Electrocatalytic Reduction of CO2 to CO by Molecular Cobalt-Polypyridine Diamine Complexes.

Cobalt complexes have previously been reported to exhibit high faradaic efficiency in reducing CO2 to CO. Herein, we synthesized capsule-like cobalt-polypyridine diamine complexes [Co(L1)](BF4)2 (1) and [Co(L2) (CH3CN)](BF4)2 (2) as catalysts for the electrocatalytic reduction of CO2. Under catalytic conditions, complexes 1 and 2 demonstrated the electrocatalytic reduction of CO2 to CO in the presence or absence of CH3OH as a proton source. Experimental and computational studies revealed that complexes 1 and 2 undergo two consecutive reversible one-electron reductions on the cobalt core, followed by the addition of CO2 to form a metallocarboxylate intermediate [CoII(L)-CO22-]0. This crucial reaction intermediate, which governs the catalytic cycle, was successfully detected using high resolution mass spectrometry (HRMS). In situ Fourier-transform infrared spectrometer (FTIR) analysis showed that methanol can enhance the rate of carbon-oxygen bond cleavage of the metallocarboxylate intermediate. DFT studies on [CoII(L)-CO22-]0 have suggested that the doubly reduced species attacks CO2 on the C atom through the dz2 orbital, while the interaction with CO2 is further stabilized by the π interaction between the metal dxz or dxz orbital with p orbitals on the O atoms. Further reductions generate a metal carbonyl intermediate [CoI(L)-CO]+, which ultimately releases CO.

Assessing the role of tumour-associated macrophage subsets in breast cancer subtypes using digital image analysis.

PURPOSE: The number of M1-like and M2-like tumour-associated macrophages (TAMs) and their ratio can play a role in breast cancer development and progression. Early clinical trials using macrophage targeting compounds are currently ongoing. However, the most optimal detection method of M1-like and M2-like macrophage subsets and their clinical relevance in breast cancer is still unclear. We aimed to optimize the assessment of TAM subsets in different breast cancer subtypes, and therefore related TAM subset numbers and ratio to clinicopathological characteristics and clinical outcome. METHODS: Tissue microarrays of 347 consecutive primary Luminal-A, Luminal-B, HER2-positive and triple-negative tumours of patients with early-stage breast cancer were serially sectioned and immunohistochemically stained for the pan-macrophage marker CD68 and the M2-like macrophage markers CD163, CSF-1R and CD206. TAM numbers were quantified using a digital image analysis algorithm. M1-like macrophage numbers were calculated by subtracting M2-like TAM numbers from the total TAM number. RESULTS: M2-like markers CD163 and CSF-1R showed a moderate positive association with each other and with CD68 (r ≥ 0.47), but only weakly with CD206 (r ≤ 0.06). CD68 + , CD163 + and CSF-1R + macrophages correlated with tumour grade in Luminal-B tumours (P < 0.001). Total or subset TAM numbers did not correlate with disease outcome in any breast cancer subtype. CONCLUSION: In conclusion, macrophages and their subsets can be detected by means of a panel of TAM markers and are related to unfavourable clinicopathological characteristics in Luminal-B breast cancer. However, their impact on outcome remains unclear. Preferably, this should be determined in prospective series.

High hepatocyte growth factor expression in primary tumor predicts better overall survival in male breast cancer.

BACKGROUND: Breast cancer is rare in men, but management is focused on tumor characteristics commonly found in female breast cancer. The tumor microenvironment of male breast cancer is less well understood, and insight may improve male breast cancer management. The hepatocyte growth factor (HGF)/c-MET axis and the stromal cell-derived factor-1 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis are prognostic in women with breast cancer. We aimed to investigate these factors in male breast cancer and correlate them with patient survival. METHODS: From 841 Dutch males with breast cancer who were enrolled in the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program (NCT01101425) and diagnosed between 1990 and 2010, archival primary tumor samples were collected. Tissue microarrays were constructed with 3 cores per sample and used for immunohistochemical analysis of HGF, c-MET, CXCL12, and CXCR4. Overall survival (OS) of the patients without metastases (M0) was analyzed using the Kaplan-Meier method. The value of the markers regarding OS was determined using univariable and multivariable Cox regression analyses, providing hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: Of 720 out of 841 patients, sufficient tissue was available for analysis; 487 out of 720 patients had M0 disease. Patients with high HGF expression and high CXCL12 expression had a superior OS (low vs high expression of both markers, 7.5 vs 13.0 years, hazard ratio [HR] 0.64, 95% CI 0.49-0.84, P = 0.001 [HGF]; 9.1 vs 15.3 years, HR 0.63, 95% CI 0.45-0.87, P = 0.005 [CXCL12]). Multivariate analysis identified HGF as an independent predictor for OS (HR 0.64, 95% CI 0.47-0.88, P = 0.001). CONCLUSIONS: HGF and CXCL12 tumor expression appear to identify male breast cancer patients with a relatively good prognosis. Possibly, this could support male breast cancer-specific management strategies in the future.

