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Abstract Understanding the fluorescence resonance energy transfer (FRET) of metal nanoparticles at the atomic level has long been a challenge due to the lack of accurate systems with definite distance and orientation of molecules. Here we present the realization of achieving FRET between two atomically precise copper nanoclusters through cocrystallization-induced spatial confinement. In this study, we demonstrate the establishment of FRET in a cocrystallized Cu8(p-MBT)8(PPh3)4@Cu10(p-MBT)10(PPh3)4 system by exploiting the overlapping spectra between the excitation of the Cu10(p-MBT)10(PPh3)4 cluster and the emission of the Cu8(p-MBT)8(PPh3)4 cluster, combined with accurate control over the confined space between the two nanoclusters. Density functional theory is employed to provide deeper insights into the role of the distance and dipole orientations of molecules to illustrate the FRET procedure between two cluster molecules at the electronic structure level.

Due to the small size, variety, and high degree of mixing of herbaceous vegetation, remote sensing-based identification of grassland types primarily focuses on extracting major grassland categories, lacking detailed depiction. This limitation significantly hampers the development of effective evaluation and fine supervision for the rational utilization of grassland resources. To address this issue, this study concentrates on the representative grassland of Zhenglan Banner in Inner Mongolia as the study area. It integrates the strengths of Sentinel-1 and Sentinel-2 active-passive synergistic observations and introduces innovative object-oriented techniques for grassland type classification, thereby enhancing the accuracy and refinement of grassland classification. The results demonstrate the following: (1) To meet the supervision requirements of grassland resources, we propose a grassland type classification system based on remote sensing and the vegetation-habitat classification method, specifically applicable to natural grasslands in northern China. (2) By utilizing the high-spatial-resolution Normalized Difference Vegetation Index (NDVI) synthesized through the Spatial and Temporal Non-Local Filter-based Fusion Model (STNLFFM), we are able to capture the NDVI time profiles of grassland types, accurately extract vegetation phenological information within the year, and further enhance the temporal resolution. (3) The integration of multi-seasonal spectral, polarization, and phenological characteristics significantly improves the classification accuracy of grassland types. The overall accuracy reaches 82.61%, with a kappa coefficient of 0.79. Compared to using only multi-seasonal spectral features, the accuracy and kappa coefficient have improved by 15.94% and 0.19, respectively. Notably, the accuracy improvement of the gently sloping steppe is the highest, exceeding 38%. (4) Sandy grassland is the most widespread in the study area, and the growth season of grassland vegetation mainly occurs from May to September. The sandy meadow exhibits a longer growing season compared with typical grassland and meadow, and the distinct differences in phenological characteristics contribute to the accurate identification of various grassland types.

Background & Aims: Previous studies demonstrated oxytocin treatment effectiveness in reducing mortality and reversing liver fibrosis in mice. However, the underlying mechanism remains obscure, given the absence of oxytocin receptor expression in hepatic stellate cells, the primary liver fibrosis effector cells. Methods: A comprehensive map of cell populations in fibrotic liver was generated using single-cell sequencing. The map enabled our study of the target cells of oxytocin action in the liver in more dimensions. Furthermore, we elucidated the mechanism of the oxytocin signaling system in hepatic macrophages using oxytocin receptor-specific knockout mice and liver fibrosis animal models. Results: The carbon tetrachloride-induced hepatic fibrosis and bile duct ligation hepatic fibrosis mouse models demonstrated that oxytocin reversed hepatic fibrosis in mice. The mapped liver cell populations demonstrated that oxytocin promoted the phenotypic switch from Ly6high to Ly6Clow in myeloid-derived macrophages. The phenotypic control of oxytocin signaling system activation on this phenotypic switch was validated using myeloid-specific oxytocin receptor knockout mice. Subsequent studies demonstrated that the calcium inward flow induced by oxytocin receptor activation activated the key orphan nuclear receptor NR4A1, which controls macrophage phenotypic switching. Specifically, calcium ions activated CREB, a key target regulator of NR4A1 expression. Conclusions: The findings established hepatic macrophages as a hub responsible for the oxytocin-mediated alleviation of liver fibrosis. This study revealed a novel pathway where oxytocin regulates macrophage phenotype. Impact and implications: Previous studies revealed for the first time the expression of oxytocin receptors in the liver. The present study shows that oxytocin reverses hepatic fibrosis and that hepatic macrophages are the central hub of oxytocin-mediated alleviation of hepatic fibrosis by promoting a phenotypic switch in hepatic macrophages, transitioning from Ly6high to Ly6Clow expression. The present study reveals a novel pathway by which oxytocin regulates macrophage phenotype. In addition, the potential applications of oxytocin and its analogues, as traditional drugs for clinical application, in the treatment of liver fibrosis deserve to be further explored.

Abstract The bus passenger detection algorithm is a key component of a public transportation bus management system. The detection techniques based on the convolutional neural network have been widely used in bus passenger detection. However, they require high memory and computational requirements, which hinder the deployment of bus passenger detectors in the bus system. In this paper, a lightweight bus passenger detection model based on YOLOv5 is introduced. To make the model more lightweight, the inner and outer cross‐stage bottleneck modules, called ICB and OCB, respectively, are proposed. The proposed module reduces the quantity of parameter and floating point operations and increases the detection speed. In addition, the neighbour feature attention pooling is adopted to improve detection accuracy. The performance of the lightweight model on the bus passenger dataset is empirically demonstrated. The experiment results demonstrate that the proposed model is lightweight and efficient. Compared lightweight YOLOv5n with the original algorithm, the model weight is reduced by 31% to 2.6M, and the detection speed is increased by 6% to 40FPS without an accuracy drop.

Land productivity is one of the sub-indicators for measuring SDG 15.3.1. Land Productivity Dynamics (LPD) is the most popular approach for reporting this indicator at the global scale. A major limitation of existing products of LPD is the coarse spatial resolution caused by remote sensing data input, which cannot meet the requirement of fine-scale land degradation assessment. To resolve this problem, this study developed a tool (HiLPD-GEE) to calculate 30 m LPD by fusing Landsat and MODIS data based on Google Earth Engine (GEE). The tool generates high-quality fused Normalized Difference Vegetation Index (NDVI) dataset for LPD calculation through gap filling and Savitzky–Golay filtering (GF-SG) and then uses the method recommended by the European Commission Joint Research Centre (JRC) to calculate LPD. The tool can calculate 30 m LPD in any spatial range within any time window after 2013, supporting global land degradation monitoring. To demonstrate the applicability of this tool, the LPD product was produced for African Great Green Wall (GGW) countries. The analysis proves that the 30 m LPD product generated by HiLPD-GEE could reflect the land productivity change effectively and reflect more spatial details. The results also provide an important insight for the GGW initiative.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) can significantly extend tumor response in patients with metastatic luminal A breast cancer, yet intrinsic and acquired resistance remains a prevalent issue. Understanding the molecular features of CDK4/6 inhibitor sensitivity and the potential efficacy of their combination with novel targeted cell death inducers may lead to improved patient outcomes. Herein, we demonstrate that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, partly underpins the efficacy of CDK4/6 inhibitors. Mechanistically, CDK4/6 inhibitors downregulate the cystine transporter SLC7A11 by inhibiting SP1 binding to the SLC7A11 promoter region. Furthermore, SLC7A11 is identified as critical for the intrinsic sensitivity of luminal A breast cancer to CDK4/6 inhibitors. Both genetic and pharmacological inhibition of SP1 or SLC7A11 enhances cell sensitivity to CDK4/6 inhibitors and synergistically inhibits luminal A breast cancer growth when combined with CDK4/6 inhibitors in vitro and in vivo. Our data highlight the potential of targeting SLC7A11 in combination with CDK4/6 inhibitors, supporting further investigation of combination therapy in luminal A breast cancer.

