band dynamic polarization control functionalities, including reconfigurable polarizing beam splitting and arbitrary linear polarization rotation, over the entire S, C, and L communication bands. To understand the uniaxial anisotropic behavior of the subwavelength grating metastructure, we further perform a mode analysis to interpret its effective anisotropic performance. Our work provides guidance and insight for designing such subwavelength metastructures for a wide range of applications of active polarization control. [ABSTRACT FROM AUTHOR]

Purpose: Unlike ordinary products, festival food gifts like mooncakes in China are prone to excessive packaging, using various materials and complicated decorations, which increases the resource and environmental burdens of consumption. This study evaluated the environmental impacts of different mooncake packaging options, including metal, wood, and paper-based packaging. Methods: This study sampled 64 mooncake packaging types (with low, medium, and high prices) in the Chinese market and employed life cycle assessment modeling to quantify and analyze the environmental impacts of different mooncake packaging types. Based on these results, this study identified environmental-friendly options and shed light on directions to alleviate unnecessary environmental impacts associated with the packaging of massive seasonal festival food. Results and discussion: The weight of packing materials associated with 1 kg of mooncake product ranged from 0.5 to 2.5 kg (with a mean value of 1.2 kg), resulting in average greenhouse gas emissions of 2 kg of CO2-eq, or approximately 67 times the value of ordinary food packing (0.03 kg of CO2-eq). Among the three packaging types, metal-based packaging had the highest environmental impacts, followed by wood and paper-based packaging. The outer packaging was the dominant contributor to the environmental impacts of metal-based packaging, while the impacts of wood and paper-based packaging were primarily derived from the middle packaging materials, which mainly consisted of individual packaging boxes and fixed pallets. Higher-priced mooncakes had heavier packaging weight and greater environmental impacts, suggesting that they bear more environmental responsibility. Conclusion: Excessive and extravagant packaging was responsible for the increasing environmental burden associated with mooncakes. For both mooncake producers and consumers, turning back to the essence of the festival itself will be crucial for mitigating the environmental impacts of packaging. This study is an initial attempt to quantify the environmental impacts of traditional festival food packaging, and the study results facilitate evidence-based policymaking to transition the festival commodity packaging sector in a more sustainable direction. [ABSTRACT FROM AUTHOR]

The La0.67(Sr1−xMgx)0.33MnO3 (x = 0, 0.1, 0.3) manganites have been prepared by sol–gel method, and the effect of Mg doping on their structure, magnetic and magnetocaloric properties has been researched. All the samples are crystallized in perovskite rhombohedral structure with space group R 3 ¯ c . The slight increases in the edge length a and the cell volume with Mg doping indicates the replacement of Mg in Mn-site. The corresponding change of structure parameters, such as Mn–O bond length and Mn–O–Mn bond angle, weakens the exchange coupling between Mn3+ and Mn4+ and results in the decrease in the Curie temperature (TC). With increasing content of Mg, the local inhomogeneity and Griffiths-like phase evolve and induce the deviation of critical exponents from the mean-field model. The existence of these short-range ferromagnetic clusters broadens the temperature range of magnetic transition process, then depresses the magnetic entropy change (|ΔSM|) and flattens the |ΔSM|-T curve. The La0.67(Sr0.7Mg0.3)0.33MnO3 possesses a table-like magnetocaloric effect near room temperature (|ΔSM| is nearly constant of 0.51 ± 0.01 J kg−1 K−1 for field change of 1 T in the temperature range of 277 ~ 302 K), which is beneficial for the Ericsson cycle magnetic refrigerator. [ABSTRACT FROM AUTHOR]