[A method of screening highly common neoantigens with immunogenicity in colorectal cancer based on public somatic mutation library].

Colorectal cancer (CRC) is a malignant cancer with high incidence and mortality in the world. Immunotherapy targeting neoantigens can induce durable tumor regression in cancer patients, but is almost limited to personalized precision therapy, due to the individual differences of unique neoantigens. With the discovery of many common oncogenic mutations, and such mutation-associated neoantigens could cover more patients, and hence are valuable in clinical field. However, whether the common neoantigens can be identified in CRC is unknown. Combining the somatic mutations data from 321 CRC patients with a filter standard and 7 predicted algorithms, we screened and obtained 25 HLA-A*1101-restricted common neoantigens with a high binding affinity (IC50<50 nmol/L) and presentation score (>0.90). Besides the positive epitope KRAS_G12V8-16, 11 out of 25 common neoantigens specifically induced in vitro pre- stimulated cytotoxic lymphocyte (CTL) to secrete interferon gamma (IFN-γ). Moreover, combining cell-sorting technology and single-cell RNA sequencing, the immune repertoire profiles of C1orf170_S418G413-421 and KRAS_G12V8-16-specific CTL were analyzed and validated. Their related T-cell receptor engineered T cell (TCR-T) cells could also recognize the neoantigens and secrete IFN-γ. Hence, we have established a method to screen for common neoantigens with immunogenicity in CRC based on the public somatic mutation library. It can provide essential peptide and TCR information for immunotherapies, such as peptides, dendritic cells (DC) vaccines, TCR-like antibodies, TCR-T, etc., for the CRC and other cancers, which has practical application value in the clinics.

Progress and challenges of sequencing and analyzing circulating tumor cells.

Circulating tumor cells (CTCs) slough off primary tumor tissues and are swept away by the circulatory system. These CTCs can remain in circulation or colonize new sites, forming metastatic clones in distant organs. Recently, CTC analyses have been successfully used as effective clinical tools to monitor tumor progression and prognosis. With advances in next-generation sequencing (NGS) and single-cell sequencing (SCS) technologies, scientists can obtain the complete genome of a CTC and compare it with corresponding primary and metastatic tumors. CTC sequencing has been successfully applied to monitor genomic variations in metastatic and recurrent tumors, infer tumor evolution during treatment, and examine gene expression as well as the mechanism of the epithelial-mesenchymal transition. However, compared with cancer biopsy sequencing and circulating tumor DNA sequencing, the sequencing of CTC genomes and transcriptomes is more complex and technically difficult. Challenges include enriching pure tumor cells from a background of white blood cells, isolating and collecting cells without damaging or losing DNA and RNA, obtaining unbiased and even whole-genome and transcriptome amplification material, and accurately analyzing CTC sequencing data. Here, we review and summarize recent studies using NGS on CTCs. We mainly focus on CTC genome and transcriptome sequencing and the biological and potential clinical applications of these methodologies. Finally, we discuss challenges and future perspectives of CTC sequencing.

Multiple IgH Isotypes Including IgD, Subclasses of IgM, and IgY Are Expressed in the Common Ancestors of Modern Birds.