Full-field optical angiography (FFOA)—a real-time non-invasive imaging technique for extracting biological blood microcirculation information—contributes to an in-depth understanding of the functional and pathological changes of biological tissues. However, owing to the limitation of the depth-of-field (DOF) of optical lenses, existing FFOA imaging methods cannot capture an image containing every blood-flow information. To address this problem, this study develops a long-DOF full-field optical angiography imaging system and proposes a novel multi-focus image fusion scheme to expand the DOF. First, FFOA images with different focal lengths are acquired by the absorption intensity fluctuation modulation effect. Second, an image fusion scheme based on gradient feature detection in a nonsubsampled contourlet transform domain is developed to capture focus features from FFOA images and synthesize an all-focused image. Specifically, FFOA images are decomposed by NSCT into coefficients and low-frequency difference images; thereafter, two gradient feature detection-based fusion rules are used to select the pre-fused coefficients. The experimental results of both phantom and animal cases show that the proposed fusion method can effectively extend the DOF and address practical FFOA image defocusing problems. The fused FFOA image can provide a more comprehensive description of blood information than a single FFOA image.

Lung cancer is a highly prevalent malignant tumor worldwide, with high incidence and death rates. Recently, there has been increasing recognition of the role of ferroptosis, a unique cell death mechanism, in lung cancer. This review aims to summarize the current research progress on the relationship between ferroptosis and lung cancer. It also provides a comprehensive analysis of the regulatory processes of ferroptosis in various stages, including epigenetics, transcription, post-transcription, translation, and post-translation. Additionally, the review explores the dual nature of ferroptosis in lung cancer progression, which presents interesting therapeutic possibilities. On one hand, ferroptosis can promote the escape of immune surveillance and reduce the efficacy of treatment in the early stages of tumors. On the other hand, it can counter drug resistance, enhance radiosensitivity, and promote immunotherapy. The article also discusses various combination treatment strategies based on the mechanism of ferroptosis. Overall, this review offers a holistic perspective on the role of ferroptosis in the onset, progression, and treatment of lung cancer. It aims to contribute to future research and clinical interventions in this field.

Abstract Previously, we identified an antibody combination A8G6 that showed promising efficacy in COVID-19 animal models and favorable safety profile in preclinical models as well as in a first-in-human trial. To evaluate the real-word efficacy of A8G6 neutralizing antibody nasal spray in post-exposure prophylaxis of COVID-19, an open-label, non-randomized, two-arm, blank-controlled, investigator-initiated trial was conducted in Chongqing, China (the register number: ChiCTR2200066416). High-risk healthy participants (18–65 years) within 72 h after close contact to COVID-19 patients were recruited and received a three-dose (1.4 mg/dose) A8G6 treatment daily or no treatment (blank control) for 7 consecutive days. SARS-CoV-2 infection occurred in 151/340 (44.4%) subjects in the blank control group and 12/173 (6.9%) subjects in the A8G6 treatment group. The prevention efficacy of the A8G6 treatment within 72 h exposure was calculated to be 84.4% (95% CI: 74.4–90.4%). Moreover, compared to the blank-control group, the time from the SARS-CoV-2 negative to the positive COVID-19 conversion was significantly longer in the AG86 treatment group (mean time: 3.4 days vs 2.6 days, p = 0.019). In the secondary end-point analysis, the A8G6 nasal treatment had no effects on the viral load at baseline SARS-CoV-2 RT-PCR positivity and the time of the negative COVID-19 conversion. Finally, except for 5 participants (3.1%) with general adverse effects, we did not observe any severe adverse effects related to the A8G6 treatment. In this study, the intranasal spray AG86 antibody cocktail showed potent efficacy for prevention of SARS-CoV-2 infection in close contacts of COVID-19 patients.

Accumulating evidence supports the association of somatic mutations with tumor occurrence and development. We aimed to identify somatic mutations with important implications in hepatocellular carcinoma (HCC) and explore their possible mechanisms. The gene mutation profiles of HCC patients were assessed, and the tumor mutation burden was calculated. Gene mutations closely associated with tumor mutation burden and patient overall survival were identified. In vivo and in vitro experiments were performed to verify the effects of putative genes on proliferation, invasion, drug resistance, and other malignant biological behaviors of tumor cells. Fourteen genes with a high mutation frequency were identified. The mutation status of 12 of these genes was closely related to the mutation burden. Among these 12 genes, LRP1B mutation was closely associated with patient prognosis. Nine genes were associated with immune cell infiltration. The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin. LRP1B could directly bind to NCSTN and affect its protein expression level, thereby regulating the PI3K/AKT pathway. Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.

Photodynamic therapy (PDT) has limited effects in treating metastatic breast cancer. Immune checkpoints can deplete the function of immune cells; however, the expression of immune checkpoints after PDT is unclear. This study investigates whether the limited efficacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the efficacy. A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives (HpD-PDT). The anti-tumor effect of HpD-PDT was observed, as well as CD4[Formula: see text]T, CD8[Formula: see text]T and calreticulin (CRT) by immunohistochemistry and immunofluorescence. Immune checkpoints on T cells were analyzed by flow cytometry after HpD-PDT. When combining PDT with immune checkpoint inhibitors, the antitumor effect and immune effect were assessed. For HpD-PDT at 100[Formula: see text]mW/cm2 and 40, 60 and 80[Formula: see text]J/cm2, primary tumors were suppressed and CD4[Formula: see text]T, CD8[Formula: see text]T and CRT were elevated; however, distant tumors couldn’t be inhibited and survival could not be prolonged. Immune checkpoints on T cells, especially PD1 and LAG-3 after HpD-PDT, were upregulated, which may explain the reason for the limited HpD-PDT effect. After PDT combined with anti-PD1 antibody, but not with anti-LAG-3 antibody, both the primary and distant tumors were significantly inhibited and the survival time was prolonged, additionally, CD4[Formula: see text]T, CD8[Formula: see text]T, IFN-[Formula: see text]CD4[Formula: see text]T and TNF-[Formula: see text]CD4[Formula: see text]T cells were significantly increased compared with HpD-PDT. HpD-PDT could not combat metastatic breast cancer. PD1 and LAG-3 were upregulated after HpD-PDT. Anti-PD1 antibody, but not anti-LAG-3 antibody, could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.

ObjectivesThis network meta-analysis assesses the outcomes of seven endoscopic approaches, offering valuable insights for researchers and practitioners in choosing the best method for thyroid cancer patients.MethodsA systematic literature search was conducted in the PubMed, Embase and Web of Science databases up to March 2023. The analysis included seven endoscopic approaches, with a focus on their respective outcomes through network meta-analysis.ResultsThis meta-analysis included 44 studies involving 8,672 patients. The axillo-bilateral breast approach (ABBA) and unilateral axillo-breast approach (UABA) showed advantages in terms of reduced operative time compared to other approaches (MD = 19.66 minutes, 95% CI = -31.66 to 70.98; MD = 30.32 minutes, 95% CI = -1.45 to 62.09, respectively). The UABA and anterior chest approach (ACA) exhibited superiority in controlling intraoperative bleeding (MD = -3.37 mL, 95% CI = -22.58 to 15.85; MD = -13.77 mL, 95% CI = -28.85 1.31, respectively). UABA and ACA also showed advantages in reducing hospital stays (MD = -0.39 days, 95% CI = -1.48 to 0.71; MD = -0.26 days, 95% CI = -1.33 to 0.81, respectively). The transoral approach (OA) yielded results comparable to those of conventional open thyroidectomy (COT) and outperformed other endoscopic surgeries with regards to lymph node retrieval and metastatic lymph node assessment. For the stimulated serum thyroglobulin (TG) levels, no significant difference was observed between bilateral axillo-breast approach (BABA) and OA compared to COT. However, chest-breast approach (CBA) showed significantly lower levels than COT (MD=-0.40 ng/ml, 95% CI =-0.72 to -0.09). Patients in the gasless unilateral transaxillary approach (GUA) group experienced a significant improvement in cosmetic satisfaction (MD=-2.08, 95% CI =-3.35 to -0.82). Importantly, no significant difference was observed in the incidence of surgical complications between endoscopic thyroidectomy and COT.ConclusionEndoscopic thyroid surgery is a safe and effective choice for thyroid cancer patients. Different approaches have their advantages, allowing personalized selection based on the patient’s needs. ABBA and UABA have shorter operative times, while UABA and ACA excel at controlling bleeding and shortening hospital stays. OA shows promise for lymph node assessment. These findings contribute to the growing evidence supporting endoscopic methods, expanding treatment options for thyroid cancer patients.

