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To investigate the family line of a pregnant woman with congenital hypofibrinogenaemia due to a de novo mutation in the fibrinogen gamma (FGG) gene and experimentally explore its molecular pathological mechanisms. Peripheral blood specimens were collected from the proband and her family members for coagulation tests to assess their coagulation function. Whole exome sequencing was used to determine the gene mutation in the family lineage. SDS-PAGE was utilized to analyze the plasma of the proband and her mother for their congenital hypofibrinogenaemia. Structural distribution was analyzed by scanning electron microscopy. Molecular modeling was performed to predict the effect of mutation sites on fibrinogen structure and function. A de novo heterozygous mutation in the FGG gene was identified: c.702G > T, with a markedly prolonged thrombin time. The thromboelastography results showed that her fibrinogen function was essentially normal. LC-MS/MS showed no plasma or mutant chains in the plasma. Molecular modeling showed that this de novo mutation altered the structure of fibrinogen in the patient and her fibrinogen was heterogeneous in diameter and sparsely networked under electron microscopy. An intermittent infusion of 6 g of fibrinogen in the prenatal period of the proband brought the fibrinogen level of the patient to 2.13 g/L. No significant haemorrhage was detected between and after the caesarean section. The FGG gene NM_021870.3: c.702G > T (p.Trp234Cys) mutation is a de novo mutation, which is heterozygous in both the proband and her mother. It’s the biogenetic basis for the pathogenicity of this congenital hypofibrinogenaemia family line.

Background Despite the success of immune checkpoint inhibitors (ICIs) in multiple malignant tumors, a significant proportion of patients remain unresponsive to treatment. Radiotherapy (RT) elicits immunogenic antitumor responses but concurrently activates several immune evasion mechanisms. Our earlier research demonstrated the efficacy of YM101, an anti-TGF-β/PD-L1 bispecific antibody, in stroma-rich tumors. Nevertheless, YM101 has demonstrated reduced effectiveness in non-inflamed tumors characterized by poor immune cell infiltration. This study investigated the potential synergy between RT and YM101 in overcoming immunotherapy resistance and mitigating RT-induced pulmonary fibrosis. Methods The antitumor activity and survival outcomes of RT plus YM101 treatment in vivo were explored in several non-inflamed murine tumor models. Furthermore, the inhibition of pulmonary metastases was assessed in a pulmonary metastasis model. The impact of RT on dendritic cell (DC) maturation was quantified by flow cytometry, whereas cytokine and chemokine secretions were measured by ELISA. To comprehensively characterize changes in the tumor microenvironment, we utilized a combination of methods, including flow cytometry, IHC staining, multiplex inmunofluorecence and RNA sequencing. Additionally, we evaluated the impact of YM101 on RT-induced pulmonary fibrosis. Results RT plus YM101 significantly inhibited tumor growth, prolonged survival and inhibited pulmonary metastases compared with monotherapies in non-inflamed tumors with poor immune infiltration. RT promoted DC maturation in a dose-dependent manner and increased the secretions of multiple proinflammatory cytokines. Mechanistically, RT plus YM101 simultaneously increased the infiltration and activation of intratumoral DCs and tumor-infiltrating lymphocytes and reshaped the tumor microenvironment landscape. Notably, YM101 attenuated both RT-induced peritumoral fibrosis and pulmonary fibrosis. Conclusions Our findings suggest that RT combined with YM101 enhances antitumor immunity and overcomes resistance in non-inflamed tumors in preclinical models, while simultaneously showing potential in mitigating RT-induced fibrosis. This combination therapy demonstrates promise in overcoming ICI resistance, while potentially sparing normal pulmonary tissue, thereby providing a strong rationale for further clinical investigations.