Although evolutionarily just as ancient as IgM, it has been thought for many years that IgD is not present in birds. Based on the recently sequenced genomes of 48 bird species as well as high-throughput transcriptome sequencing of immune-related tissues, we demonstrate in this work that the ostrich (Struthio camelus) possesses a functional δ gene that encodes a membrane-bound IgD H chain with seven CH domains. Furthermore, δ sequences were clearly identified in many other bird species, demonstrating that the δ gene is widely distributed among birds and is only absent in certain bird species. We also show that the ostrich possesses two µ genes (µ1, µ2) and two υ genes (υ1, υ2), in addition to the δ and α genes. Phylogenetic analyses suggest that subclass diversification of both the µ and υ genes occurred during the early stages of bird evolution, after their divergence from nonavian reptiles. Although the positions of the two υ genes are unknown, physical mapping showed that the remaining genes are organized in the order µ1-δ-α-µ2, with the α gene being inverted relative to the others. Together with previous studies, our data suggest that birds and nonavian reptile species most likely shared a common ancestral IgH gene locus containing a δ gene and an inverted α gene. The δ gene was then evolutionarily lost in selected birds, whereas the α gene lost in selected nonavian reptiles. The data obtained in this study provide significant insights into the understanding of IgH gene evolution in tetrapods.

Single-cell RNA sequencing reveals dynamic changes in A-to-I RNA editome during early human embryogenesis.

BACKGROUND: A-to-I RNA-editing mediated by ADAR (adenosine deaminase acting on RNA) enzymes that converts adenosine to inosine in RNA sequence can generate mutations and alter gene regulation in metazoans. Previous studies have shown that A-to-I RNA-editing plays vital roles in mouse embryogenesis. However, the RNA-editing activities in early human embryonic development have not been investigated. RESULTS: Here, we characterized genome-wide A-to-I RNA-editing activities during human early embryogenesis by profiling 68 single cells from 29 human embryos spanning from oocyte to morula stages. We demonstrate dynamic changes in genome-wide RNA-editing during early human embryogenesis in a stage-specific fashion. In parallel with ADAR expression level changes, the genome-wide A-to-I RNA-editing levels in cells remained relatively stable until 4-cell stage, but dramatically decreased at 8-cell stage, continually decreased at morula stage. We detected 37 non-synonymously RNA-edited genes, of which 5 were frequently found in cells of multiple embryonic stages. Moreover, we found that A-to-I editings in miRNA-targeted regions of a substantial number of genes preferably occurred in one or two sequential stages. CONCLUSIONS: Our single-cell analysis reveals dynamic changes in genome-wide RNA-editing during early human embryogenesis in a stage-specific fashion, and provides important insights into early human embryogenesis.

Wettability of a Single Carbon Fiber.

Wettability as determined from contact angle measurements is a suitable parameter for characterizing the physical bonding of a polymer matrix and reinforcing fibers, but it is very challenging to measure the capillary force exerted by a probe liquid on a fiber accurately for very fine fibers such as single carbon fibers. Herein, we propose an innovative method for measuring dynamic contact angles with a tensiometer, considering both the intrinsic variability of the carbon fiber diameter and the extremely small amplitude of the capillary forces, allowing the measurement of reliable dynamic contact angles over a large range of contact line velocities. The analysis of the contact angle dynamics by the molecular-kinetic theory permits us to check the relevancy of the measured contact angles and to obtain the static contact angle value, improving the prospect of employing tensiometry to better understand the wetting behavior of carbon fibers.

B→πll Form Factors for New Physics Searches from Lattice QCD.

The rare decay B→πℓ^{+}ℓ^{-} arises from b→d flavor-changing neutral currents and could be sensitive to physics beyond the standard model. Here, we present the first ab initio QCD calculation of the B→π tensor form factor f_{T}. Together with the vector and scalar form factors f_{+} and f_{0} from our companion work [J. A. Bailey et al., Phys. Rev. D 92, 014024 (2015)], these parametrize the hadronic contribution to B→π semileptonic decays in any extension of the standard model. We obtain the total branching ratio BR(B^{+}→π^{+}µ^{+}µ^{-})=20.4(2.1)×10^{-9} in the standard model, which is the most precise theoretical determination to date, and agrees with the recent measurement from the LHCb experiment [R. Aaij et al., J. High Energy Phys. 12 (2012) 125].

Hyperactive external awareness against hypoactive internal awareness in disorders of consciousness using resting-state functional MRI: highlighting the involvement of visuo-motor modulation.