Abstract Background Although immunotherapy has been considered as a potent strategy for lung adenocarcinoma (LUAD), only a small part of patients was served as potentially clinical benefiters. Immunogenic cell death (ICD), a type of regulated cell death (RCD), which enable to reshape the tumor immune microenvironment and contribute to the immunotherapy efficiency. Developing a novel ICD-based signature may be a potential strategy to differentiate prognosis of patients with LUAD and predict efficacy of immunotherapy. Methods In this study, 34 ICD-related genes (ICDRGs) were identified and analyzed in LUAD samples from the Cancer Genome Atlas (TCGA). 572 patients with LUAD were divided into two distinct clusters according to ICDRGs expression levels. Patients were subsequently classified into two distinct gene subtypes based on differentially expressed genes (DEGs) analyzed between two ICD-related clusters. We further developed and validated a novel ICD-related score (ICDRS) followed by comprehensive investigation about the landscape of the prognosis, immune-based features, immunotherapautic responses and sensitivity of target drugs in patients with LUAD. Results After confirming transcriptomic aberrations and appraising prognostic value of ICDRGs, two ICD-associated subtypes were initially determined by consensus clustering in accordance with differentially expressional levels of ICDRGs. It was shown that patients in the ICD high-subtype possessed the superior clinical prognosis, abundant immune cell infiltration and higher involvement in immune-related signaling compared with the ICD low-subtype. A signature of ICD-related score (ICDRS) was further established and validated, which was served as an independent prognostic indicator for LUAD patients. These comprehensive results revealed that the high-score patients represented better clinical prognosis, higher immune infiltration-related characteristics, stronger expression of immune checkpoints, and better response to immune checkpoint inhibitor therapy and multiple targeted drugs. To further verify our analysis, we selected TLR4 as the representative of ICDRGs and evaluated its expression on the lung normal cells and cancer cells in vitro. Then, relative animal experiments were performed in vivo, with results of that the stimulation of TLR4 suppressed the growth of lung cancer. Conclusions In conclusion, our comprehensive analysis of ICDRGs in LUAD demonstrated their function in serving as a biomarker of predicting prognosis and clinical effects of immunotherapy and targeted drugs, which is meaningful to improve our understanding of ICDRGs and brought inspirations about evaluating prognosis and developing effective therapeutic strategies to patients with LUAD.

Abstract Background Sebaceous glands (SGs) synthesize and secret sebum to protect and moisturize the dermal system via the complicated endocrine modulation. Dysfunction of SG are usually implicated in a number of dermal and inflammatory diseases. However, the molecular mechanism behind the differentiation, development and proliferation of SGs is far away to fully understand. Methods Herein, the rat volar and mammary tissues with abundant SGs from female SD rats with (post-natal day (PND)-35) and without puberty onset (PND-25) were arrested, and conducted RNA sequencing. The protein complex of Neuropeptide Y receptor Y2 (NPY2R)/NPY5R/Nuclear factor of activated T cells 1 (NFATc1) was performed by immunoprecipitation, mass spectrum and gel filtration. Genome-wide occupancy of NFATc1 was measured by chromatin immunoprecipitation sequencing. Target proteins’ expression and localization was detected by western blot and immunofluorescence. Results NPY2R gene was significantly up-regulated in volar and mammary SGs of PND-25. A special protein complex of NPY2R/NPY5R/NFATc1 in PND-25. NFATc1 was dephosphorylated and activated, then localized into nucleus to exert as a transcription factor in volar SGs of PND-35. NFATc1 was especially binding at enhancer regions to facilitate the distal SG and sebum related genes’ transcription. Dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) contributed to NFATc1 phosphorylation in PND-25, and inactivated of DYRK1A resulted in NFATc1 dephosphorylation and nuclear localization in PND-35. Conclusions Our findings unmask the new role of NPY2R/NFATc1/DYRK1A in pubertal SG, and are of benefit to advanced understanding the molecular mechanism of SGs’ function after puberty, and provide some theoretical basis for the treatment of acne vulgaris from the perspective of hormone regulation. Graphical Abstract

Little is known about the difference in durability of HBsAg seroclearance induced by nucleoside analogs (NAs) or by interferon (IFN). A real-world, retrospective cohort study was conducted. Patients were assigned into two groups: NAs monotherapy-induced HBsAg seroclearance subjects and IFN monotherapy induced-HBsAg seroclearance subjects. A total of 198 subjects, comprised by 168 NAs monotherapy-induced and 30 IFN monotherapy-induced, who achieved HBsAg seroclearance were included in this study. The one-year probabilities of confirmed HBsAg seroclearance were significantly different in patients with NAs monotherapy and IFN monotherapy (0.960 (with 95% CI 0.922–0.999) vs. 0.691 (with 95% CI 0.523–0.913), log-rank-P = 4.04e-4). 73.3% (11 of 15) HBsAg recurrence occurred within one year after HBsAg seroclearance. The one-year probabilities of confirmed HBsAg seroclearance were higher in IFN monotherapy patients with anti-HBs than in IFN monotherapy patients without anti-HBs (0.839 (with 95% CI 0.657–1.000) vs. 0.489 (with 95% CI 0.251–0.953), log-rank test, P = 0.024). Our study thus provided novel insights into the durability of HBsAg seroclearance induced by NAs or IFN monotherapy. In particular, the HBsAg seroreversion rate was relatively high in IFN monotherapy subjects. The presence of anti-HBs was significantly correlated with a longer durability of functional cure induced by IFN treatment. And one-year follow-up in HBsAg seroclearance achieved individuals is proper for averting HBsAg seroreversion and other liver disease.

Abstract Background Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSCATV-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSCATV-EV. Methods MSCATV-EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSCATV-EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo. Results MSCATV-EV significantly reduced the amount of CD68+ total macrophages and increased CD206+ M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group (P

The Redamen rare metal deposit is located in the south western part of Keeryin pegmetite typed ore field in western Sichuan. It is a special deposit in the aspects of surrounding rock, element mineralization zoning and distance. The ore with different elevation (3540~3830 m) of the same vein and the same orebody is systematically collected, spodumene single mineral is selected to analyze the C-H-O isotope composition and features of inclusions in different minerals.The inclusions in minerals are mainly liquid-rich inclusions. The salinity of the inclusions in spodumene is 8%~20%, and the homogenization temperature is 180~330℃. The inclusions belong to the ore-forming fluid with medium-low salinity and medium-high temperature. The inclusions in quartz have salinity of 0%~8%, homogenization temperature of 150~240℃, and belong to low salinity and low temperature fluid. The results of C-H-O isotope test show that the δD/‰ of spotamene in the Redamen rare metal deposit ranges from -97.5 to -104.7 (average of -102.8). Compared with the Lijiagou deposit in the southeast of the ore field, the δD/‰ of spodumene is obviously smaller, with the δ18OH2O/‰ ranging from -0.34 to 2.88 (average of 1.032). However, it is basically consistent with the main metallogenic period of spodumene in Lijiagou deposit, indicating that the ore-forming fluid of late mineralization (that is, the main metallogenic period of spodumene) is mixed with meteoric water. The δ13CV-PDB/‰ of spodumene in the Redamen rare metal deposit ranges from -10 to -16.6, with an average of -12.7, indicating that the carbon source in the main mineralization period (spodumene formation period) has a mixed nature of magmatic system and meteoric precipitation system, which is related to the low temperature alteration of magmatic mantle source (granite, mantle multi-phase system) and may be mixed with CO2 generated by the decarboxylation of deposited organic materials. Through the study of mineral C-H-O isotopes and fluid inclusions, the source and evolution process of ore-forming fluids were further clarified.