Background Lenvatinib is an oral small molecule inhibitor approved for treating patients with unresectable hepatocellular carcinoma (HCC) worldwide. Increasing cell sensitivity to lenvatinib would be an effective method of improving therapeutic efficacy. Methods High throughput methods was used to scan the differentially expressed genes (DEGs) related to lenvatinib sensitivity in HCC cells. Gain- and loss-function experiments were used to explore the functions of these DEGs in HCC and lenvatinib sensitivity. CO-IP assay and rescue experiments were utilized to investigate the mechanism. Results We identified that RAR responder protein 1 (RARRES1), a podocyte-specific growth arrest gene, was among significantly upregulated DEGs in HCC cells following lenvatinib treatment. Functional analysis showed that ectopic RARRES1 expression decreased HCC progression in vitro and in vivo, as well as improving tumor sensitivity to lenvatinib, while RARRES1 silencing increased HCC cell proliferation and migration. Mechanistically, co-immunoprecipitation assays demonstrated that RARRES1 interacted with serine protease inhibitor Kazal-type 2 (SPINK2) in HCC cells. Further, SPINK2 overexpression suppressed HCC cell proliferation and migration, as well as increasing sensitivity to lenvatinib whereas SPINK2 knockdown promoted cell progression and decreased lenvatinib sensitivity. The mRNA and protein levels of RARRES1 and SPINK2 were low in HCC tissue samples, relative to those in normal liver tissue. Conclusions Our findings highlighted that RARRES1 can inhibit HCC progression and regulate HCC sensitivity to lenvatinib by interacting SPINK2, representing a new tumor suppressor RARRES1/SPINK2 axis in HCC that modulates sensitivity to lenvatinib.

Vertical bone augmentation is an important challenge in dental implantology. Existing vertical bone augmentation techniques, along with bone grafting materials, have achieved certain clinical progress but continue to have numerous limitations. In order to evaluate the possibility of using biomaterials to develop bone substitutes, medical devices and/or new bone grafting techniques for vertical bone augmentation, it is essential to establish clinically relevant animal models to investigate their biocompatibility, mechanical properties, applicability and safety. The present review discusses recent animal experiments related to vertical bone augmentation. In addition, surgical protocols for establishing relevant preclinical models with various animal species were reviewed. The present study aims to provide guidance for selecting experimental animal models of vertical bone augmentation.

This article presents the results of an examination of self-determination theory; in this examination, the theory is extended through deeper insight into the compensatory association between autonomy and relatedness satisfaction. This study is designed to investigate whether the mutual influence of autonomy satisfaction and relatedness satisfaction on positive affect (PA), negative affect (NA), and aggressive feelings is best described as compensatory. The results of two laboratory studies verify a compensatory relationship and confirm a mediation by meaningful existence. The results verify the compensation effects of high relatedness satisfaction on NA and aggressive feelings when autonomy satisfaction is low. With role-playing and nonrole-playing digital game manipulation, the results are stronger when the participants were being themselves rather than playing a character.

Herbicides are used to control weeds in agricultural crops such as alfalfa ( Medicago sativa L.), which is a forage crop. It is unclear what, if any, effect herbicides have on greenhouse gas (GHG) emissions when used on alfalfa. Our study was conducted in 2017 and 2018 to investigate the effects of two herbicides (Quizalofop-p-ethyl, QE and Bentazone, BT) on methane (CH 4 ), carbon dioxide (CO 2 ) and nitrous oxide (N 2 O) emissions from soil planted with alfalfa. QE is used to control grasses and BT is used for broadleaf weed control. Soil CO 2 emissions and soil uptake of CH 4 increased significantly in both years following the QE and BT treatments, although CO 2 emissions differed significantly between the trial years. N 2 O emissions decreased relative to the control and showed no significant differences between the trial years. The application of QE and BT on alfalfa resulted in a significant increase in CO 2 emissions which contributed to a significant increase in GHG emissions. The application of QE influenced GHG emissions more than BT. We demonstrated the potential effect that herbicide applications have on GHG fluxes, which are important when considering the effect of agricultural practices on GHG emissions and the potential for global warming over the next 100 years.