Resting-state functional MRI (fMRI) has emerged as a valuable tool to characterize the complex states encompassing disorders of consciousness (DOC). Awareness appears to comprise two coexistent, anticorrelated components named the external and internal awareness networks. The present study hypothesizes that DOC interrupts the balance between the internal and external awareness networks. To gain more understanding of this phenomenon, the present study analyzed resting-state fMRI data from 12 patients with DOC versus 12 healthy age-matched controls. The data were explored using independent component analysis and amplitude of low-frequency fluctuation (ALFF) analysis. The results indicated that DOC deactivated midline areas associated with internal awareness. In addition, external awareness was strengthened in DOC because of increased activation in the insula, lingual gyrus, paracentral and supplementary motor area. The activity patterns suggested strengthened external awareness against weakened internal awareness in DOC. In particular, increased activity found in the insula, lingual gyrus, paracentral and supplementary motor area of patients with DOC implied possible involvement of augmented visuo-motor modulation in these patients. DOC is probably related to hyperactive external awareness opposing hypoactive internal awareness. This unique pattern of brain activity may potentially be a prognostic marker for DOC.

Determination of |V(us)|| from a lattice QCD calculation of the K → πℓν semileptonic form factor with physical quark masses.

We calculate the kaon semileptonic form factor f+(0) from lattice QCD, working, for the first time, at the physical light-quark masses. We use gauge configurations generated by the MILC Collaboration with Nf = 2 + 1 + 1 flavors of sea quarks, which incorporate the effects of dynamical charm quarks as well as those of up, down, and strange. We employ data at three lattice spacings to extrapolate to the continuum limit. Our result, f+(0) = 0.9704(32), where the error is the total statistical plus systematic uncertainty added in quadrature, is the most precise determination to date. Combining our result with the latest experimental measurements of K semileptonic decays, one obtains the Cabibbo-Kobayashi-Maskawa matrix element |V(us)| = 0.22290(74)(52), where the first error is from f+(0) and the second one is from experiment. In the first-row test of Cabibbo-Kobayashi-Maskawa unitarity, the error stemming from |V(us)| is now comparable to that from |V(ud)|.

Regulator of G protein signalling 18 promotes osteocyte proliferation by activating the extracellular signal­regulated kinase signalling pathway.

Osteocyte function is critical for metabolism, remodelling and regeneration of bone tissue. In the present study, the roles of regulator of G protein signalling 18 (RGS18) were assessed in the regulation of osteocyte proliferation and bone formation. Target genes and signalling pathways were screened using the Gene Expression Omnibus (GEO) database and Gene Set Enrichment Analysis (GSEA). The function of RGS18 and the associated mechanisms were analysed by Cell Counting Kit 8 assay, 5­ethynyl­2'­deoxyuridine assay, flow cytometry, reverse transcription­quantitative PCR, western blotting and immunostaining. Overlap analysis of acutely injured subjects (AIS) and healthy volunteers (HVs) from the GSE93138 and GSE93215 datasets of the GEO database identified four genes: KIAA0825, ANXA3, RGS18 and LIPN. Notably, RGS18 was more highly expressed in peripheral blood samples from AIS than in those from HVs. Furthermore, RGS18 overexpression promoted MLO­Y4 and MC3T3­E1 cell viability, proliferation and S­phase arrest, but inhibited apoptosis by suppressing caspase­3/9 cleavage. Silencing RGS18 exerted the opposite effects. GSEA of GSE93138 revealed that RGS18 has the ability to regulate MAPK signalling. Treatment with the MEK1/2 inhibitor PD98059 reversed the RGS18 overexpression­induced osteocyte proliferation, and treatment with the ERK1/2 activator 12­O­tetradecanoylphorbol­13­acetate reversed the effects of RGS18 silencing on osteocyte proliferation. In conclusion, RGS18 may contribute to osteocyte proliferation and bone fracture healing via activation of ERK signalling.

NOP14 as a Potential Predictor of Adult-Type Diffuse Glioma Prognosis and Immunotherapy, is Related to Cell Migration, Proliferation, and CD8+T Cell Infiltration.