Abstract Background Parasite diversity and population structure influence malaria control measures. Malaria transmission at international borders affects indigenous residents and migrants, defying management efforts and resulting in malaria re-introduction. Here we aimed to determine the extent and distribution of genetic variations in Plasmodium vivax populations and the complexity of infections along the China–Myanmar border. Methods We collected clinical P. vivax samples from local and migrant malaria patients from Laiza and Myitsone, Kachin State, Myanmar, respectively. We characterized the polymorphisms in two P. vivax merozoite surface protein markers, Pvmsp-3α and Pvmsp-3β, by PCR-restriction fragment length polymorphism (PCR–RFLP) analysis. We sought to determine whether these genetic markers could differentiate these two neighboring parasite populations. Results PCR revealed three major size variants for Pvmsp-3α and four for Pvmsp-3β among the 370 and 378 samples, respectively. PCR–RFLP resolved 26 fragment-size alleles by digesting Pvmsp-3α with Alu I and Hha I and 28 alleles by digesting Pvmsp-3β with Pst I. PCR–RFLP analysis of Pvmsp-3α found that infections in migrant laborers from Myitsone bore more alleles than did infections in residents of Laiza, while such difference was not evident from genotyping Pvmsp-3β. Infections originating from these two places contained distinct but overlapping subpopulations of P. vivax. Infections from Myitsone had a higher multiplicity of infection as judged by the size of the Pvmsp-3α amplicons and alleles after Alu I/Hha I digestion. Conclusions Migrant laborers from Myitsone and indigenous residents from Laiza harbored overlapping but genetically distinct P. vivax parasite populations. The results suggested a more diverse P. vivax population in Myitsone than in the border town of Laiza. PCR–RFLP of Pvmsp-3α offers a convenient method to determine the complexity of P. vivax infections and differentiate parasite populations.

IntroductionThis study aimed to systematically review research on cinacalcet and secondary hyperparathyroidism (SHPT) using machine learning-based statistical analyses.MethodsPublications indexed in the Web of Science Core Collection database on Cinacalcet and SHPT published between 2000 and 2022 were retrieved. The R package “Bibliometrix,” VOSviewer, CiteSpace, meta, and latent Dirichlet allocation (LDA) in Python were used to generate bibliometric and meta-analytical results.ResultsA total of 959 articles were included in our bibliometric analysis. In total, 3753 scholars from 54 countries contributed to this field of research. The United States, Japan, and China were found to be among the three most productive countries worldwide. Three Japanese institutions (Showa University, Tokai University, and Kobe University) published the most articles on Cinacalcet and SHPT. Fukagawa, M.; Chertow, G.M.; Goodman W.G. were the three authors who published the most articles in this field. Most articles were published in Nephrology Dialysis Transplantation, Kidney International, and Therapeutic Apheresis and Dialysis. Research on Cinacalcet and SHPT has mainly included three topics: 1) comparative effects of various treatments, 2) the safety and efficacy of cinacalcet, and 3) fibroblast growth factor-23 (FGF-23). Integrated treatments, cinacalcet use in pediatric chronic kidney disease, and new therapeutic targets are emerging research hotspots. Through a meta-analysis, we confirmed the effects of Cinacalcet on reducing serum PTH (SMD = -0.56, 95% CI = -0.76 to -0.37, p = 0.001) and calcium (SMD = -0.93, 95% CI = -1.21to -0.64, p = 0.001) and improving phosphate (SMD = 0.17, 95% CI = -0.33 to -0.01, p = 0.033) and calcium-phosphate product levels (SMD = -0.49, 95% CI = -0.71 to -0.28, p = 0.001); we found no difference in all-cause mortality (RR = 0.97, 95% CI = 0.90 to 1.05, p = 0.47), cardiovascular mortality (RR = 0.69, 95% CI = 0.36 to 1.31, p = 0.25), and parathyroidectomy (RR = 0.36, 95% CI = 0.09 to 1.35, p = 0.13) between the Cinacalcet and non-Cinacalcet users. Moreover, Cinacalcet was associated with an increased risk of nausea (RR = 2.29, 95% CI = 1.73 to 3.05, p = 0.001), hypocalcemia (RR = 4.05, 95% CI = 2.33 to 7.04, p = 0.001), and vomiting (RR = 1.90, 95% CI = 1.70 to 2.11, p = 0.001).DiscussionThe number of publications indexed to Cinacalcet and SHPT has increased rapidly over the past 22 years. Literature distribution, research topics, and emerging trends in publications on Cinacalcet and SHPT were analyzed using a machine learning-based bibliometric review. The findings of this meta-analysis provide valuable insights into the efficacy and safety of cinacalcet for the treatment of SHPT, which will be of interest to both clinical and researchers.

As an important clinically oriented information fusion technology, multimodal medical image fusion integrates useful information from different modal images into a comprehensive fused image. Nevertheless, existing methods routinely consider only energy information when fusing low-frequency or base layers, ignoring the fact that useful texture information may exist in pixels with lower energy values. Thus, erroneous textures may be introduced into the fusion results. To resolve this problem, we propose a novel multimodal brain image fusion algorithm based on error texture removal. A two-layer decomposition scheme is first implemented to generate the high- and low-frequency subbands. We propose a salient feature detection operator based on gradient difference and entropy. The proposed operator integrates the gradient difference and amount of information in the high-frequency subbands to effectively identify clearly detailed information. Subsequently, we detect the energy information of the low-frequency subband by utilizing the local phase feature of each pixel as the intensity measurement and using a random walk algorithm to detect the energy information. Finally, we propose a rolling guidance filtering iterative least-squares model to reconstruct the texture information in the low-frequency components. Through extensive experiments, we successfully demonstrate that the proposed algorithm outperforms some state-of-the-art methods. Our source code is publicly available at https://github.com/ixilai/ETEM.

The United Nations Sustainable Development Goals (SDGs) establish a fresh global framework for evaluating the development agenda, emphasizing prosperity, growth, inclusivity, and transparency while safeguarding our planet Earth. Land Degradation Neutrality (LDN) represents a clear target for assessing the achievement of SDG 15.3. In response to the shortcomings of the African Great Green Wall initiative with respect to LDN monitoring, reporting, and intervention, we developed an online tool, the Great Green Wall Big Data Facilitator (GGW-BDF), based on earth observation data (e.g. SDGSAT-1), cutting-edge big data analysis technologies, and Chinese experience in combating desertification, to support the implementation of the African Great Green Wall initiative. The GGW-BDF comprises an LDN data portal, desertification control knowledge, and e-learning resources. This study highlights the functionality of this tool to support stakeholders across countries in monitoring LDN while providing the successful technoloiges to restore degraded or barren land. The contributions of the GGW-BDF are very useful in supporting the Pan-African Agency of the Great Green Wall (PAGGW), and will hopefully be continuously upgraded for being a part of the federated toolbox of the Group on Earth Observation (GEO) LDN Flagship.