Objective Dysregulation of KLF7 participates in the development of various cancers, but it is unclear whether there is a link between HCC and aberrant expression of KLF7. The aim of this study was to investigate the role of KLF7 in proliferation and migration of hepatocellular carcinoma (HCC) cells. Methods CCK8, colony growth, transwell, cell cycle analysis and apoptosis detection were performed to explore the effect of KLF7, VPS35 and Ccdc85c on cell function in vitro. Xenografted tumor growth was used to assess in vivo role of KLF7. Chip-qPCR and luciferase reporter assays were applied to check whether KLF7 regulated VPS35 at transcriptional manner. Co-IP assay was performed to detect the interaction between VPS35 and Ccdc85c. Immunohistochemical staining and qRT-PCR analysis were performed in human HCC sampels to study the clinical significance of KLF7, VPS35 and β-catenin. Results Firstly, KLF7 was highly expressed in human HCC samples and correlated with patients’ differentiation and metastasis status. KLF7 overexpression contributed to cell proliferation and invasion of HCC cells in vitro and in vivo. KLF7 transcriptional activation of VPS35 was necessary for HCC tumor growth and metastasis. Further, co-IP studies revealed that VPS35 could interact with Ccdc85c in HCC cells. Rescue assay confirmed that overexpression of VPS35 and knockdown of Ccdc85c abolished the VPS35-medicated promotion effect on cell proliferation and invasion. Finally, KLF7/VPS35 axis regulated Ccdc85c, which involved in activation of β-catenin signaling pathway, confirmed using β-catenin inhibitor, GK974. Functional studies suggested that downregulation of Ccdc85c partly reversed the capacity of cell proliferation and invasion in HCC cells, which was regulated by VPS35 upregulation. Lastly, there was a positive correlation among KLF7, VPS35 and active-β-catenin in human HCC patients. Conclusion We demonstrated that KLF7/VPS35 axis promoted HCC cell progression by activating Ccdc85c-medicated β-catenin pathway. Targeting this signal axis might be a potential treatment strategy for HCC.

Colorectal cancer (CRC) progression is driven by complex metabolic alterations, including aberrant N‐glycosylation patterns that critically influence tumor development. However, the metabolic and functional roles of N‐glycosylation in CRC remain poorly understood. Herein, comprehensive proteomic and N‐linked intact glycoproteomics analyses are performed on 45 CRC tumors, and normal adjacent tissues (NATs) are matched, identifying 7125 intact N‐glycopeptides from 704 glycoproteins. Through analysis of glycoform expression profiles and structural characteristics, a glycosylation site–protein function association network is constructed to uncover metabolic dysregulation driven by N‐glycosylation in CRC. Moreover, an arithmetic model is developed that integrates N‐glycan expression patterns, which effectively distinguishes tumors from NATs, reflecting metabolic reprogramming in cancer. These findings identify Chloride Channel Accessory 1 (CLCA1) and Olfactomedin 4 (OLFM4) as potential metabolic biomarkers for CRC diagnosis. Immunohistochemistry and Cox regression analyses validated the prognostic power of these markers. Notably, the critical role of specific N‐glycosylation at N196 of Adipocyte plasma membrane‐associated protein (APMAP) is highlighted, a key player in tumor metabolism and CRC progression, providing a potential target for therapeutic intervention. These findings offer valuable insights into the metabolic roles of N‐glycosylation in CRC, advancing biomarker discovery, enhancing metabolic‐based diagnostic precision, and improving personalized treatment strategies targeting cancer metabolism. The comprehensive proteomic and N‐glycoproteomic analyses of 45 colorectal cancer tissues with matched normal adjacent tissues identified 7125 intact N‐glycopeptides from 704 glycoproteins. A glycosylation site‐protein function network revealing metabolic dysregulation is constructed and a model differentiating tumors from normal tissues is developed. CLCA1 and OLFM4 are validated as diagnostic biomarkers, while site‐specific glycosylation at APMAP‐N196 emerged as a therapeutic target.

Background: The C-terminally encoded peptide (CEP) family has been shown to play vital roles in plant growth. Although a genome-wide analysis of this family has been performed in Arabidopsis, little is known regarding CEPs in apple (Malus domestica). Methods: Here, a comprehensive bioinformatics approach was applied to identify MdCEPs in apple, and 12 MdCEP genes were identified and distributed on 6 chromosomes. Results: MdCEP1 peptide had an inhibitory effect on root growth of apple seedlings, indicating that MdCEP1 played a negative role in root development. In addition, the serine and glycine residues remained conserved within the CEP domains, and MdCEP1 lost its function after mutation of these two key amino acids, suggesting that Ser10 and Gly14 residues are crucial for MdCEPs-mediated root growth of apple. