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Abstract Oracle bones (Obs) are a significant carrier of the shang dynasty civilization, primarily consisting of tortoise shells and animal bones, through the study of which we can gain a deeper understanding of the political, economic, religious, and cultural aspects of the shang dynasty. The oracle bone drill chisel (Obdc) is considered an essential non-textual material. The segmentation of Obdc assists archaeologists determine the approximate age of the Obs, which possesses considerable research value. However, the breakage of thousands of years of underground buried Obs, the blurring of the edges of the area burned by the Obdc, the different shapes, and the inconsistent number have brought challenges to the accurate segmentation of the Obdc. In this article, we propose a group convolutional attention and pvt dual-branch network (GCA-PVT-Net) for Obdc segmentation. To our knowledge, this paper is the first to research the automatic segmentation of Obdc. It is a hybrid Convolutional neural network (CNN) and Transformer framework. The work offers the following contributions: (1) The Obdc images are labeled based on the delineation criteria of different drill chisel (DC) shapes to create the Obdc dataset. (2) A convolutional attention module (CAM) is proposed as both an encoder and decoder. The feature extraction process, which effectively integrates global and local information, ensures better modeling of long-term correlations in images while preserving details. (3) A channel feature aggregation module (CFAM) is designed to enhance the effective integration of channel features, enabling feature fusion across various branches and at different levels. (4) The edge deep supervision strategy is applied to smooth the jagged edge of the predicted images at the decoder’s end. Extensive experiments on the Obdc dataset show that GCA-PVT-Net outperforms other state-of-the-art (SOTA) methods. The comparative experimental results show that the edge accuracy and segmentation accuracy of the model reach the top 1.

Abstract FBXO32, a member of the F-box protein family, is known to play both oncogenic and tumor-suppressive roles in different cancers. However, the functions and the molecular mechanisms regulated by FBXO32 in lung adenocarcinoma (LUAD) remain unclear. Here, we report that FBXO32 is overexpressed in LUAD compared with normal lung tissues, and high expression of FBXO32 correlates with poor prognosis in LUAD patients. Firstly, we observed with a series of functional experiments that FBXO32 alters the cell cycle and promotes the invasion and metastasis of LUAD cells. We further corroborate our findings using in vivo mouse models of metastasis and confirmed that FBXO32 positively regulates LUAD tumor metastasis. Using a proteomic-based approach combined with computational analyses, we found a positive correlation between FBXO32 and the PI3K/AKT/mTOR pathway, and identified PTEN as a FBXO32 interactor. More important, FBXO32 binds PTEN via its C-terminal substrate binding domain and we also validated PTEN as a bona fide FBXO32 substrate. Finally, we demonstrated that FBXO32 promotes EMT and regulates the cell cycle by targeting PTEN for proteasomal-dependent degradation. In summary, our study highlights the role of FBXO32 in promoting the PI3K/AKT/mTOR pathway via PTEN degradation, thereby fostering lung adenocarcinoma progression.

Stem-like CD8+ T cells (TSL) are a subset of immune cells with superior persistence and antitumor immunity. They are TCF1+ PD-1+ and important for the expansion of tumor specific CD8+ T cells in response to checkpoint blockade immunotherapy. In acute infections, naïve CD8+ T cells differentiate into effector and memory CD8+ T cells; in cancer and chronic infections, persistent antigen stimulation can lead to T cell exhaustion. Recent studies have highlighted the dichotomy between late dysfunctional (or exhausted) T cells (TLD) that are TCF1– PD-1+ and self-renewing TCF1+ PD-1+ TSL from which they derive. TCF1+ TSL cells are considered to have stem cell-like properties akin to memory T cell populations and can give rise to cytotoxic effector and transitory T cell phenotypes (TTE) which mediate tumor control. In this review, we will discuss recent advances made in research on the formation and expansion of TSL, as well as distinct niches required for their differentiation and maintenance in the setting of cancer. We will also discuss potential strategies to generate these cells, with clinical implications for stemness enhancement in vaccine design, immune checkpoint blockade (ICB), and adoptive T cell therapies.

Numerous sedimentary phosphorites in Southwest China were formed around the Precambrian–Cambrian transition (PC–C), including the upper Ediacaran Doushantuo Formation and lower Cambrian Gezhongwu Formation. The Gezhongwu phosphorites in Zhijin exhibit marked rare earth element (REE) enrichment (>1000 ppm), and may represent new REE resources. Although the main characteristics of the Gezhongwu phosphorites have been well constrained, the REE enrichment mechanisms remain unclear. We undertook a comparative study of three typical sedimentary phosphorites with variable REE contents formed at the PC–C transition in central Guizhou Province, Southwest China. These include sections A and B of the Doushantuo phosphorites (560 ± 8 Ma) from the Weng’an area (i.e., WA-A and WA-B), and the Gezhongwu phosphorites (527 ± 24 Ma) from the Zhijin area (ZJ). The phosphorites were investigated with state-of-the-art macroscale to nanoscale analytical techniques. In contrast to the extraordinary REE enrichment in the ZJ phosphorites (average ΣREE = 1157 ppm), the phosphorites in WA-A (average ΣREE = 234 ppm) and WA-B (average ΣREE = 114 ppm) are REE-poor. Elemental mapping by laser ablation–inductively coupled plasma–mass spectrometry, along with transmission electron microscopy analyses, showed the REEs in the studied phosphorites are hosted in nanoscale francolites. The 87Sr/86Sr and Y/Ho ratios of the francolite grains indicate that greater terrigenous input may have led to more REE enrichment in the WA-A than WA-B phosphorites, but this cannot explain the extraordinary REE enrichment in the ZJ phosphorites. The F/P2O5 values of the francolite grains in the ZJ phosphorites (∼0.097) are higher than those in the WA-A (∼0.084) and WA-B (∼0.084) phosphorites, and the grain size of the francolite in the ZJ phosphorites (∼89.9 nm) is larger than those in the WA-A (∼56.6 nm) and WA-B (∼57.4 nm) phosphorites, indicative of more intense reworking of the ZJ than WA phosphorites during early diagenesis. A plot of Nd concentration versus Ce/Ce* reveals that lower sedimentation rates characterized the ZJ phosphorites. Therefore, intense sedimentary reworking during early diagenesis resulted in more REEs being sequestered by the marine phosphates from seawater and pore waters at a lower sedimentation rate, which resulted in the extraordinary REE enrichment in the ZJ phosphorites. Our findings highlight the multiple factors that controlled formation of sedimentary phosphorites around the PC–C transition (especially the intense reworking and redox conditions of the overlying seawater), and provide further insights into REE enrichment in sedimentary phosphorites worldwide.

Abstract Background People with hypertension have a higher risk of developing Parkinson’s disease (PD), epidemiological evidence suggests that multiple antihypertensives may affect the occurrence and development of PD with inconsistent results. With multisource data, we sought to determine whether specific antihypertensive classes elevated or reduced the risk for PD. Methods We used a mixed methods approach that combines 4 methodologies. First, we conducted a disproportionality analysis using the reports causing adverse events in the US Food and Drug Administration Adverse Events Reporting System (FAERS) to explore the effect of different classes of antihypertensive medications on the risk of PD; based on the findings from FAERS, a meta-analysis and a UK Biobank cohort analysis were used to further assess the association of drug use with PD; finally, we employed Mendelian randomization (MR) analysis to validate the causal relationship between the drug target and the occurrence of PD. Results In the disproportionality analysis using the FAERS (N = 187,266), nonselective beta-adrenoceptor blockers (NBBs) were demonstrated to have a significant association with PD (reporting odds ratio (ROR) = 3.13; 95% CI 2.33–4.22). In the meta-analysis of 12 studies with 12,183,809 participants, PD risk was elevated in NBBs (RR, 1.64; 95% CI, 1.19–2.09) when stratified by subtypes of BBs. Among the 105,763 participants included in the cohort analysis using data from the UK Biobank, individuals who used NBBs had a significantly increased risk of PD compared to nonusers (HR, 1.47; 95% CI 1.04–2.06). The MR analysis revealed a significant association between higher expression of the β2 adrenergic receptor (ADRB2) gene, a drug target blocked by NBBs, and a reduced risk of PD (OR, 0.85; 95% CI 0.73–0.99). Conclusions Our comprehensive study indicated that regular NBB use is associated with an increased risk of PD. In light of the detrimental effects of NBBs on PD, some people should choose alternative antihypertensive treatments.

Abstract Background Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma subtype which remains incurable despite multimodal approach including chemoimmunotherapy followed by stem cell transplant, targeted approaches such as the BTK inhibitor ibrutinib, and CD19 chimeric antigen receptor (CAR) T cells. CD74 is a nonpolymorphic type II integral membrane glycoprotein identified as an MHC class II chaperone and a receptor for macrophage migration inhibitory factor. Our group previously reported on CD74's abundant expression in MCL and its ability to increase via pharmacological inhibition of autophagosomal degradation. Milatuzumab, a fully humanized anti-CD74 monoclonal antibody, demonstrated significant activity in preclinical lymphoma models but failed to provide meaningful benefits in clinical trials mainly due to its short half-life. We hypothesized that targeting CD74 using a CAR-T cell would provide potent and durable anti-MCL activity. Methods We engineered a second generation anti-CD74 CAR with 4-1BB and CD3ζ signaling domains (74bbz). Through in silico and rational mutagenesis on the scFV domain, the 74bbz CAR was functionally optimized for superior antigen binding affinity, proliferative signaling, and cytotoxic activity against MCL cells in vitro and in vivo. Results Functionally optimized 74bbz CAR-T cells (clone 42105) induced significant killing of MCL cell lines, and primary MCL patient samples including one relapse after commercial CD19 CAR-T cell therapy with direct correlation between antigen density and cytotoxicity. It significantly prolonged the survival of an animal model established in NOD-SCIDγc−/− (NSG) mice engrafted with a human MCL cell line Mino subcutaneously compared to controls. Finally, while CD74 is also expressed on normal immune cell subsets, treatment with 74bbz CAR-T cells resulted in minimal cytotoxicity against these cells both in vitro and in vivo. Conclusions Targeting CD74 with 74bbz CAR-T cells represents a new cell therapy to provide a potent and durable and anti-MCL activity.

Impact events have played a crucial role in the formation and evolution of the Moon, as evidenced by the numerous of impact craters on its surface, indicating a long history spanning over 4 billion years characterized by numerous such occurrences. As the moon evolved, it is likely that the early impact craters formed by the bombardment event have subsequently been overlaid by later impacts. However, limited samples and research methods have hindered the discovery of evidence of impacts on the lunar surface. Therefore, this article gives an overview of the study of shock metamorphism in lunar minerals, some new progress in the past 2 decades is reviewed, and the implications of these new discoveries for the composition of the Moon’s crust, history of impact, and the Moon’s evolution are discussed. In addition, some of the issues and limitations that have arisen in the study of lunar shock metamorphism are also summarized. Given the difficulties in the studying of lunar high-pressure minerals and shock metamorphic microstructure using traditional optical microscope, we suggest that the latest nanomineralogical research methods, such as focused ion beam, electron backscatter diffraction, atom probe tomography, Raman spectroscopy, and 3-dimensional electron diffraction, are rational and essential to address the challenges associated with the research on lunar shock metamorphism.

Abstract Multiphase oxidation of methane sulfinic acid (MSIA) by ozone (O3) in deliquesced aerosol particles is an important but poorly constrained reaction in the marine boundary layer, hindering the accurate prediction of radiative forcing of natural aerosols. Large uncertainties arise from the unmeasured reaction rate constant for the aerosol multiphase reaction between O3 and methanesulfinate (MSI−), the dominant MSIA species in sea salt aerosols. Here, we directly measured kMSI−+O3 by performing flow cell experiments coupled with a Raman spectroscopy to investigate the kinetics of multiphase oxidation of MSI− by O3 in pH‐buffered deliquesced aerosol particles relevant to marine atmospheric conditions. kMSI−+O3 for aerosol particles was determined to be (2.2 ± 0.5) × 107 M−1 s−1, 10 times the value in dilute solutions. This higher rate constant would increase the yield of methane sulfonic acid from multiphase oxidation of MSIA and has important implications for accurate modeling of sulfur species.

Objectives To explore the association between non-high-density lipoprotein (non-HDL) and mortality risk, both short-term and long-term, in Chinese people.Design A prospective cohort study.Setting The National Basic Public Health Service (BPHS) in China.Participants Including 621 164 elderly individuals around Hunan Province who underwent healthcare management receiving check-ups in China BPHS from 2010 to 2020. Exclusion criteria: (1) missing information on gender; (2) missing records of lipid screening; (3) missing information on key covariates; and (4) missing records of comorbidities (cardiovascular disease, hypertension, diabetes, cancer.)Primary and secondary outcome measures The study’s primary endpoint was all-cause and cause-specific mortality, sourced from Hunan’s CDC(Center for Disease Control and Prevention)-operated National Mortality Surveillance System, tracking participants until 24 February 2021.Results 26 758 (4.3%) deaths were recorded, with a median follow-up of 0.83 years. Association between non-HDL and mortality was non-linear after multivariable adjustment, with the optimum concentration (OC) being 3.29 and 4.85 mmol/L. Compared with OC, the risk increased by 1.12-fold for non-HDL

Abstract Despite the fact that the response of tropical hydroclimate to North Atlantic cooling events during the Heinrich Stadial 1 (HS1) has been extensively studied in African, South American and Indonesia, the nature of such responses remains debated. Here we investigate the tropical hydroclimate pattern over the Indo-Asian-Australian monsoon region during the HS1 by integrating hydroclimatic records, and examining a δ18Oseawater record from Globigerinoides ruber (white) in the tropical Indian Ocean. Our findings indicate that tropical hydrological conditions were synchronously arid in both hemispheres during the early HS1 (~18.3-16.3 ka) in the Indo-Asian-Australian monsoon region, except for a narrow, wet hydrological belt in northern low latitudes, suggesting the existence of a contracted tropical precipitation belt at that time. This study reveals that the meltwater discharge and resulting changes in global temperatures and El Niño exerted a profound influence on the tropical hydroclimate in the Indo-Asian-Australian monsoon region during the early HS1.