ABSTRACTIn the past decades, the environment has changed drastically in China with rapid economic development. Lack of data, especially data with spatiotemporal information, has however hindered evaluating progress of environmental indicators in the global Sustainable Development Goal (SDG) framework. Here, we evaluate and explore geospatial information of 20 environmental SDG indicators from six SDGs in China from 2010 to 2020 using big data. We show China has improved rapidly in most of the 20 indicators, except for indicator 13.2.2 (CO2 emission). 63.5% of China’s land mass showed improved states for the SDG indicators. By 2020, four of the indicators were found to have achieved their 2030 targets. It is predicted from the existing data that 10 of the 20 indicators can achieve their targets smoothly by 2030, but two indicators will lag behind. We quantitatively show China’s progress towards the environmental SDG indicators, and put forward timelines and suggestions for policy makers.

Abstract Background Bone marrow cells (BMCs), especially mesenchymal stem cells (MSCs), have shown attractive application prospects in acute myocardial infarction (AMI). However, the weak efficacy becomes their main limitation in clinical translation. Based on the anti-inflammation and anti-apoptosis effects of a Chinese medicine-Tongxinluo (TXL), we aimed to explore the effects of TXL-pretreated MSCs (MSCsTXL) in enhancing cardiac repair and further investigated the underlying mechanism. Methods MSCsTXL or MSCs and the derived exosomes (MSCsTXL-exo or MSCs-exo) were collected and injected into the infarct zone of rat hearts. In vivo, the anti-apoptotic and anti-inflammation effects, and cardiac functional and histological recovery were evaluated. In vitro, the apoptosis was evaluated by western blotting and flow cytometry. miRNA sequencing was utilized to identify the significant differentially expressed miRNAs between MSCsTXL-exo and MSCs-exo, and the miRNA mimics and inhibitors were applied to explore the specific mechanism. Results Compared to MSCs, MSCsTXL enhanced cardiac repair with reduced cardiomyocytes apoptosis and inflammation at the early stage of AMI and significantly improved left ventricular ejection fraction (LVEF) with reduced infarct size in an exosome-dependent way. Similarly, MSCsTXL-exo exerted superior therapeutic effects in anti-apoptosis and anti-inflammation, as well as improving LVEF and reducing infarct size compared to MSCs-exo. Further exosomal miRNA analysis demonstrated that miR-146a-5p was the candidate effector of the superior effects of MSCsTXL-exo. Besides, miR-146a-5p targeted and decreased IRAK1, which inhibited the nuclear translocation of NF-κB p65 thus protecting H9C2 cells from hypoxia injury. Conclusions This study suggested that MSCsTXL markedly facilitated cardiac repair via a new mechanism of the exosomal transfer of miR-146a-5p targeting IRAK1/NF-κB p65 pathway, which has great potential for clinical translation.

Resumo Fundamento A eficiência do manejo invasivo em pacientes mais velhos (≥75 anos) com infarto do miocárdio sem supradesnivelamento do segmento ST (IAMSSST) permanece ambígua. Objetivos Avaliar a eficiência do tratamento invasivo em pacientes idosos com IAMSSST com base em metanálise e análise sequencial de estudo (TSA). Métodos Ensaios clínicos randomizados relevantes (ECR) e estudos observacionais foram incluídos. Os resultados primários foram morte por todas as causas, infarto do miocárdio, acidente vascular cerebral e hemorragia grave. O odd ratio agrupado (OR) e o intervalo de confiança de 95% (IC) foram calculados. P

In this study, the spreading morphologies and deposition behaviors of molten droplet in a single detonation sprayed shot under different oxygen-fuel ratio conditions are characterized in detail to reveal the formation mechanism of Fe-based amorphous coatings. Additionally, the porosities, micro-hardness, amorphous phase content and wear behavior of the coatings were also carefully evaluated to correlate the relationship between preparation process parameters, particle deposition behavior, spreading morphology, and mechanical properties. The results indicate that the spraying oxygen-fuel ratio (OF) parameter can determine the microstructure change of the coating, which is considered to be a reflection of the molten state of the sprayed particles. The low OF reduces the combustion efficiency, making the coating particles deposited in a form similar to cold spraying, resulting in uneven coating structure. In the case of medium OF (2.00), amorphous particles can form completely melted droplets and spread well on the substrate, and produce a good metallurgical bond with the substrate. Thanks to the good spread of the amorphous droplets, the OF-2.00 coating displays a very uniform and dense structure and uniformly distributed microhardness, which also makes its wear resistance (0.63 × 10−6 mm3 N−1 m−1) increased by about 8 times compared with OF-1.43 coating.

Worldwide, the incidence rate of breast cancer is the highest in women. Approximately 2.3 million people were newly diagnosed and 0.685 million were dead of breast cancer in 2020, which continues to grow. Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with a higher risk of recurrence and metastasis, but disappointly, there are no effective and specific therapies clinically, especially for patients presenting with metastatic diseases. Therefore, it is urgent to develop a new type of cancer therapy for survival improvisation and adverse effects alleviation of breast cancers. Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed, photochemistry-based cancer therapy. It was drive by an antibody–photoabsorber conjugate (APC) which is triggered by near-infrared light. The key part of APC is a cancer-targeting monoclonal antibody (mAb) that can bind to receptors or antigens on the surface of tumor cells. Because of this targeted conjugate accumulation, subsequent deployment of focal NIR-light results in functional damage on the targeted cell membranes without harming the immediately adjacent receptor-negative cells and evokes a kind of photochemical, speedy, and highly specific immunogenic cell death (ICD) of cancer cells with corresponding antigens. Subsequently, immature dendritic cells adjacent to dying cancer cells will become mature, further inducing a host-oriented anti-cancer immune response, complicatedly and comprehensively. Currently, NIR-PIT has progressed into phase 3 clinical trial for recurrent head and neck cancer. And preclinical studies have illustrated strong therapeutic efficacy of NIR-PIT targeting various molecular receptors overexpressed in breast cancer cells, including EGFR, HER2, CD44c, CD206, ICAM-1 and FAP-α. Thereby, NIR-PIT is in early trials, but appears to be a promising breast cancer therapy and moving into the future. Here, we present the specific advantages and discuss the most recent preclinical studies against several transmembrane proteins of NIR-PIT in breast cancers.

IntroductionDespite the many benefits immunotherapy has brought to patients with different cancers, its clinical applications and improvements are still hindered by drug resistance. Fostering a reliable approach to identifying sufferers who are sensitive to certain immunotherapeutic agents is of great clinical relevance.MethodsWe propose an ELISE (Ensemble Learning for Immunotherapeutic Response Evaluation) pipeline to generate a robust and highly accurate approach to predicting individual responses to immunotherapies. ELISE employed iterative univariable logistic regression to select genetic features of patients, using Monte Carlo Tree Search (MCTS) to tune hyperparameters. In each trial, ELISE selected multiple models for integration based on add or concatenate stacking strategies, including deep neural network, automatic feature interaction learning via self-attentive neural networks, deep factorization machine, compressed interaction network, and linear neural network, then adopted the best trial to generate a final approach. SHapley Additive exPlanations (SHAP) algorithm was applied to interpret ELISE, which was then validated in an independent test set.ResultRegarding prediction of responses to atezolizumab within esophageal adenocarcinoma (EAC) patients, ELISE demonstrated a superior accuracy (Area Under Curve [AUC] = 100.00%). AC005786.3 (Mean [|SHAP value|] = 0.0097) was distinguished as the most valuable contributor to ELISE output, followed by SNORD3D (0.0092), RN7SKP72 (0.0081), EREG (0.0069), IGHV4-80 (0.0063), and MIR4526 (0.0063). Mechanistically, immunoglobulin complex, immunoglobulin production, adaptive immune response, antigen binding and others, were downregulated in ELISE-neg EAC subtypes and resulted in unfavorable responses. More encouragingly, ELISE could be extended to accurately estimate the responsiveness of various immunotherapeutic agents against other cancers, including PD1/PD-L1 suppressor against metastatic urothelial cancer (AUC = 88.86%), and MAGE−A3 immunotherapy against metastatic melanoma (AUC = 100.00%).DiscussionThis study presented deep insights into integrating ensemble deep learning with self-attention as a mechanism for predicting immunotherapy responses to human cancers, highlighting ELISE as a potential tool to generate reliable approaches to individualized treatment.

Abstract Background Bone marrow-derived mesenchymal stem cells (MSCs), which possess immunomodulatory characteristic, are promising candidates for the treatment of acute myocardial infarction (AMI). However, the low retention and survival rate of MSCs in the ischemic heart limit their therapeutic efficacy. Strategies either modifying MSCs or alleviating the inflammatory environment, which facilitates the recruitment and survival of the engrafted MSCs, may solve the problem. Thus, we aimed to explore the therapeutic efficacy of sequential transplantation of exosomes and combinatorial pretreated MSCs in the treatment of AMI. Methods Exosomes derived from MSCs were delivered to infarcted hearts through intramyocardial injection followed by the intravenous infusion of differentially pretreated MSCs on Day 3 post-AMI. Enzyme linked immunosorbent assay (ELISA) was performed to evaluate the inflammation level as well as the SDF-1 levels in the infarcted border zone of the heart. Echocardiography and histological analysis were performed to assess cardiac function, infarct size, collagen area and angiogenesis. Results Sequential transplantation of exosomes and the combinatorial pretreated MSCs significantly facilitated cardiac repair compared to AMI rats treated with exosomes alone. Notably, compared to the other three methods of cotransplantation, combinatorial pretreatment with hypoxia and Tongxinluo (TXL) markedly enhanced the CXCR4 level of MSCs and promoted recruitment, which resulted in better cardiac function, smaller infarct size and enhanced angiogenesis. We further demonstrated that exosomes effectively reduced apoptosis in MSCs in vitro. Conclusion Sequential delivery of exosomes and pretreated MSCs facilitated cardiac repair post-AMI, and combined pretreatment with hypoxia and TXL better enhanced the cardioprotective effects. This method provides new insight into the clinical translation of stem cell-based therapy for AMI.

Changes in land productivity have been endorsed by the Inter Agency Expert Group on Sustainable Development Goals (IAEG-SDGs) as key indicators for monitoring SDG 15.3.1. Multiple vegetation parameters from optical remote sensing techniques have been widely utilized across different land productivity decline processes and scales. However, there is no consensus on indicator selection and their effectiveness at representing land productivity declining at different scales. This study proposes a fusion framework that incorporates the trends and consistencies within the four commonly used remote sensing-based vegetation indicators. We analyzed the differences among the four vegetation parameters in different land cover and climate zones, finally producing a new global land productivity dynamics (LPD) product with confidence level degrees. The LPD classes indicated by the four vegetation indicators(VIs) showed that all three levels (low, medium, and high confidence) of increasing area account for 23.99% of the global vegetated area and declining area account for 7.00%. The Increase high-confidence(HC) area accounted for 2.77% of the total area, and the Decline-HC accounted for 0.35% of the total area. This study demonstrates the accuracy of the high-confidence (HC) area for the evaluation of land productivity decline and increase. The “forest” landcover type and “humid” climate zone had the largest increasing and declining area but had the lowest high-confidence proportion. The data product provides an important and optional reference for the assessment of SDG 15.3.1 at global and regional scales according to the specific application target. The “Global Land Productivity Dynamic dataset” is available in the Science Data Bank at http://www.doi.org/10.11922/sciencedb.j00076.00084.

Full-field optical angiography (FFOA) has considerable potential for clinical applications in the prevention and diagnosis of various diseases. However, owing to the limited depth of focus attainable using optical lenses, only information about blood flow in the plane within the depth of field can be acquired using existing FFOA imaging techniques, resulting in partially unclear images. To produce fully focused FFOA images, an FFOA image fusion method based on the nonsubsampled contourlet transform and contrast spatial frequency is proposed. Firstly, an imaging system is constructed, and the FFOA images are acquired by intensity-fluctuation modulation effect. Secondly, we decompose the source images into low-pass and bandpass images by performing nonsubsampled contourlet transform. A sparse representation-based rule is introduced to fuse the lowpass images to effectively retain the useful energy information. Meanwhile, a contrast spatial frequency rule is proposed to fuse bandpass images, which considers the neighborhood correlation and gradient relationships of pixels. Finally, the fully focused image is produced by reconstruction. The proposed method significantly expands the range of focus of optical angiography and can be effectively extended to public multi-focused datasets. Experimental results confirm that the proposed method outperformed some state-of-the-art methods in both qualitative and quantitative evaluations.

Infrared (IR) and visible image fusion is an important data fusion and image processing technique that can accurately and comprehensively integrate the thermal radiation and texture details of source images. However, existing methods neglect the high-contrast fusion problem, leading to suboptimal fusion performance when thermal radiation target information in IR images is replaced by high-contrast information in visible images. To address this limitation, we propose a contrast-balanced framework for IR and visible image fusion. Specifically, a novel contrast balance strategy is proposed to process visible images and reduce energy while allowing for detailed compensation of overexposed areas. Moreover, a contrast-preserving guided filter is proposed to decompose the image into energy-detail layers to reduce high contrast and filter information. To effectively extract the active information in the detail layer and the brightness information in the energy layer, we proposed a new weighted energy-of-Laplacian operator and a Gaussian distribution of the image entropy scheme to fuse the detail and energy layers, respectively. The fused result was obtained by adding the detail and energy layers. Extensive experimental results demonstrate that the proposed method can effectively reduce the high contrast and highlighted target information in an image while simultaneously preserving details. In addition, the proposed method exhibited superior performance compared to the state-of-the-art methods in both qualitative and quantitative assessments.

Drug resistance in Plasmodium falciparum compromises the effectiveness of antimalarial therapy. This study aimed to evaluate the extent of drug resistance in parasites obtained from international travelers returning from Ghana to guide the management of malaria cases. Eighty-two clinical parasite isolates were obtained from patients returning from Ghana in 2016–2018, of which 29 were adapted to continuous in vitro culture. Their geometric mean IC50 values to a panel of 11 antimalarial drugs, assessed using the standard SYBR Green-I drug sensitivity assay, were 2.1, 3.8, 1.0, 2.7, 17.2, 4.6, 8.3, 8.3, 19.6, 55.1, and 11,555 nM for artemether, artesunate, dihydroartemisinin, lumefantrine, mefloquine, piperaquine, naphthoquine, pyronaridine, chloroquine, quinine, and pyrimethamine, respectively. Except for chloroquine and pyrimethamine, the IC50 values for other tested drugs were below the resistance threshold. The mean ring-stage survival assay value was 0.8%, with four isolates exceeding 1%. The mean piperaquine survival assay value was 2.1%, all below 10%. Mutations associated with chloroquine resistance (pfcrt K76T and pfmdr1 N86Y) were scarce, consistent with the discontinuation of chloroquine a decade ago. Instead, the pfmdr1 86N-184F-1246D haplotype was predominant, suggesting selection by the extensive use of artemether-lumefantrine. No mutations in the pfk13 propeller domain were detected. The pfdhfr/pfdhps quadruple mutant IRNGK associated with resistance to sulfadoxine-pyrimethamine reached an 82% prevalence. In addition, five isolates had pfgch1 gene amplification but, intriguingly, increased susceptibilities to pyrimethamine. This study showed that parasites originating from Ghana were susceptible to artemisinins and the partner drugs of artemisinin-based combination therapies. Genotyping drug resistance genes identified the signature of selection by artemether-lumefantrine. Parasites showed substantial levels of resistance to the antifolate drugs. Continuous resistance surveillance is necessary to guide timely changes in drug policy.