The gravity field is one of the Earth's basic physical fields. The geoid can be calculated and the tectonic activity underground can be inversed by gravity anomaly. With the development of various ship-borne gravimeters and navigation technology, including the Global Navigation Satellite System (GNSS) and Strapdown Inertial Navigation System (SINS), the precision of marine gravimetry has been significantly improved (achieve or better than 1mGal). Errors arising from calculations of the correction term have become the main source of gravity measurement errors. At present, the traditional approach is to deploy a GNSS antenna, connect the GNSS antenna to the gravimeter, record the real-time position through data acquisition software, and then use this position to calculate the gravity correction item afterward. Two errors are inevitable. (1) The GNSS antenna position error is large. The pseudorange point positioning method is generally used to obtain real-time GNSS antenna positions, and the positioning accuracy is poor compared with that of precise point positioning. (2) The position coordinates of the gravimeter contain systematic errors related to the ship's attitude. In this paper, a joint experiment including GNSS antenna arrays and ship-borne gravimeters was designed to evaluate the measurement accuracy via repeat lines on the same ship. The experimental results show the following: (1) attitude accuracies of 0.0299° for the yaw angle, 0.0361° for the pitch angle, and 0.1671° for the roll angle can be obtained at baseline lengths of 25 and 4 m. (2) The GNSS antenna array has an obvious role in determining the point acceleration in the low-frequency band (0–0.01 Hz) and the point position and velocity in the high-frequency band (0.01–1 Hz). (3) The vertical position eccentricity causes an absolute error of 1 mGal and a relative error of 10 - 1 mGal in gravity measurements and can be corrected by the GNSS antenna array method. (4) Using a GNSS antenna array can obviously improve the measurement accuracy of an instrument with a precision equaling or exceeding 1 mGal, but cannot obviously improve that to an instrument with poor precision (2 mGal or below). [ABSTRACT FROM AUTHOR]

Objective: To observe the lacunar-like changes in cesarean scar pregnancy (CSP) ultrasonography in first trimester and to explore its relationship with clinical outcome in early pregnancy termination.Methods: This is a retrospective case-control study. Patients who were diagnosed as CSP and chose to terminate pregnancy from January 2017 to April 2020 were enrolled. According to occurrence of lacunar-like change in chorion membrane, patients were divided into case and control group. The clinical manifestation, laboratory test, ultrasound data, and outcome were compared.Results: Fifty-five CSP patients were enrolled with 20 (36.4%) in case group and 35 (63.6%) in control group. As for ultrasound features, the maximum outer diameter of gestational mass (5.6 ± 2.5 cm vs. 3.9 ± 1.5 cm), the maximum thickness of the chorion membrane (median number 1.1 cm vs. 0.7 cm), the longitudinal diameter of the implanting part of gestational mass in uterine lower segment (3.3 ± 1.8 cm vs. 1.2 ± 0.5 cm), uterine lower segment protrusion incidence (12, 60% vs. 2, 5.7%), and the crown-rump length of fetus (median number 1.7 cm vs. 0.7 cm) were bigger or higher in case group than that of the control group; the minimum thickness of the uterine lower segment myometrium (median number 0.08 cm vs. 0.20 cm) was significantly thinner in case group. CDFI grading of case group was different from control group with more cases in higher grades. As for clinical outcome, the patients of case group showed more frequency of CSP lesion resection under open surgery or laparoscopy (7, 35% vs. 1, 2.86%) rather than suction curettage, more blood loss in surgery (median number 35 ml vs. 20 ml) and more hospitalization days (median number 7.5 d vs. 3.5 d) than control group.Conclusions: Lacunar-like change of chorion can be detected in early gestation and may act as a predictor of complicated and worse clinical outcome. [ABSTRACT FROM AUTHOR]

The large number of spatial modes supported by standard multimode fibers is a promising platform for boosting the channel capacity of quantum and classical communications by orders of magnitude. However, the practical use of long multimode fibers is severely hampered by modal crosstalk and polarization mixing. To overcome these challenges, we develop and experimentally demonstrate a vectorial time reversal technique, which is accomplished by digitally pre-shaping the wavefront and polarization of the forward-propagating signal beam to be the phase conjugate of an auxiliary, backward-propagating probe beam. Here, we report an average modal fidelity above 80% for 210 Laguerre-Gauss and Hermite-Gauss modes by using vectorial time reversal over an unstabilized 1-km-long fiber. We also propose a practical and scalable spatial-mode-multiplexed quantum communication protocol over long multimode fibers to illustrate potential applications that can be enabled by our technique. The use of long multimode fibers for multiplexed quantum communication is hindered by modal crosstalk and polarisation mixing. Here, the authors use an auxiliary laser beam sent backwards from Bob to Alice, allowing her to pre-compensate for the spatial distortions and polarisation scrambling. [ABSTRACT FROM AUTHOR]