BACKGROUND: World Health Organization (WHO) grade 4 adult-type diffuse glioma is the most malignant primary tumor of the brain. Nucleolar protein 14 (NOP14) is recognized to contribute significantly to the assembly of small ribosomal subunits. However, the specific involvement of NOP14 in diverse cancers remains poorly understood, particularly its role in adult-type diffuse glioma, which has yet to be elucidated. METHODS: A total of 20 adult-type diffuse glioma samples with varying WHO stages were collected. The protein level of NOP14 was detected using immunohistochemistry. Additionally, NOP14 expression in LN229 and U251 cell lines and collected clinical tissue samples was quantified using the Western blot technique. Furthermore, the correlation between NOP14 and clinicopathological features, survival rates, matrix and immune scores, and immune components was investigated using data from the Cancer Gene Atlas database. RESULTS: NOP14 exhibited high expression in adult-type diffuse glioma patients, with the highest expression observed in the LN229 cell line. Moreover, elevated NOP14 expression was significantly correlated with poorer overall survival and demonstrated an association with unfavorable pathological features in a cohort of 703 glioblastoma (GBM) patients. Evidence of a connection between NOP14 and the tumor microenvironment was presented. Elevated NOP14 was linked to the infiltration of CD8+T cell and factors related to epithelial-mesenchymal transition. In in vitro assay, NOP14 was capable of suppressing adult-type diffuse glioma cell invasion and metastasis. CONCLUSIONS: NOP14 holds great promise as a candidate biomarker for detecting prognostic, molecular, and immune signatures of adult-type diffuse glioma.

Systolic blood pressure and early neurological deterioration in minor stroke: A post hoc analysis of ARAMIS trial.

BACKGROUND: Systolic blood pressure (SBP) was a predictor of early neurological deterioration (END) in stroke. We performed a secondary analysis of ARAMIS trial to investigate whether baseline SBP affects the effect of dual antiplatelet versus intravenous alteplase on END. METHODS: This post hoc analysis included patients in the as-treated analysis set. According to SBP at admission, patients were divided into SBP ≥140 mmHg and SBP <140 mmHg subgroups. In each subgroup, patients were further classified into dual antiplatelet and intravenous alteplase treatment groups based on study drug actually received. Primary outcome was END, defined as an increase of ≥2 in the NIHSS score from baseline within 24 h. We investigated effect of dual antiplatelet vs intravenous alteplase on END in SBP subgroups and their interaction effect with subgroups. RESULTS: A total of 723 patients from as-treated analysis set were included: 344 were assigned into dual antiplatelet group and 379 into intravenous alteplase group. For primary outcome, there was more treatment effect of dual antiplatelet in SBP ≥140 mmHg subgroup (adjusted RD, -5.2%; 95% CI, -8.2% to -2.3%; p < 0.001) and no effect in SBP <140 mmHg subgroup (adjusted RD, -0.1%; 95% CI, -8.0% to 7.7%; p = 0.97), but no significant interaction between subgroups was found (adjusted p = 0.20). CONCLUSIONS: Among patients with minor nondisabling acute ischemic stroke, dual antiplatelet may be better than alteplase with respect to preventing END within 24 h when baseline SBP ≥140 mmHg.

Reversible Constrained Dissociation and Reassembly of MXene Films.

Enabling materials to undergo reversible dynamic transformations akin to the behaviors of living organisms represents a critical challenge in the field of material assembly. The pursuit of such capabilities using conventional materials has largely been met with limited success. Herein, the discovery of reversible constrained dissociation and reconfiguration in MXene films, offering an effective solution to overcome this obstacle is reported. Specifically, MXene films permit rapid intercalation of water molecules between their distinctive layers, resulting in a significant expansion and exhibiting confined dissociation within constrained spaces. Meanwhile, the process of capillary compression driven by water evaporation reinstates the dissociated MXene film to its original compact state. Further, the adhesive properties emerging from the confined disassociation of MXene films can spontaneously induce fusion between separate films. Utilizing this attribute, complex structures of MXene films can be effortlessly foamed and interlayer porosity precisely controlled, using only water as the inducer. Additionally, a parallel phenomenon has been identified in graphene oxide films. This work not only provides fresh insights into the microscopic mechanisms of 2D materials such as MXene but also paves a transformative path for their macroscopic assembly applications in the future.

The sources and metabolic dynamics of Schistosoma japonicum DNA in serum of the host.