Although numerous studies have explored the relationship between selenium intake and thyroid diseases, few epidemiological studies have investigated the association between selenium intake and thyroid hormones. Therefore, we conducted this analysis to investigate the association between dietary selenium intake and thyroid hormones. Our sample included 5,575 adults (age ≥ 20) years from the National Health and Nutrition Examination Survey (NHANES) 2007–2012. Thyroid hormones, including total triiodothyronine (T3), total thyroxine (T4), free T3 (FT3), free T4 (FT4), and thyroid-stimulating hormone (TSH), were detected. Multivariable linear regression models showed that log10-transformed selenium intake (LogSe) was negatively correlated with TT4 (β = −0.383, 95% CI: −0.695, −0.070) and TT4/TT3 (β = −0.003, 95% CI: −0.006, −0.0004) in U.S. adults. Besides, additional stratified analyses by sex demonstrated that LogSe was negatively associated with TT4 (β = −0.007, 95% CI: −0.013, −0.001) and TT4/TT3 (β = −0.664, 95% CI: −1.182, −0.146) and positively associated with FT4/TT4 (β = 0.031, 95% CI: 0.004, 0.059) in male adults. Meanwhile, subgroup analysis by iodine status showed that LogSe was negatively associated with TT4 (β = −0.006, 95% CI: −0.011, −0.002), FT4/FT3 (β = −0.011, 95% CI: −0.023, −0.00002) and TT4/TT3 (β = −0.456, 95% CI: −0.886, −0.026) in iodine sufficiency but not in iodine deficiency adults. Our results demonstrated that the increased dietary selenium intake was negatively correlated with TT4 and TT4/TT3 in U.S. adults. Furthermore, the association between dietary selenium intake and thyroid hormones was more pronounced in males and iodine sufficiency adults.

Cancer vaccines exhibit specificity, effectiveness, and safety as an alternative immunotherapeutic strategy to struggle against malignant diseases, especially with the rapid development of mRNA cancer vaccines in recent years. However, how to maintain long-term immune memory after vaccination, especially T cells memory, to fulfill lasting surveillance against cancers, is still a challenging issue for researchers all over the world. IL-7 is critical for the development, maintenance, and proliferation of T lymphocytes, highlighting its potential role as an adjuvant in the development of cancer vaccines. Here, we summarized the IL-7/IL-7 receptor signaling in the development of T lymphocytes, the biological function of IL-7 in the maintenance and survival of T lymphocytes, the performance of IL-7 in pre-clinical and clinical trials of cancer vaccines, and the rationale to apply IL-7 as an adjuvant in cancer vaccine-based therapeutic strategy.

BackgroundThe efficacy of immune checkpoint inhibitors (ICIs) in pretreated EGFR-mutated non-small cell lung cancer (NSCLC) patients is controversial. We conducted this multicenter retrospective study to examine the efficacy of ICIs in a real world setting.Patients and methodsWe collected 116 consecutive NSCLC patients with sensitive EGFR mutations who received ICIs alone or in combination after failure to respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and 99 patients were included for final analysis. The impacts of ICIs on the patients’ objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. The relationships between outcomes and clinical characteristics were analyzed.ResultsThe ORR in patients with target lesions was 31.25% (95% CI: 22.18-41.52), and the DCR in all patients was 65.66% (95% CI: 55.44-74.91). The overall median PFS was 5.0 months (95% CI: 3.0-6.6), and the median OS was 15.9 months (95% CI: 10.8-23.8). The outcomes were better in patients receiving combination therapy with ECOG scores of 0-1 and no more than 2 lines of prior therapy, with a median PFS of 7.4 months (95% CI: 3.0-13.3) and a median OS of 29.0 months (95% CI: 11.7-NE). Primary EGFR mutation type and treatment mode were found to have a notable impact on clinical outcomes. Both median PFS and OS in patients with EGFR L858R mutation were significantly shorter than those in patients with EGFR exon 19 deletion (19del) (PFS: 2.5 versus 6.7 months, HR: 1.80, log-rank P=0.011; OS: 9.8 versus 26.9 months, HR: 2.48, log-rank P=0.002). Patients receiving combination therapy had notably longer median PFS and OS than those receiving monotherapy (PFS: 5.2 versus 3.0 months, HR: 0.54, log-rank P=0.020; OS: 19.0 versus 7.4 months, HR: 0.46, log-rank P=0.009).ConclusionsOur study suggests that ICI-based combination therapy is a potential strategy for EGFR-mutated NSCLC patients after EGFR-TKI failure. The efficacy may differ according to EGFR subtypes.

Abstract The emergence and dissemination of colistin resistance in Enterobacteriaceae mediated by plasmid-borne mcr genes in recent years now pose a threat to public health. In this study, we isolated and characterized colistin-resistant and/or mcr-positive E. coli from pig farms in Central China. Between 2018 and 2019, 594 samples were collected and recovered 445 E. coli isolates. Among them, 33 with colistin resistance phenotypes and 37 that were positive for mcr genes were identified, including 34 positive for mcr-1, one positive for mcr-3, and two positive for both mcr-1 and mcr-3. An insertion of nine bases (“CTGGATACG”) into mcr-1 in four mcr-positive isolates led to gene dysfunction, and therefore did not confer the colistin resistance phenotype. Antimicrobial susceptibility testing revealed that 37 mcr-positive isolates showed severe drug resistance profiles, as 50% of them were resistant to 20 types of antibiotics. Multilocus sequence typing revealed a heterogeneous group of sequence types in mcr-positive isolates, among which ST10 (5/37), ST156 (5/37), and ST617 (4/37) were the predominant types. Plasmid conjugation assays showed that mcr-carrying plasmids of 25 mcr-positive isolates were conjugated with E. coli recipient, with conjugation frequencies ranging from 1.7 × 10-6 to 4.1 × 10-3 per recipient. Conjugation of these mcr genes conferred a colistin resistance phenotype upon the recipient bacterium. PCR typing of plasmids harbored in the 25 transconjugants determined six types of plasmid replicons, including IncX4 (14/25), FrepB (4/25), IncI2 (3/25), IncHI2 (2/25), FIB (1/25), and IncI1 (1/25). This study contributes to the current understanding of antibiotic resistance and molecular characteristics of colistin-resistant E. coli in pig farms.

Gout, the most prevalent inflammatory arthritis, is becoming increasingly prevalent in the United States and across the world, and it adversely impacts people’s quality of life and their health. Few studies have focused on the relationship between daily dietary quality and gout, so the topic requires further exploration. Data were derived from the National Health and Nutrition Examination Survey 2007–2016, and the inclusion criteria of the analytic sample were (1) adults, age ≥20 years, with complete information about HEI-2015, gout, and uric acid; (2) complete information of demographics, lifestyle (BMI, smoking, drinking), and disease history [hypertension, chronic kidney disease (CKD), diabetes]. The quality of the daily diet was reflected using the Healthy Eating Index 2015 (HEI-2015). The baseline features of different groups were examined using the Scott-Rao chi-square tests, and the association between the HEI-2015 score and the risk of gout/hyperuricemia (HUA) was investigated using weighted logistic regression models. The effects of different dietary components in the HEI-2015 on reducing the risk of gout/HUA were evaluated by weighted quantile sum (WQS) regression models. After adjusting for demographic characteristics, behavioral covariates, and disease history, higher HEI-2015 scores were associated with a significantly lower risk of gout (OR: 0.878, 95% CI: 0.876–0.880) and HUA (OR: 0.978, 95% CI: 0.976–0.979) in weighted logistic regression. Dairy, whole grains, plant proteins, and added sugar contributed greatly in HEI-2015 to reducing gout risk (weights of WQS index: 42, 17.18, 16.13, and 7.93%, respectively). Dairy, total fruits, greens and beans, and plant proteins contributed greatly in HEI-2015 to reducing HUA risk (weights of WQS index: 28.9, 17.13, 16.84, and 11.39%, respectively). As the result, adherence to the American Dietary Guidelines may assist to decrease the risk of gout/HUA in American adults, and greater emphasis should be placed on dairy products, whole grains, fruits, legumes, and added sugars.