Abstract Background The prevalence of type 2 diabetes mellitus (T2DM) currently was increased in some countries of the world like China. However, the epidemiological trends of T2DM attributable to non-high body mass index (BMI) remain unclear. Thus, we aimed to describe the burden of T2DM attributable to non-high BMI. Methods To estimate the burden of T2DM attributable to non-high BMI, data from the Global Burden of Disease Study 2019 were used to calculate the deaths and disability-adjusted life years (DALYs) by age, sex, year, and location. The estimated annual percentage change (EAPC) was applied in the analysis of temporal trends in T2DM from 1990 to 2019. Results Globally in 2019, the number of death cases and DALYs of T2DM attributable to non-high BMI accounted for 57.9% and 48.1% of T2DM-death from all risks, respectively. Asia accounted for 59.5% and 63.6% of the global non-high-BMI-related death cases and DALYs of T2DM in 2019, respectively. From 1990 to 2019, regions in the low-income experienced a rise in DALYs attributable to non-high BMI. As compared to other age groups, older participants had higher deaths and DALYs of T2DM attributable to non-high BMI. The death and DALY rates of T2DM due to non-high BMI were higher in males and people in regions with low socio-demographic index (SDI) countries. Conclusions The burden of T2DM attributable to non-high BMI is higher in the elderly and in people in regions with low- and middle-SDI, resulting in a substantial burden on human health and the social cost of healthcare.

Abstract One of the paradoxes of the Archean rock record is how evidence for oxidative continental weathering is plausible when the atmosphere lacked oxygen prior to the Great Oxidation Event ca. 2.5 billion years ago. We detected reactive oxygen species (ROS) production at various silicate-water interfaces in a simulated Archean atmosphere and calculated homolysis rates of silicon–oxygen bonds in these minerals. We find that ROS can be produced while silicates were eroded and transported by streams to depositional basins. The magnitude of ROS production increases from mafic- to felsic-silicates. During early continent formation, e.g., the Kaapvaal and Pilbara basins in the Paleoarchean, the emplacement of granitoids and their subsequent exposure to physical weathering might have annually provided at least 1.73 × 108 mol O2 before the biological O2 production. Importantly, this process could have oxidatively mobilized redox-sensitive elements to seawater, increasing the availability of bioessential nutrient elements for the Archean biosphere.

Abstract Background While epidemiological studies have found correlations between light at night (LAN) and health effects, none has so far investigated the impacts of LAN on population mortality yet. We aimed to estimate the relative risk for mortality from exposure to LAN in Mainland China. Methods This time-stratified case-crossover nationwide study used NPP-VIIRS to obtain daily LAN data of Mainland China between 2015 and 2019. The daily mortality data were obtained from the Disease Surveillance Point System in China. Conditional Poisson regression models were applied to examine the relative risk (RR) for mortality along daily LAN in each county, then meta-analysis was performed to combine the county-specific estimates at the national or regional level. Results A total of 579 counties with an average daily LAN of 4.39 (range: 1.02–35.46) were included in the main analysis. The overall RRs per 100 nW/cm2/sr increases in daily LAN were 1.08 (95%CI: 1.05–1.11) for all-cause mortality and 1.08 (95%CI: 1.05–1.11) for natural-cause mortality. A positive association between LAN and all natural cause-specific mortality was observed, of which the strongest effect was observed on mortality caused by neuron system disease (RR = 1.32, 95%CI: 1.14–1.52). The results were robust in both younger and old, as well as in males and females. The more pronounced effect of LAN was observed in median LAN-level regions. Combined with an exposure–response curve, our study suggests a non-linear association between LAN and mortality in China. Conclusions Our study shows LAN is associated with mortality in China, particularly for neuron system disease-related mortality. These findings have important implications for public health policy establishment to minimize the health consequences of light pollution.

The generation of reactive oxygen species (ROS) at the pyrite–water interface is an important discovery for both early Earth’s and present environments in the past two decades. In these revealed reactions, pyrite can oxidize water to ROS and reduce O2 and ROS to water. However, the two types of reactions are controversial. The underlying physical theory responsible for the reactions has yet to be elucidated. In this study, we established a surface structure-dependent model of oxidation and reduction potentials (ORP) for semiconductors. Surface atomic structure-dependent electronic structures were adopted to estimate the ORP of pyrite. We apply this model to gain insights into the generation of ROS at the pyrite–water interface. The results demonstrate that the surface structure of pyrite controls its ORP, and ROS production can only occur on certain pyrite facets. The {210} and {111} facets with certain defects (e.g., 210-2S′ and 111-3S, respectively) could oxidize either H2O or OH− to O2, and ROS form during the oxidation of pyrite surfaces by O2. This suggests that surface effects play a crucial role in governing the ORP of semiconducting minerals. Accurately calculating surface ORP could potentially be used to better understand redox reactions and develop more efficient catalysts.

To improve the efficiency of reversible solid oxide cell (rSOC) systems, an rSOC thermal management system architecture is proposed, achieving integrated and efficient operation of rSOC. A 20 kW level rSOC integrated thermal management system with fuel cell and electrolysis cell modes is established using ASPEN PLUS software. The system characteristics of different system operating parameters under fuel cell and electrolysis cell modes are studied. Exergy analysis and energy analysis are conducted on the system under different operating modes, The distribution of exergy flow, the exergy loss between the system and its components, and the influence of fuel utilization on the electrical efficiency and exergy efficiency of the rSOC integrated thermal management system are obtained. The results show that compared to traditional solid oxide electrolysis cell systems, the proposed rSOC integrated thermal management system can improve the electrolysis efficiency of the system to over 70 %. In addition, the exergy loss of the system and components mainly exists in heat exchanger 1 in the fuel cell mode, and mainly in the stack in the electrolysis cell mode. The system efficiency of both fuel cell and electrolysis cell modes increases with the increase in fuel utilization rate. Compared to electrolysis cell mode, the system's exergy loss in fuel cell mode is more sensitive to fuel utilization efficiency.

Richter’s Transformation is a treatment-resistant and fatal progression from Chronic Lymphocytic Leukemia (CLL) to an aggressive lymphoma. Here, the authors show that PRMT5 is upregulated months prior to and after transformation, PRMT5 overexpression in a CLL mouse model leads to increased risk of transformation, and that targeted PRMT5 inhibition prolongs survival and delays disease development.