Free-space optical communication is a promising means to establish versatile, secure and high-bandwidth communication between mobile nodes for many critical applications. While the spatial modes of light offer a degree of freedom to increase the information capacity of an optical link, atmospheric turbulence can introduce severe distortion to the spatial modes and lead to data degradation. Here, we demonstrate experimentally a vector-beam-based, turbulence-resilient communication protocol, namely spatial polarization differential phase shift keying (SPDPSK), that can reliably transmit high-dimensional information through a turbulent channel without the need of any adaptive optics for beam compensation. In a proof-of-principle experiment with a controllable turbulence cell, we measure a channel capacity of 4.84 bits per pulse using 34 vector modes through a turbulent channel with a scintillation index of 1.09, and 4.02 bits per pulse using 18 vector modes through even stronger turbulence corresponding to a scintillation index of 1.54. Resistance to turbulence is an ongoing challenge for point-to-point freespace communications. Here the authors present a protocol for encoding a large amount of information in vector beams that are transmittable through a moderately strong turbulent channel without adaptive beam compensation. [ABSTRACT FROM AUTHOR]

Objective: To compare the clinical and ultrasound characteristics of cesarean scar pregnancy (CSP) and other lower uterine segment pregnancies (LUSPs) to enable differential diagnosis of the two pathologies in the first trimester. Methods: A retrospective analysis of early pregnancies with a gestational sac located in the lower uterine segment with cesarean section history in our hospital from December 2011 to February 2018 was performed. According to the diagnoses, the patients were divided into the CSPs group and the other LUSPs group. The clinical and ultrasound features were compared. Results: A total of 38 patients were enrolled with 16 (42.1%) CSPs and 22 (57.9%) other LUSPs. Compared to the other LUSPs group, the CSPs group had thinner lower uterine myometrium (0.16 ± 0.11 cm versus 0.32 ± 0.14 cm, p =.000), larger maximum diameter of the gestational sac (5.14 ± 2.08 cm versus 3.77 ± 1.24 cm, p =.028); the distribution of the villous chorion sites (p =.001) and the main blood supply sites (p =.000) of the gestational sac were different between the two groups. Surgical bleeding volume during the termination of gestation was higher in the CSPs group than in the other LUSPs group (p =.028). Conclusion: Patients with CSPs and other LUSPs have different imaging characteristics on ultrasound. The prognosis of these patients also differs. Ultrasound feature is very useful in the differential diagnosis of these two clinical-mimicking pathologies. [ABSTRACT FROM AUTHOR]

In this paper we propose an end-fire antenna fed by a spoof surface plasmon transmission line that can exhibit a conical directional response. The plasmonic transmission line is composed of metallic strips of periodic sawtooth grooves that taper towards the firing end of the strip. By tapering the sawtooth grooves, reflection is suppressed, and a high gain is achieved when the spoof surface plasmons radiate into free space. Simulated results indicate that our antenna can achieve high efficiency and a maximum gain of 12.4 dBi within a wide operating band from 6 to 13 GHz. The antenna proposed in this paper has a simple and compact structure with a lateral dimension of approximately 0.19 λ 0 * 0.32 λ 0 and shows great potential for use in spoof surface plasmon polariton communication systems along with integrated circuits. [ABSTRACT FROM AUTHOR]

Purpose: Although X-inactive specific transcript (XIST) is known to play a critical role in the pathogenesis of melanoma, the mechanisms through which this remains unclear. Methods: RNAseq, immunohistochemistry, and qRT-PCR were used to identify the levels of XIST, miR-139-5p, and Rho-Associated Coiled-Coil Containing Protein Kinase-1 (ROCK1) in melanoma tissues and cells. A subcellular fractionation assay was used to determine the location of XIST. CCK-8 and colony formation assays were used to evaluate cellular proliferation. Cell migration and wound healing assays were used to detect the effects on cell migration. RNA pull-down was used to confirm the interaction between XIST and miR-139-5p. Besides, the xenograft tumor experiment was performed to further verify the roles of XIST in melanoma. Results: In this study, an increased level of XIST was revealed in melanoma tissues and cells, which was associated with higher TNM stage and positive lymph node metastasis. XIST was found to function as a "molecular sponge" of miR-139-5p to facilitate cellular functions. Moreover, these consequences could be partially reversed by inhibition of miR-139-5p. MiR-139-5p was found to target ROCK1 directly, leading to suppression of ROCK1 expression; this effect could be partially reversed by inhibiting XIST expression. Furthermore, the deletion of ROCK1 induced anti-oncogenic effects similar to those seen with knockout of XIST. Upregulation of miR-139-5p and knockdown of XIST could inhibit cell functions in melanoma. Conclusion: Our findings suggested that the lncRNA XIST facilitates cellular functions in melanoma via the miR-139-5p/ROCK1 pathway. [ABSTRACT FROM AUTHOR]