Abstract Background Glucuronic acid metabolism participates in cellular detoxification, extracellular matrix remodeling and cell adhesion and migration. Here, we aimed to explore the crosstalk between dysregulated glucuronic acid metabolism and crucial metastatic signalling in glutathione S‐transferase zeta 1 (GSTZ1)‐deficient hepatocellular carcinoma (HCC). Methods Transwell, HCC xenograft and Gstz1−/‐ mouse models were used to examine the role of GSTZ1 in HCC metastasis. Non‐targeted and targeted metabolomics and global transcriptomic analyses were performed to screen significantly altered metabolic and signalling pathways in GSTZ1 overexpressing hepatoma cells. Further, RNA‐binding protein immunoprecipitation, Biotin‐RNA pull‐down, mRNA decay assays and luciferase reporter assays were used to explore the interaction between RNA and RNA‐binding proteins. Results GSTZ1 was universally silenced in both human and murine HCC cells, and its deficiency contributed to HCC metastasis in vitro and in vivo. UDP‐glucose 6‐dehydrogenase (UGDH)‐mediated UDP‐glucuronic acid (UDP‐GlcUA) accumulation promoted hepatoma cell migration upon GSTZ1 loss. UDP‐GlcUA stabilized TGFβR1 mRNA by enhancing its binding to polypyrimidine tract binding protein 3, contributing to the activation of TGFβ/Smad signalling. UGDH or TGFβR1 blockade impaired HCC metastasis. In addition, UGDH up‐regulation and UDP‐GlcUA accumulation correlated with increased metastatic potential and decreased patient survival in GSTZ1‐deficient HCC. Conclusions GSTZ1 deficiency and subsequent up‐regulation of the glucuronic acid metabolic pathway promotes HCC metastasis by increasing the stability of TGFβR1 mRNA and activating TGFβ/Smad signalling. UGDH and a key metabolite, UDP‐GlcUA, may serve as prognostic markers. Targeting UGDH might be a promising strategy for HCC therapy.

Photodynamic therapy (PDT) not only destroys tumor cells directly but also induced anti-tumor immune response through damage-associated molecular patterns (DAMPs). It is reported that anti-tumor response was associated with light dose and photosensitizer used in PDT. In this study, 4T1 tumor cells were implanted on both the right and left flanks of mice. Only the right tumor was treated by HpD-PDT, while the left tumor was not irradiated. The anti-tumor immune response induced by HpD-PDT was investigated. The expression of DAMPs and co-stimulatory molecules induced by HpD-PDT were tested by immunofluorescence and flow cytometry in vivo. Different light doses of PDT were designed to treat 4T1 cells. The killing effect was assessed by CCK-8 kit and apoptosis kit. The expression of DAMPs on 4T1 cells after HpD-PDT were evaluated by flow cytometry, western blot and ATP kit. This study showed that CD4[Formula: see text]T, CD8[Formula: see text]T and the production of IFN-[Formula: see text] were increased significantly on day 10 in right-tumor after PDT treatment compared with control group. HpD-PDT enhanced the expression of calreticulin (CRT) on tumor tissue. Importantly, co-stimulatory molecular OX-40 and 4-1BB were elevated on CD8[Formula: see text]T cells. In vitro, immunogenic death of 4T1 cells was induced after PDT. Besides, the expression of DAMPs increased with the increasing of energy density. This study indicates that anti-tumor immune effect was induced by HpD-PDT. The knowledge of the involvement of CRT, ATP and co-stimulatory molecules uncovers important mechanistic insight into the anti-tumor immunogenicity. It was the first time that co-stimulatory molecules were investigated and found to elevate after PDT.

A multi-sensor medical-image fusion technique, which integrates useful information from different single-modal images of the same tissue and provides a fused image that is more comprehensive and objective than a single-source image, is becoming an increasingly important technique in clinical diagnosis and treatment planning. The salient information in medical images often visually describes the tissue. To effectively embed salient information in the fused image, a multi-sensor medical image fusion method is proposed based on an embedding bilateral filter in least squares and salient detection via a deformed smoothness constraint. First, source images are decomposed into base and detail layers using a bilateral filter in least squares. Then, the detail layers are treated as superpositions of salient regions and background information; a fusion rule for this layer based on the deformed smoothness constraint and guided filtering was designed to successfully conserve the salient structure and detail information of the source images. A base-layer fusion rule based on modified Laplace energy and local energy is proposed to preserve the energy information of these source images. The experimental results demonstrate that the proposed method outperformed nine state-of-the-art methods in both subjective and objective quality assessments on the Harvard Medical School dataset.

Abstract Background Loop-mediated isothermal amplification (LAMP) has been widely used to diagnose various infectious diseases. Malaria is a globally distributed infectious disease attributed to parasites in the genus Plasmodium. It is known that persons infected with Plasmodium vivax and P. ovale are prone to clinical relapse of symptomatic blood-stage infections. LAMP has not previously been specifically evaluated for its diagnostic performance in detecting P. ovale in an epidemiological study, and no commercial LAMP or rapid diagnostic test (RDT) kits are available for specifically diagnosing infections with P. ovale. Methods An assay was designed to target a portion of mitochondrial DNA (mtDNA) among Plasmodium spp., the five human Plasmodium species and two other assays were designed to target the nuclear 18S ribosomal DNA gene (18S rDNA) of either P. vivax or P. ovale for differentiating the two species. The sensitivity of the assays was compared to that of nested PCR using defined concentrations of plasmids containing the target sequences and using limiting dilutions prepared from clinical isolates derived from Chinese workers who had become infected in Africa or near the Chinese border with Myanmar. Results The results showed that 102 copies of the mitochondrial target or 102 and 103 copies of 18S rDNA could be detected from Plasmodium spp., P. vivax and P. ovale, respectively. In 279 clinical samples, the malaria Pan mtDNA LAMP test performed well when compared with a nested PCR assay (95% confidence interval [CI] sensitivity 98.48–100%; specificity 90.75–100%). When diagnosing clinical cases of infection with P. vivax, the 18S rDNA assay demonstrated an even great sensitivity (95.85–100%) and specificity (98.1–100%). The same was true for clinical infections with P. ovale (sensitivity 90.76–99.96%; specificity 98.34–100%). Using plasmid-positive controls, the limits of detection of Malaria Pan, 18S rDNA P. vivax and 18S rDNA P. ovale LAMP were 100-, 100- and tenfold lower than those of PCR, respectively. Conclusion The novel LAMP assays can greatly aid the rapid, reliable and highly sensitive diagnosis of infections of Plasmodium spp. transmitted among people, including P. vivax and P. ovale, cases of which are most prone to clinical relapse. Graphic abstract

Thousands of long non-coding RNAs (lncRNAs) have been discovered in human genomes by gene chip, next-generation sequencing, and/or other methods in recent years, which represent a significant subset of the universal genes involved in a wide range of biological functions. An abnormal expression of lncRNAs is associated with the growth, invasion, and metastasis of various types of human cancers, including hepatocellular carcinoma (HCC), which is an aggressive, highly malignant, and invasive tumor, and a poor prognosis in China. With a more in-depth understanding of lncRNA research for HCC and the emergence of new molecular-targeted therapies, the diagnosis, treatment, and prognosis of HCC will be considerably improved. Therefore, this review is expected to provide recommendations and directions for future lncRNA research for HCC.