The transition of gold nanoparticles to gold-bearing veinlets could occur by solid-state pipe-diffusion and elemental migration from the interior of pyrite grains to the surfaces, according to direct observations and density functional theory calculations

IntroductionThe occurrence of metastasis is a threat to patients with colon cancer (CC), and the liver is the most common metastasis organ. However, the role of the extrahepatic organs in patients with liver metastasis (LM) has not been distinctly demonstrated. Therefore, this research aimed to explore the prognostic value of extrahepatic metastases (EHMs).MethodsIn this retrospective study, a total of 13,662 colon patients with LM between 2010 and 2015 were selected from the Surveillance, Epidemiology, and End Results database (SEER). Fine and Gray’s analysis and K–M survival analysis were utilized to explore the impacts of the number of sites of EHMs and different sites of EHMs on prognosis. Finally, a prognostic nomogram model based on the number of sites of EHMs was constructed, and a string of validation methods was conducted, including concordance index (C-index), receiver operating characteristic curves (ROC), and decision curve analysis (DCA).ResultsPatients without EHMs had better prognoses in cancer-specific survival (CSS) and overall survival (OS) than patients with EHMs (p < 0.001). Varied EHM sites of patients had different characteristics of primary location site, grade, and histology. Cumulative incidence rates for CSS surpassed that for other causes in patients with 0, 1, 2, ≥ 3 EHMs, and the patients with more numbers of sites of EHMs revealed worse prognosis in CSS (p < 0.001). However, patients with different EHM sites had a minor difference in cumulative incidence rates for CSS (p = 0.106). Finally, a nomogram was constructed to predict the survival probability of patients with EHMs, which is based on the number of sites of EHMs and has been proven an excellent predictive ability.ConclusionThe number of sites of EHMs was a significant prognostic factor of CC patients with LM. However, the sites of EHMs showed limited impact on survival. Furthermore, a nomogram based on the number of sites of EHMs was constructed to predict the OS of patients with EHMs accurately.

Background. Transcatheter aortic valve replacement (TAVR) is known to increase the incidence of conduction disturbances compared to surgical aortic valve replacement; however, there are limited data on the impact and duration of these conduction disturbances on longer term outcomes. Objective. To determine the differential impact of persistent versus nonpersistent new-onset conduction disturbances on TAVR-related complications and outcomes. Methods. This is a single-center retrospective analysis of 927 consecutive patients with aortic stenosis who underwent TAVR at Yale New Haven Hospital from July 2012 to August 2019. Patients with new-onset conduction disturbances within 7 days following TAVR were selected for this study. Persistent and nonpersistent disturbances were, respectively, defined as persisting or not persisting on all patient ECGs for up to 1.5 years after TAVR or until death. Results. Within 7 days after TAVR, conduction disturbances occurred in 42.3% (392/927) of the patients. Conduction disturbances persisted in 150 (38%) patients and did not persist in 187 (48%) patients, and 55 (14%) patients were excluded for having mixed (both persistent and nonpersistent) disturbances. Compared with nonpersistent disturbances, patients with persistent disturbances were more likely to receive a PPM within 7 days after the TAVR procedure (46.0% versus 4.3%, p

Background: Hexokinase 3 (HK3) is one of the key enzymes involved in glucose phosphorylation (the first step in most glucose metabolic pathways). Many studies have demonstrated the vital role of dysregulation of HK3 in several tumors. However, there is a need for in-depth characterization of the role of HK3 in glioblastoma multiforme (GBM).Methods: All data were sourced from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA). Kaplan-Meier analysis and univariate regression were applied for survival analysis. Gene set enrichment analysis (GSEA) was used for enrichment analysis. Tumor Immune Single Cell Hub (TISCH) database was applied for single-cell analysis. Tumor Immune Dysfunction and Exclusion (TIDE) analysis was applied to evaluate the immune response.Results: HK3 expression was upregulated in GBM and correlated with poor prognosis. The high HK3 expression group was primarily enriched in adaptive immune response, chemokine signaling pathway, and cytokine-cytokine receptor interaction. The high HK3 expression group showed significantly greater enrichment of the majority of immune cells and immune-related pathways. HK3 showed significant correlation with most immune cells, especially macrophages (p < .001, R = .81). TISCH analysis showed that HK3 was predominantly expressed in macrophages in most cancers. HK3 showed significant correlation with most immune-related genes, such as PD-1 (p < .001, R = .41), PDL-1 (p < .001, R = .27), and CTLA-4 (p < .001, R = .29). TIDE analysis revealed that the low HK3 expression group has a lower TIDE score and may benefit from immunotherapy. Drug sensitivity analysis showed that patients with high HK3 expression frequently showed drug resistance.Conclusion: HK3 was associated with poor prognosis and may serve as a biomarker of macrophages in GBM. HK3 was also associated with immune response and drug resistance. Our findings may provide novel insights for GBM immunotherapy.

Hydrogen peroxide (H2O2) has been proposed as an electron donor for photosynthesis before water, however, the amount of H2O2 available on early Earth was thought to be limited. Here the authors propose a new abiotic pathway wherein abrasion of quartz surfaces would have provided enough H2O2.

Background Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy. However, most patients with cancer fail to respond clinically. One potential reason is the accumulation of immunosuppressive transforming growth factor β (TGFβ) in the tumor microenvironment (TME). TGFβ drives cancer immune evasion in part by inducing regulatory T cells (Tregs) and limiting CD8+ T cell function. Glycoprotein-A repetitions predominant (GARP) is a cell surface docking receptor for activating latent TGFβ1, TGFβ2 and TGFβ3, with its expression restricted predominantly to effector Tregs, cancer cells, and platelets.Methods We investigated the role of GARP in human patients with cancer by analyzing existing large databases. In addition, we generated and humanized an anti-GARP monoclonal antibody and evaluated its antitumor efficacy and underlying mechanisms of action in murine models of cancer.Results We demonstrate that GARP overexpression in human cancers correlates with a tolerogenic TME and poor clinical response to ICB, suggesting GARP blockade may improve cancer immunotherapy. We report on a unique anti-human GARP antibody (named PIIO-1) that specifically binds the ligand-interacting domain of all latent TGFβ isoforms. PIIO-1 lacks recognition of GARP-TGFβ complex on platelets. Using human LRRC32 (encoding GARP) knock-in mice, we find that PIIO-1 does not cause thrombocytopenia; is preferentially distributed in the TME; and exhibits therapeutic efficacy against GARP+ and GARP- cancers, alone or in combination with anti-PD-1 antibody. Mechanistically, PIIO-1 treatment reduces canonical TGFβ signaling in tumor-infiltrating immune cells, prevents T cell exhaustion, and enhances CD8+ T cell migration into the TME in a C-X-C motif chemokine receptor 3 (CXCR3)-dependent manner.Conclusion GARP contributes to multiple aspects of immune resistance in cancer. Anti-human GARP antibody PIIO-1 is an efficacious and safe strategy to block GARP-mediated LTGFβ activation, enhance CD8+ T cell trafficking and functionality in the tumor, and overcome primary resistance to anti-PD-1 ICB. PIIO-1 therefore warrants clinical development as a novel cancer immunotherapeutic.