The efficacy of immunotherapy against colorectal cancer (CRC) is impaired by insufficient immune cell recruitment into the tumor microenvironment. Our study shows that targeting circDNA2v, a circular RNA commonly overexpressed in CRC, can be exploited to elicit cytotoxic T cell recruitment. circDNA2v functions through binding to IGF2BP3, preventing its ubiquitination, and prolonging the IGF2BP3 half-life, which in turn sustains mRNA levels of the protooncogene c-Myc. Targeting circDNA2v by gene silencing downregulates c-Myc to concordantly induce tumor cell senescence and the release of proinflammatory mediators. Production of CXCL10 and interleukin-9 by CRC cells is elicited through JAK-STAT1 signaling, in turn promoting the chemotactic and cytolytic activities of CD8+ T cells. Clinical evidence associates increased circDNA2v expression in CRC tissues with reductions in CD8+ T cell infiltration and worse outcomes. The regulatory relationship between circDNA2v, cellular senescence, and tumor-infiltrating lymphocytes thus provides a rational approach for improving immunotherapy in CRC. [Display omitted] • circDNA2v prevents IGF2BP3 turnover in CRC cells to stabilize c-Myc mRNA levels • Knockdown of circDNA2v induces high levels of senescence and proinflammatory SASP release • Enhanced CXCL10/IL-9 production by senescent CRC cells results from JAK-STAT signaling • CXCL10 and IL-9 release by senescent CRC cells recruits and activates CD8+ T cells Wu et al. disclose the oncogenic function of circDNA2v in colorectal cancer linked with maintaining c-Myc expression. circDNA2v silencing induces senescence in CRC cells, with the associated proinflammatory cytokine release promoting intratumoral T cell infiltration, proposing that targeting circDNAv2 can reprogram the tumor immune balance and potentially augment immunotherapy approaches. [ABSTRACT FROM AUTHOR]

Background: Only a fraction of red blood cell (RBC) transfusion recipients form alloantibodies, and variables determining responsiveness or nonresponsiveness are poorly understood. We and others have previously shown in animal models that pretreatment with toll-like receptor agonists that mimic different types of infections impacts the magnitude or frequency of RBC alloantibody responses. We hypothesized that influenza infection, coexistent with transfusion, would impact responses to transfused RBCs in a manner dependent on Type 1(α/β) interferon (IFN) signaling and tested this in a murine model.Study Design and Methods: Wild-type mice or mice lacking the ability to respond to Type 1 IFN were infected with influenza prior to the transfusion of transgenic murine RBCs (K1) expressing the human KEL glycoprotein or the triple fusion HOD protein. Alloantibody responses were measured longitudinally after transfusion by flow cytometric crossmatch, and posttransfusion RBC recovery and survival was evaluated.Results: Influenza-infected mice transfused with K1 RBCs developed robust anti-KEL alloantibodies, whereas animals transfused in the absence of infection remained nonresponders; influenza-associated RBC alloimmunization was also observed after transfusion of HOD RBCs. Recipient Type 1 IFN production was critical to the mechanism of action of influenza-induced RBC alloimmunization, with alloimmunization being significantly decreased in mice unable to sense Type 1 IFN (through antibody blockade or genetic approaches).Conclusion: These and other data suggest that Type 1 IFN responses to toll-like receptor agonists or infections regulate RBC alloantibody responses. Studies investigating whether such a correlation exists in humans may be informative. [ABSTRACT FROM AUTHOR]