The polymerase chain reaction (PCR) assay has turned out to be one of the most potential tools for diagnosis of schistosomiasis. However, the source and metabolic dynamics of Schistosoma japonicum DNA in the blood of hosts is not clear. In this study, rabbit models with monosexual and mixed sexual cercariae infection were established to interpret the source of the parasite DNA in serum of the hosts. Following administration of praziquantel at 7 weeks postinfection, the metabolic mechanism of S. japonicum DNA in serum of the hosts was studied. The findings showed that, for the monosexual cercariae infection, the parasite DNA was detectable in serum of the host from day 3 to week 3 postinfection, while for the mixed sexual cercariae infection, the detection results were continually positive during the 7 weeks after infection. After treatment with praziquantel, detection of S. japonicum DNA in rabbit sera became positive at the second day posttreatment, and the positive period lasted 3 weeks in the monosexual cercariae infection group. However, with the mixed sexual cercariae infection group, the PCR results remained positive for 16 weeks after treatment. We conclude that the S. japonicum DNA in host serum primarily comes from the residual body of dead schistosomula and/or tegument shedding of worm growing in the first 4 weeks postinfection, while during the spawning stage of the female schistosome, the parasite DNA mainly comes from the disintegration of inactive eggs. The duration from treatment to total elimination of worm origin DNA in serum is not exceeding 3 weeks. However, the DNA release from inactive eggs can last for more than 16 weeks. Further studies are needed to address the sources and metabolic dynamics of S. japonicum DNA in human serum.

Molecular and functional imaging in cancer-targeted therapy: current applications and future directions.

Targeted anticancer drugs block cancer cell growth by interfering with specific signaling pathways vital to carcinogenesis and tumor growth rather than harming all rapidly dividing cells as in cytotoxic chemotherapy. The Response Evaluation Criteria in Solid Tumor (RECIST) system has been used to assess tumor response to therapy via changes in the size of target lesions as measured by calipers, conventional anatomically based imaging modalities such as computed tomography (CT), and magnetic resonance imaging (MRI), and other imaging methods. However, RECIST is sometimes inaccurate in assessing the efficacy of targeted therapy drugs because of the poor correlation between tumor size and treatment-induced tumor necrosis or shrinkage. This approach might also result in delayed identification of response when the therapy does confer a reduction in tumor size. Innovative molecular imaging techniques have rapidly gained importance in the dawning era of targeted therapy as they can visualize, characterize, and quantify biological processes at the cellular, subcellular, or even molecular level rather than at the anatomical level. This review summarizes different targeted cell signaling pathways, various molecular imaging techniques, and developed probes. Moreover, the application of molecular imaging for evaluating treatment response and related clinical outcome is also systematically outlined. In the future, more attention should be paid to promoting the clinical translation of molecular imaging in evaluating the sensitivity to targeted therapy with biocompatible probes. In particular, multimodal imaging technologies incorporating advanced artificial intelligence should be developed to comprehensively and accurately assess cancer-targeted therapy, in addition to RECIST-based methods.

Preparation and Properties of Polyvinylpyrrolidone/Sodium Carboxymethyl Cellulose Soluble Microneedles.

Transdermal drug delivery is a new means of delivering drugs through the skin to achieve therapeutic effects. Microneedles have several advantages, including low cost, easy self-administration, and high delivery efficiency. Different polymers affect the morphology, mechanical properties, and drug delivery efficiency of microneedles. To study the performance and limitations of microneedles (MNs), we prepared different ratios of polymers. MNs were fabricated from polyvinylpyrrolidone (PVP) and sodium carboxymethyl cellulose (CMC-Na) using the centrifugal molding method. Needle morphology, formability, and other properties of the polymers were evaluated to compare the performances of MNs with different ratios. PVP and CMC-Na were intermixed at different ratios with water as the solvent. The soluble MNs were prepared by mold casting. The morphology, thermodynamic properties, and crystallinity were studied using scanning electron microscopy (SEM), thermogravimetric analysis (TG), differential scanning calorimetric analysis (DSC), and X-ray diffraction (XRD). The results showed that composite microneedles have good thermal stability. Among the different compositions tested, the 10% PVP/2% CMC-Na composite microneedle demonstrated the best performance with a regular surface morphology and relatively high thermal decomposition and melting temperatures. These results indicate that microneedles with appropriate ratios of two different materials possess good formability and other properties.

Silicon composition and stoichiometric ratios with other nutrients in the lower Minjiang River, Southeast China.