Abstract Introduction The lungs are extremely vulnerable to ischemia/reperfusion (I/R), which is characterized by intense inflammation, oxidative stress, alveolar damage, and vascular permeability. Parecoxib sodium (Pare) has been shown to exert protective effects against multiple I/R‐induced tissue injuries. However, its role in I/R‐induced lung injury remains unknown. This study aimed to reveal the roles and mechanisms of Pare in pulmonary I/R injury. Methods Sixty‐six rats were randomly divided into three groups: The sham‐operated group, the pulmonary I/R group, and the Pare‐pretreated I/R group. Pare at 10 mg/kg or saline (vehicle control) were intraperitoneally administered to rats once per day for 5 consecutive days before ischemia. Serum and tissue samples were harvested following 2 h of reperfusion. The oxygenation index (OI) and alveolar‐arterial oxygen partial pressure difference (PA‐aO2) were analyzed. The levels or activities of malondialdehyde, superoxidase dismutase, catalase, glutathione peroxidase, intracellular reactive oxygen species, tumor necrosis factor‐α, interleukin (IL)‐6, and IL‐8 were examined. The mitochondrial membrane potential was measured. The protein expression levels of the extracellular signal‐regulated kinase (ERK), nuclear factor‐κB (NF‐κB) and their phosphorylated forms, and hypoxia‐inducible factor‐1α (HIF‐1α) were detected. Histological changes were observed using hematoxylin and eosin staining. Moreover, the survival rate following pulmonary I/R injury was recorded daily. Results Pare significantly increased the OI, decreased the PA‐aO2, increased the levels of antioxidants, while decreasing the levels of oxidants, and alleviated mitochondrial dysfunction and the histopathological damage induced by I/R. Furthermore, Pare inhibited the expression of proinflammatory cytokines, suppressed the activation of ERK and NF‐κB, further increased HIF‐1α expression, and significantly improved the rat survival rate. Conclusions Pare pretreatment attenuated lung I/R injury by inhibiting oxidative stress and the inflammatory response possibly via inhibiting the activation of the ERK/NF‐κB pathway and further activating the HIF‐1α pathway.

Smokers (SM) have increased lung immune cell counts and inflammatory gene expression compared to electronic cigarette (EC) users and never-smokers (NS). The objective of this study is to further assess associations for SM and EC lung microbiomes with immune cell subtypes and inflammatory gene expression in samples obtained by bronchoscopy and bronchoalveolar lavage (n = 28). RNASeq with the CIBERSORT computational algorithm were used to determine immune cell subtypes, along with inflammatory gene expression and microbiome metatranscriptomics. Macrophage subtypes revealed a two-fold increase in M0 (undifferentiated) macrophages for SM and EC users relative to NS, with a concordant decrease in M2 (anti-inflammatory) macrophages. There were 68, 19, and 1 significantly differentially expressed inflammatory genes (DEG) between SM/NS, SM/EC users, and EC users/NS, respectively. CSF-1 and GATA3 expression correlated positively and inversely with M0 and M2 macrophages, respectively. Correlation profiling for DEG showed distinct lung profiles for each participant group. There were three bacteria genera–DEG correlations and three bacteria genera–macrophage subtype correlations. In this pilot study, SM and EC use were associated with an increase in undifferentiated M0 macrophages, but SM differed from EC users and NS for inflammatory gene expression. The data support the hypothesis that SM and EC have toxic lung effects influencing inflammatory responses, but this may not be via changes in the microbiome.

Abstract Background The interaction between astrocytes and microglia plays a vital role in the damage and repair of brain lesions due to traumatic brain injury (TBI). Recent studies have shown that exosomes act as potent mediators involved in intercellular communication. Methods In the current study, the expression of inflammatory factors and miR-873a-5p in the lesion area and oedema area was evaluated in 15 patients with traumatic brain injury. Exosomes secreted by astrocytes were detected by immunofluorescence, Western blot and electron microscopy. A mouse model of TBI and an in vitro model of LPS-induced primary microglia were established to study the protective mechanism of exosomes from miR-873a-5p overexpressing in TBI-induced nerve injury. Results We discovered that exosomes derived from activated astrocytes promote microglial M2 phenotype transformation following TBI. More than 100 miRNAs were detected in these astrocyte-derived exosomes. miR-873a-5p is a major component that was highly expressed in human traumatic brain tissue. Moreover, miR-873a-5p significantly inhibited LPS-induced microglial M1 phenotype transformation and the subsequent inflammation through decreased phosphorylation of ERK and NF-κB p65. This effect also greatly improved the modified neurological severity score (mNSS) and attenuated brain injury in a strictly controlled cortical impact mouse model. Conclusions Taken together, our research indicates that miRNAs in the exosomes derived from activated astrocytes play a key role in the astrocyte-microglia interaction. miR-873a-5p, as one of the main components of these astrocyte-derived exosomes, attenuated microglia-mediated neuroinflammation and improved neurological deficits following TBI by inhibiting the NF-κB signalling pathway. These findings suggest a potential role for miR-873a-5p in treating traumatic brain injury.

Heterogeneous graph representation learning is to learn effective representations for nodes or (sub)graphs, which preserve node attributes and structural information. However, it is challenging to design a representation learning method for heterogeneous information networks (HINs) due to their diversity. Most of the existing HIN-oriented learning methods define a series of meta-paths. Then, they aggregate the representations learned from different meta-paths in the same hidden space. These methods do not consider semantic differences of different meta-paths, which leads to semantic confusion. And further affects the effectiveness of the learned representation. Given these issues, we introduce a Semantic Aware HIN Representation learning Network (SAHRN), which takes into account the semantics of different meta-paths. We mitigate the problem of semantic confusion by projecting nodes’ features into different hidden spaces separately according to different meta-paths. To further expand the scope of aggregation and enrich the aggregated information, we also design various variants of our model by adding layer aggregation. Extensive experiments on three standard HIN datasets show that SAHRN achieves consistent improvements compared to state-of-the-art graph representation learning methods. The experiments and analyses on each component of the model show the effectiveness of the proposed method. The source code is available on https://github.com/pingpingand/SAHRN.

Vaccinia virus (VV) is the most studied member of the poxvirus family, is responsible for the successful elimination of smallpox worldwide, and has been developed as a vaccine vehicle for infectious diseases and cancer immunotherapy. We have previously shown that the unique potency of VV in the activation of CD8+ T cell response is dependent on efficient activation of the innate immune system through Toll-like receptor (TLR)-dependent and -independent pathways. However, it remains incompletely defined what regulate CD8+ T cell response to VV infection. In this study, we showed that γδT cells play an important role in promoting CD8+ T cell response to VV infection. We found that γδT cells can directly present viral antigens in the context of MHC-I for CD8+ T cell activation to VV in vivo, and we further demonstrated that cell-intrinsic MyD88 signaling in γδT cells is required for activation of γδT cells and CD8+ T cells. These results illustrate a critical role for γδT cells in the regulation of adaptive T cell response to viral infection and may shed light on the design of more effective vaccine strategies based on manipulation of γδT cells.

Excessive exposure to manganese (Mn) can cause cognitive impairment, a common feature of Alzheimer's disease (AD), but the mechanisms remain unclear. Amyloid precursor protein (APP) is key to AD pathogenesis, and whether APP and its secretase processing are involved in Mn-induced cognitive impairment remains unknown. In the present study, we established a model of Mn-induced neurotoxicity in vivo (male C57BL/6, 0–100 mg/kg Mn, 90 days, gastric gavage) and in vitro (Neuro-2a (N2a) cells, 0–800 μM Mn for 24 h; APP overexpression and APP shRNA N2a cells, 0 and 800 μM Mn for 24 h). We found impaired cognition of Mn-treated mice. Both in vivo and in vitro results consistently showed that Mn exposure inhibited the expression of APP, α-secretase, soluble APP alpha protein (sAPPα), and synapse proteins as well as the activity of α-secretase. However, Mn exposure showed no effect on the protein levels of β-secretase, Aβ40, and Aβ42 or the activity of β-secretase. Collectively, these findings demonstrate key roles of APP and its α-secretase processing in the regulation of Mn-induced cognitive impairment, which may act as a target for ameliorating Mn-induced neurotoxicity.