Background: Claudin18.2 (CLDN18.2), a gastric-specific membrane protein, has been regarded as a potential therapeutic target for gastric cancer and other cancer types. The aim of our study was to elucidate whether chimeric antigen receptor T (CAR T) cells redirected to CLDN18.2 have the potential to be used in the treatment of this deadly disease.Methods: CLDN18.2-specific humanized antibodies were developed using hybridoma and humanization technology. CLDN18.2-specific CAR T cells were prepared by lentiviral vector transduction. In vitro antitumor activities and cytokine production of the CAR T cells to gastric cancer cell lines were examined by cytotoxicity and ELISA assay. In vivo antitumor activities of CAR T cells were evaluated in mice bearing gastric cancer cell line and patient-derived tumor xenograft (PDX) models (n ≥ 6 mice per group). All statistical tests were two-sided.Results: Humanized CLDN18.2-specific hu8E5 and hu8E5-2I single-chain fragment variables (scFv) were successfully developed. CLDN18.2-specific CAR T cells were developed using hu8E5 or hu8E5-2I scFv as targeting moieties. Both hu8E5-28Z and hu8E5-2I-28Z CAR T cells comprising the CD28 costimulatory domain potently suppressed tumor growth in a cancer cell line xenograft mouse model (mean [SD] tumor volume: hu8E5-28Z = 118.0 [108.6] mm3 and hu8E5-2I-28Z group = 75.5 [118.7] mm3 vs untransduced T cell group = 731.8 [206.3] mm3 at day 29 after tumor inoculation, P < .001). Partial or complete tumor elimination was observed in CLDN18.2-positive gastric cancer PDX models treated with the hu8E5-2I-28Z CAR T cells (P < .001), which persist well in vivo and infiltrate efficiently into the tumor tissues. Although the CLDN18.2 CAR T cells could lyse target cells expressing murine CLDN18.2 (mCLDN18.2), no obvious deleterious effect on the normal organs including the gastric tissues was observed in the mice.Conclusions: CLDN18.2-specific CAR T cells could be a promising treatment strategy for gastric cancer and potentially other CLDN18.2-positive tumors. [ABSTRACT FROM AUTHOR]

Our recent clinical study demonstrated that glypican-3 (GPC3)-specific chimeric antigen receptor-modified T (CAR-T) cells are a promising treatment for hepatocellular carcinoma (HCC). However, the interaction of programmed cell death 1 (PD-1) and PD-L1-mediated T-cell inhibition is involved in immune evasion in a wide range of solid tumors, including HCC. To overcome this problem, we introduced a fusion protein composed of a PD-1 extracellular domain and CH3 from IgG4 into GPC3-specific CAR-T cells (GPC3-28Z) to block the PD-1/PD-L1 pathway. GPC3-specific CAR-T cells carrying the PD-1-CH3 fusion protein (sPD1) specifically recognized and lysed GPC3-positive HCC cells. The proliferation capacity of GPC3-28Z-sPD1 T cells after weekly stimulation with target cells was much higher than that of control GPC3-28Z T cells. Additionally, the coexpression of sPD1 could protect CAR-T cells from exhaustion when incubated with target cells, as phosphorylated AKT and Bcl-xL expression levels were higher in GPC3-28Z-sPD1 T cells than in GPC3-28Z cells. Importantly, in two HCC tumor xenograft models, GPC3-28Z-sPD1 T cells displayed a significantly higher tumor suppression capacity than GPC3-28Z T cells. In addition, an increased number of CD3+ T cells in the circulation and tumors and increased granzyme B levels and decreased Ki67 expression levels in the tumors were observed in the mice treated with GPC3-28Z-sPD1 T cells. Together, these data indicated that GPC3-specific CAR-T cells carrying sPD1 show promise as a treatment for patients with HCC. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has made unprecedented breakthrough in the fields of chimeric antigen receptor-redirected T (CAR T) cell therapy and immune modulation. Combination of CAR modification and the disruption of endogenous inhibitory immune checkpoints on T cells represent a promising immunotherapeutic modality for cancer treatment. However, the potential for the treatment of hepatocellular carcinoma (HCC) has not been explored. In this study, the gene expressing the programmed death 1 receptor (PD-1) on the Glypican-3 (GPC3)-targeted second-generation CAR T cells employing CD28 as the co-stimulatory domain was disrupted using the CRISPR/Cas9 gene-editing system. It was found that, in vitro , the CAR T cells with the deficient PD-1 showed the stronger CAR-dependent anti-tumor activity against native programmed death 1 ligand 1-expressing HCC cell PLC/PRF/5 compared with the wild-type CAR T cells, and meanwhile, the CD4 and CD8 subsets, and activation status of CAR T cells were stable with the disruption of endogenous PD-1. Additionally, the disruption of PD-1 could protect the GPC3-CAR T cells from exhaustion when combating with native PD-L1-expressing HCC, as the levels of Akt phosphorylation and anti-apoptotic protein Bcl-xL expression in PD-1 deficient GPC3-CAR T cells were significantly higher than those in wild-type GPC3-CAR T cells after coculturing with PLC/PRF/5. Furthermore, the in vivo anti-tumor activity of the CAR T cells with the deficient PD-1 was investigated using the subcutaneous xenograft tumor model established by the injection of PLC/PRF/5 into NOD-scid-IL-2Rγ-/- (NSG) mice. The results indicated that the disruption of PD-1 enhanced the in vivo anti-tumor activity of CAR T cells against HCC, improved the persistence and infiltration of CAR T cells in the NSG mice bearing the tumor, and strengthened the inhibition of tumor-related genes expression in the xenograft tumors caused by the GPC3-CAR T cells. This study indicates the enhanced anti-tumor efficacy of PD-1-deficient CAR T cells against HCC and suggests the potential of precision gene editing on the immune checkpoints to enhance the CAR T cell therapies against HCC. [ABSTRACT FROM AUTHOR]