Over the past decades, rivers have delivered imbalanced nutrient loads to coastal marine ecosystems due to human activities, which leads to serious regional or global eutrophication problems. The Minjiang River is heavily influenced by human activities. To understand the changing characteristics of nutrient transport ratios in the Minjiang River waters, we measured the seasonal variations of carbon, nitrogen, phosphorus and silicon nutrients in the lower surface waters of the Minjiang River between July 2019 and July 2020. The results showed that the annual average contents of dissolved silicon (DSi), lithogenic silicon (LSi) and biogenic silicon (BSi) in the surface waters of the lower Minjiang River were 5.30, 4.58 and 2.37 mg·L-1, respectively. There were large seasonal differences among these parameters, with higher content of DSi than LSi and BSi in summer, higher content of DSi than BSi and LSi in autumn and higher content of LSi than DSi and BSi in winter. The proportions of DSi in total silicon tended to decrease gradually from land to sea, while the proportion of BSi was on the contrary. In term of stoichiometric ratios, the Minjiang River mostly presented carbon or phosphorus limitation and was unlimited by silicon or nitrogen. About 1.03×1010 mol DSi and 0.46 ×1010 mol BSi were delivered via the Minjiang River to the ocean yearly, showing a decreasing trend year by year. Based on the data in recent years, the nutrient loads of carbon, nitrogen, and phosphorus transported by Minjiang River showed an increasing trend. The imbalanced nutrient loads may lead to changes in the structure and function of the river, estuary, and offshore ecosystems. The study of nutrient stoichiometric ratios can provide a theoretical basis for solving the problems in structural balance of nutrients and eutrophication in Minjiang River estuary and adjacent marine waters.

MCM10 as a novel prognostic biomarker and its relevance to immune infiltration in gliomas.

BACKGROUND: Gliomas are one of the most common malignancies in the central nervous system (CNS). Members of the minichromosomal maintenance protein (MCM) family play an essential role in diagnosing and prognosis of malignant tumors. MCM10 is found in gliomas, but the prognosis and immune infiltration of gliomas has not been elucidated. OBJECTIVE: To explore the biological function and immune infiltration of MCM10 in gliomas and provide a reference for the diagnosis, treatment, and prognostic evaluation. METHODS: The MCM10 expression profile and the clinical information database of glioma patients were obtained from the China Glioma Genome Atlas (CGGA) and Cancer Genome Atlas (TCGA) glioma data. We analyzed the MCM10 expression levels in various cancers from The TCGA.RNA sequencing data were analyzed using the R packages to determine differentially expressed genes (DEGs) between high- and low MCM10 expressing GBM tissues from the TCGA-GBM database. The Wilcoxon rank sum test was used to compare MCM10 expression levels in glioma and normal brain tissue. To evaluate the value of MCM10 expressions in the prognosis of glioma patients by the Kaplan-Meier survival analysis, a univariate Cox analysis, multivariate Cox analysis, and a ROC curve analysis were used to analyze the correlation of MCM10 expression and the clinicopathological features of glioma patients using the TCGA database data. Subsequently, a functional enrichment analysis was performed to explore its potential signaling pathways and biological functions. Moreover, a single-sample gene set enrichment analysis was used to assess the extent of immune cell infiltration. Lastly, the authors constructed a nomogram to predict the overall survival rate (OS) of gliomas at 1, 3 and 5 years after diagnosis. RESULTS: MCM10 is highly expressed in 20 cancer types including gliomas, and MCM10 expression was an independent adverse prognostic factor in glioma patients. Similarly, high expression of MCM10 was associated with advanced age (60 years), increased tumor grade, tumor recurrence or development of a secondary tumor, IDH wild-type, and non-codeletion of 1p19q (p< 0.01). The OS nomogram generated a consistency index of 0.821. The results of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) functional analysis showed that the cell-cycle-related and tumor-related signaling pathways were significantly enriched in the MCM10 high expression phenotype. Moreover, signaling pathways were significantly enriched in Gene Set Enrichment Analysis (GSEA), including Rho GTPases, M phase, DNA repair, extracellular matrix organization, and nuclear receptors. Furthermore, MCM10 over expression was negatively correlated with the level of immune cell infiltration in natural killer CD56 bright cells, follicular helper T cells, plasmacytoma dendritic cells, and dendritic cells. CONCLUSION: MCM10 is an independent prognostic index of glioma patients, and the high expression of MCM10 suggests a poor prognosis; MCM10 expression is closely related to the immune cell infiltration of gliomas, and MCM10 may be related to drug resistance and development of gliomas.