In this paper, to study the development of load-carrying capacity and long-term creep performance of reinforced concrete beams under different corrosion patterns, the rate-dependent model of concrete is used as the basis to consider the creep development process from the meso-scale level. The porosity mechanics method is used to simulate the generation and penetration process of corrosion products. Three corrosion conditions are set: bottom longitudinal reinforcement corrosion, top longitudinal reinforcement corrosion and all reinforcement corrosion. The corrosion rate is used as the variable in each corrosion condition. The results show that: (1) the greater the corrosion rate in all conditions, the lower the bearing capacity. In addition, the corrosion of top longitudinal reinforcement causes the damage form of the beam to change to brittle damage; (2) the creep coefficient decreases with the increase in corrosion rate in all working conditions, but the main factor for this phenomenon is the obvious increase in initial deformation. Consequently, it is not suitable to follow the conventional creep concept (deformation development/initial deformation) for the development of plastic deformation of damaged members. It is more reasonable to use the global deflection to describe the long-term deformation of corrosion-damaged members.

Objective: To analyze the risk factors of transient neurological deficits (TND) and perioperative stroke in patients with MMD after extracranial–intracranial revascularization. Methods: A retrospective analysis of the clinical data of 183 patients with MMD undergoing 203 EC–IC bypass operation procedures from January 2018 to August 2020. According to whether TND and stroke occurred within 14 days after operation, univariate analysis and multivariate logistic regression were used. Results: TND occurred in 26 cases (12.8%) of revascularization. The results of the univariate analysis showed that history of diabetes, multiple episodes of preoperative symptoms, lesions involving the posterior circulation, and high postoperative blood pressure are the risk factors of TND. Further multivariate logistic regression analysis showed that multiple episodes of preoperative symptoms (p = 0.016) and lesions involving the posterior circulation (p = 0.014) are the independent risk factors for TND. Perioperative stroke occurred in 12 cases (5.9%). The results of the univariate analysis showed that older age, history of hypertension, preoperative cerebral infarction as the main symptom, lesions involving the posterior circulation, and high perioperative blood pressure are the risk factors of perioperative stroke. The results of multivariate logistic regression analysis showed that preoperative cerebral infarction as the main symptom (p = 0.015) is an independent risk factor for perioperative stroke. The occurrence of perioperative complications was not related to the improvement of follow-up mRS (Modified Rankin Scale) score and long-term cerebral rehemorrhage. Conclusions: Clinically, patients with MMD have multiple episodes of preoperative symptoms, lesions involving the posterior circulation, and preoperative cerebral infarction and should be attached when undergoing revascularization.

Non-line-of-sight (NLOS) target detection utilizing multipath plays an important role in anti-terrorism, urban warfare, indoor rescue and intelligent driving. In this paper, an imaging method based on single-channel ultra-wideband (UWB) radar and dual-view observation is proposed for detecting NLOS targets. First, the cause of producing ghosts from a single view in a previous study is analyzed in detail. On this basis, with focusing on dual-view observation, the ghost problem is handled at two levels. From the level of the radar echo, path partition is conducted with the utilization of dual-view observation, solving the problem of uneven energy among multipaths. After that, two images are generated by multipath imaging, respectively, which reduces the accumulation of ghosts. From the level of the image, owing to the distinct distribution of ghosts between the imaging result, the ghosts at different locations are eliminated by image fusion. Experimental results demonstrate that compared with single view and direct multipath imaging, the approach based on dual-view observation successfully eliminates most ghosts while retaining the targets in both single-target and double-targets scenarios, which verifies the effectiveness of the method.

Cancer immunotherapy has revolutionized the field of oncology in recent years. Harnessing the immune system to treat cancer has led to a large growth in the number of novel immunotherapeutic strategies, including immune checkpoint inhibition, chimeric antigen receptor T-cell therapy and cancer vaccination. In this review, we will discuss the current landscape of immuno-oncology research, with a focus on elements that influence immunotherapeutic outcomes. We will also highlight recent advances in basic aspects of tumor immunology, in particular, the role of the immunosuppressive cells within the tumor microenvironment in regulating antitumor immunity. Lastly, we will discuss how the understanding of basic tumor immunology can lead to the development of new immunotherapeutic strategies.

The spatial distribution patterns of central Yellow Sea Mud (CYSM) thicknesses and their temporal evolution during the Holocene are here updated using data from 10 new cores, in combination with the previously-published data for 64 cores from this area. Of these 74 cores, 15 exhibit clear AMS 14C dating constraints. Three subareas of mud deposition can be delineated using analyses of spatiotemporal mud thickness distributions and the variations between these. A depocenter subarea, with mud thicknesses >4 m, lies in the northwestern part of the CYSM; the mean sedimentation rate (SR) is relatively high in this subarea, with two high SR stages occurring at ∼6.1–5.4 ka and ∼4–2.5 ka. An adjacent subarea surrounds the depocenter subarea; this subarea has mud thicknesses between 2 and 4 m, and a high mid-Holocene SR which evinces a gradually decreasing trend after 5 ka. A distal periphery subarea lies in the eastern part of the CYSM, with mud thicknesses between 0.5 and −2 m, and a low mean SR that has been generally stable over the last 7 ka. Our results indicate that both sedimentary sources and hydrological dynamics played important roles in the formation of CYSM. The Yellow River may be the principal sedimentary source for CYSM, as mud thickness decreases gradually from northwest to southeast. Different mud subareas appear to be affected by different hydrological dynamics: in the depocenter subarea, oceanic current fronts seem to play an important role in mud deposition, while in the adjacent subarea and the distal periphery subarea, weak tidal currents appear to be the dominant depositional control. The generally decreasing trend in the SR of the adjacent subarea indicate that the East Asian winter monsoon (EAWM) potentially controlled changes in CYSM sedimentary sources after 7 ka.

Background Previous studies have investigated the association of ambient air pollution with blood pressure (BP) in children and adolescents, however, the results are not consistent. We conducted a systematic review and meta‐analysis to assess the relationship between short‐term and long‐term ambient air pollutant exposure with BP values among children and adolescents. Methods and Results We searched PubMed, Web of Science, and Embase before September 6, 2020. Two reviewers independently searched and selected studies, extracted data, and assessed study quality. The studies were divided into groups by composition of air pollutants (NO2, particulate matter (PM) with diameter ≤10 μm or ≤2.5 μm) and length of exposure. The beta regression coefficients (β) and their 95% CIs were calculated to evaluate the strength of the effect with each 10 μg/m3 increase in air pollutants. Out of 36 650 articles, 14 articles were included in this meta‐analysis. The meta‐analysis showed short‐term exposure to PM with diameter ≤10 μm (β=0.267; 95% CI, 0.033‒0.501) was significantly associated with elevated systolic BP values. In addition, long‐term exposure to PM with diameter ≤2.5 μm (β=1.809; 95% CI, 0.962‒2.655), PM with diameter ≤10 μm (β=0.526; 95% CI, 0.095‒0.958), and NO2 (β=0.754; 95% CI, 0.541‒0.968) were associated with systolic BP values and long‐term exposure to PM with diameter ≤2.5 μm (β=0.931; 95% CI, 0.157‒1.705), and PM with diameter ≤10 μm (β=0.378; 95% CI, 0.022‒0.735) was associated with diastolic BP. Conclusions Our study indicates that both short‐term and long‐term exposure to some ambient air pollutants may increase BP values among children and adolescents.