Summary Cancer-associated fibroblasts (CAFs) provide critical metabolites for tumor growth and undergo metabolic reprogramming to support glycolysis. However, the molecular mechanisms responsible for this change remain unclear. Here, we report that TGF-β1- or PDGF-induced CAFs switch from oxidative phosphorylation to aerobic glycolysis. We identify downregulation of isocitrate dehydrogenase 3α (IDH3α) as a marker for this switch. Furthermore, miR-424 downregulates IDH3α during CAF formation. Downregulation of IDH3α decreases the effective level of α-ketoglutarate (α-KG) by reducing the ratio of α-KG to fumarate and succinate, resulting in PHD2 inhibition and HIF-1α protein stabilization. The accumulation of HIF-1α, in turn, promotes glycolysis by increasing the uptake of glucose, upregulating expression of glycolytic enzymes under normoxic conditions, and inhibiting oxidative phosphorylation by upregulating NDUFA4L2. CAFs from tumor samples exhibit low levels of IDH3α, and overexpression of IDH3α prevents transformation of fibroblasts into CAFs. Our studies reveal IDH3α to be a critical metabolic switch in CAFs. [ABSTRACT FROM AUTHOR]

Upon the treatment of Fas ligand, different types of cells exhibit different apoptotic mechanisms, which are determined by a complex network of biological pathways. In order to derive a quantitative interpretation of the cell sensitivity and apoptosis pathways, we have developed an ordinary differential equation model. Our model is intended to include all of the known major components in apoptosis pathways mediated by Fas receptor. It is composed of 29 equations using a total of 49 rate constants and 13 protein concentrations. All parameters used in our model were derived through nonlinear fitting to experimentally measured concentrations of four selected proteins in Jurkat T-cells, including caspase-3, caspase-8, caspase-9, and Bid. Our model is able to correctly interpret the role of kinetic parameters and protein concentrations in cell sensitivity to FasL. It reveals the possible reasons for the transition between type-I and type-II pathways and also provides some interesting predictions, such as the more decisive role of Fas over Bax in apoptosis pathway and a possible feedback mechanism between type-I and type-II pathways. But our model failed in predicting FasL-induced apoptotic mechanism of NCI-60 cells from their gene-expression levels. Limitations in our model are also discussed. [ABSTRACT FROM AUTHOR]

The article presents a study by M. Fridman and colleagues on a device that has the capability to hide events that occur during a specific time window. The study sued transformation optics, spatial cloaking, and radio frequency. Results showed that a detected signal from the device associated with the event has become more tenfold weaker that its original event, leading for the event to be cloaked.