The programmed death-1 (PD-1) and the PD ligand 1 (PD-L1) interaction represents a key immune checkpoint within the tumor microenvironment (TME), and PD-1 blockade has led to exciting therapeutic advances in clinical oncology. Although IFN-γ–dependent PD-L1 induction on tumor cells was initially thought to mediate the suppression on effector cells, recent studies have shown that PD-L1 is also expressed at high level on tumor-associated macrophages (TAMs) in certain types of tumors. However, the precise role of PD-L1 expression on TAMs in suppressing antitumor immunity within the TME remains to be defined. Using a myeloid-specific Pdl1-knockout mouse model, here we showed definitive evidence that PD-L1 expression on TAMs is critical for suppression of intratumor CD8+ T cell function. We further demonstrated that tumor-derived Sonic hedgehog (Shh) drives PD-L1 expression in TAMs to suppress tumor-infiltrating CD8+ T cell function, leading to tumor progression. Mechanistically, Shh-dependent upregulation of PD-L1 in TAMs is mediated by signal transducer and activator of transcription 3, a cascade that has not been previously reported to our knowledge. Last, single-cell RNA sequencing analysis of human hepatocellular carcinoma revealed that PD-L1 is mainly expressed on M2 TAMs, supporting the clinical relevance of our findings. Collectively, our data revealed an essential role for Shh-dependent PD-L1 upregulation in TAMs in suppressing antitumor immunity within the TME, which could lead to the development of new immunotherapeutic strategies for treating cancer.

Chinese question entity discovery and linking (QEDL) may encounter short texts and small-scale annotated datasets, which may invalidate certain machine learning algorithms. In this paper, we propose a progressive joint framework for Chinese QEDL, which leverages the mutual dependency information of these two tasks to enhance the performance with each other. The framework uses the candidate entity generation (CEG) of entity linking to iteratively augment the overall process of entity discovery that consists of mention generation, filtering and merging modules. In mention generation module, to reduce the hand-crafted effort of the rule-based entity discovery, we develop a question representation method to generate domain-independent entity discovery rules, and use CEG to check the extracted mentions in priority order. This module can embed extracted mentions into other entity discovery methods as one feature or as extra mentions to alleviate insufficiencies of annotated datasets. The mentions filtering module leverages the joint features of extracted mentions and CEG's entities to build a voting model and filter out low-confidence mentions. Moreover, the mentions merging module merges different patterns' mention-entity pairs and check their corresponding candidate entities with CEG. During entity linking, we incorporate the joint features of questions, extracted mentions and CEG's entities into a ranking model for entity disambiguation. Finally, we conduct experiments on two real datasets and compare our approach with other state-of-the-art methods. The results illustrate that the proposed framework can reduce error accumulation and flexibly combine different entity discovery methods, which significantly improves the performance on small-scale datasets.

The development of immunotherapies for lymphoma has undergone a revolutionary evolution over the past decades. Since the advent of rituximab as the first successful immunotherapy for B-cell non-Hodgkin lymphoma over two decades ago, a plethora of new immunotherapeutic approaches to treat lymphoma has ensued. Four of the most exciting classes of immunotherapies include: chimeric antigen receptor T-cells, bispecific antibodies, immune checkpoint inhibitors, and vaccines. However, with addition of these novel therapies the appropriate timing of treatment, optimal patient population, duration of therapy, toxicity, and cost must be considered. In this review, we describe the most-promising immunotherapeutic approaches for the treatment of lymphoma in clinical development, specifically focusing on clinical trials performed to date and strategies for improvement.

Objective: Several heavy metals have been reported to be associated with metabolic syndrome(MetS) in general population, while effects of multiple metals exposure on MetS in residents living in heavy metal polluted regions have not been investigated. We aimed to assess the association of 23 metal levels and MetS among population living in China’s heavy metal polluted regions. Methods: From August 2016 to July 2017, a total of 2109 eligible participants were consecutively enrolled in our study in Hunan province, China. The levels of plasma and urine metals were measured by inductively coupled plasma mass spectrometer (ICP-MS). MetS was defined by the criteria of the International Diabetes Federation. Multivariable regression models were applied to analysis the potential relationship. Results: In the overall population, crude model showed positive relationship of plasma titanium (Ti) with MetS and negative association of urine vanadium, iron, and selenium with MetS. After adjusted for potential confounders, only plasma Ti was positive associated with MetS (adjusted OR for Q4 versus Q1: 1.46; 95% CI: 1.06–1.99), and this positive correlation was explained by abdominal obesity (OR = 1.84, 95% CI: 1.41–2.39) and high triglycerides (OR = 2.23, 95% CI: 1.68–2.96). Further linear regression analysis revealed significant association of plasma Ti levels with waist circumference (β = 0.0056, 95% CI: 0.0004–0.0109, P = 0.036) and triglycerides (β = 0.0012, 95% CI: 0.0006–0.0019, P

This study aimed to analyze the effect of the enhanced recovery after surgery (ERAS) protocol on the recovery of gastrointestinal function in patients with lumbar disc herniation after discectomy. A total of 179 patients with lumbar disc herniation were randomly divided into the ERAS and non-ERAS groups. The non-ERAS group received routine nursing, and the ERAS group received ERAS strategy. The two groups were compared for general recovery indicators such as postoperative hemoglobin and prealbumin, satisfaction, and length of hospital stay. Gastrointestinal function was also evaluated, such as postoperative feeding time, intestinal chirping recovery time, intestinal exhaust gas recovery time, and complications such as ileus, nausea, and vomiting. The satisfaction of patients in the ERAS group (86.15 ± 2.43) was significantly higher than that in the non-ERAS group (77.19 ± 3.32), and the difference was statistically significant (P

Summary: Due to the lack of effective early diagnostic measures and treatment methods, bladder cancer has become a malignant tumor that seriously threatens people's lives and health. Here, we reported that LINC00162, a super-enhancer long noncoding RNA, was highly expressed in bladder cancer cells and tissues. And LINC00162 was negatively correlated with neighboring PTTG1IP expression. Knocking down LINC00162 expression can inhibit the proliferative activity of bladder cancer cells and the growth of transplanted tumors in vivo, while knocking down the expression of PTTG1IP could restore the proliferative activity of bladder cancer cells. In addition, both LINC00162 and PTTG1IP were found to be able to bind to THRAP3, a transcription-related protein. And THRAP3 can regulate PTTG1IP expression. Finally, we demonstrated a mechanism that LINC00162 could regulate PTTG1IP expression through binding THRAP3. This study provided a potential target molecule for clinical treatment of bladder cancer.

Abstract Background Pixatimod (PG545) is a novel clinical-stage immunomodulatory agent capable of inhibiting the infiltration of tumor-associated macrophages (TAMs) yet also stimulate dendritic cells (DCs), leading to activation of natural killer (NK) cells. Preclinically, pixatimod inhibits heparanase (HPSE) which may be associated with its inhibitory effect on TAMs whereas its immunostimulatory activity on DCs is through the MyD88-dependent TLR9 pathway. Pixatimod recently completed a Phase Ia monotherapy trial in advanced cancer patients. Methods To characterize the safety of pixatimod administered by intravenous (IV) infusion, a one month toxicology study was conducted to support a Phase Ia monotherapy clinical trial. The relative exposure (AUC) of pixatimod across relevant species was determined and the influence of route of administration on the immunomodulatory activity was also evaluated. Finally, the potential utility of pixatimod in combination with PD-1 inhibition was also investigated using the syngeneic 4T1.2 breast cancer model. Results The nonclinical safety profile revealed that the main toxicities associated with pixatimod are elevated cholesterol, triglycerides, APTT, decreased platelets and other changes symptomatic of modulating the immune system such as pyrexia, changes in WBC subsets, inflammatory changes in liver, spleen and kidney. Though adverse events such as fever, elevated cholesterol and triglycerides were reported in the Phase Ia trial, none were considered dose limiting toxicities and the compound was well tolerated up to 100 mg via IV infusion. Exposure (AUC) up to 100 mg was considered proportional with some accumulation upon repeated dosing, a phenomenon also noted in the toxicology study. The immunomodulatory activity of pixatimod was independent of the route of administration and it enhanced the effectiveness of PD-1 inhibition in a poorly immunogenic tumor model. Conclusions Pixatimod modulates innate immune cells but also enhances T cell infiltration in combination with anti-PD-1 therapy. The safety and PK profile of the compound supports its ongoing development in a Phase Ib study for advanced cancer/pancreatic adenocarcinoma with the checkpoint inhibitor nivolumab (Opdivo®). Trial registration ClinicalTrials.gov Identifier: NCT02042781. First posted: 23 January, 2014 - Retrospectively registered.

Abstract Diesel exhaust particles (DEPs) are common airborne ultrafine particles (UFPs); however, few studies have examined their effects on the gastrointestinal tract. To investigate the interaction of gut microbiota and DEPs‐induced colonic injury, adult C57BL/6 mice are kept in whole‐body inhalation chambers and exposed to filtered room air (FRA) or DEPs (300 µg m−3) 1 h per day for 28 consecutive days. DEPs exposure results in colon epithelial injury with inflammatory cell infiltration and mucus depletion. Abundance of Lactobacillus in murine feces is transiently increased following 7‐day DEPs exposure and then decreased until the end of 28‐day exposure. A reduction of the colonic mucus layer thickness is observed in mice receiving gut microbiota from DEPs‐exposed mice. Mechanistically, RNA‐sequencing suggests disruption of the nitrogen metabolism pathway in DEPs‐exposed NCM460 cells. Upregulation of carbonic anhydrase 9 (CA9) expression levels is observed in epithelia following DEPs exposure both in vivo and in vitro. Oral administration of probiotics protects the mice against DEPS‐induced colon epithelial injury. The results strongly suggest the involvement of gut microbiota in response to DEPs exposure and subsequently epithelial injury in vivo. Supplementation with probiotic may be a potential way to protect against UFPs‐induced colon epithelial injury.

Text classification is a fundamental research direction, aims to assign tags to text units. Recently, graph neural networks (GNN) have exhibited some excellent properties in textual information processing. Furthermore, the pre-trained language model also realized promising effects in many tasks. However, many text processing methods cannot model a single text unit’s structure or ignore the semantic features. To solve these problems and comprehensively utilize the text’s structure information and semantic information, we propose a Bert-Enhanced text Graph Neural Network model (BEGNN). For each text, we construct a text graph separately according to the co-occurrence relationship of words and use GNN to extract text features. Moreover, we employ Bert to extract semantic features. The former part can take into account the structural information, and the latter can focus on modeling the semantic information. Finally, we interact and aggregate these two features of different granularity to get a more effective representation. Experiments on standard datasets demonstrate the effectiveness of BEGNN.

Tumor-associated macrophages (TAMs) represent the most abundant leukocyte population in most solid tumors and are greatly influenced by the tumor microenvironment. More importantly, these macrophages can promote tumor growth and metastasis through interactions with other cell populations within the tumor milieu and have been associated with poor outcomes in multiple tumors. In this review, we examine how the tumor microenvironment facilitates the polarization of TAMs. Additionally, we evaluate the mechanisms by which TAMs promote tumor angiogenesis, induce tumor invasion and metastasis, enhance chemotherapeutic resistance, and foster immune evasion. Lastly, we focus on therapeutic strategies that target TAMs in the treatments of cancer, including reducing monocyte recruitment, depleting or reprogramming TAMs, and targeting inhibitory molecules to increase TAM-mediated phagocytosis.

Conditional power based on classical Brownian motion (BM) has been widely used in sequential monitoring of clinical trials, including those with the covariate adaptive randomization design (CAR). Due to some uncontrollable factors, the sequential test statistics under CAR procedures may not satisfy the independent increment property of BM. We confirm the invalidation of BM when the error terms in the linear model with CAR design are not independent and identically distributed. To incorporate the possible correlation structure of the increment of the test statistic, we utilize the fractional Brownian motion (FBM). We conducted a comparative study of the conditional power under BM and FBM. It was found that the conditional power under FBM assumption was mostly higher than that under BM assumption when the Hurst exponent was greater than 0.5.

Food is a daily requirement for everyone, while production patterns are seasonal. Producing sufficient nutrients is becoming more difficult because water and soil resources are already stressed and are becoming increasingly strained by climate change. Improving food security requires expertise in various areas, including sophisticated climate models, genetics research, market and household behaviour modelling, political shock modelling, and comprehensive environmental research. Additionally, governments stockpile grains to enhance national food security. These reserves should engage in markets only according to clear and transparent regulations and within defined price ranges to facilitate market functioning. It increases the demand for better technology in public administration to boost the management and distribution capacity while concentrating on improved controls and transparent governance systems. Blockchain technology emerges as a promising technology to enhance visibility, transparency, and data integrity with an immutable distributed ledger to increase trust in the parties’ business transactions. This paper discusses blockchain technology and its potential role in strategic grain reserve management.

We compared the characteristics of cases of highly pathogenic avian influenza (HPAI) and low pathogenic avian influenza (LPAI) A(H7N9) virus infections in China. HPAI A(H7N9) case-patients were more likely to have had exposure to sick and dead poultry in rural areas and were hospitalized earlier than were LPAI A(H7N9) case-patients.

Chimeric antigen receptors (CAR) are fusion proteins engineered from antigen recognition, signaling, and costimulatory domains that can be used to reprogram T cells to specifically target tumor cells expressing specific antigens. Current CAR-T cell technology utilizes the patient’s own T cells to stably express CARs and has achieved exciting clinical success in the past few years. However, current CAR-T cell therapy still faces several challenges, including suboptimal persistence and potency, impaired trafficking to solid tumors, local immunosuppression within the tumor microenvironment and intrinsic toxicity associated with CAR-T cells. This review focuses on recent strategies to improve the clinical efficacy of CAR-T cell therapy and other exciting CAR approaches currently under investigation, including CAR natural killer (NK) and NKT cell therapies.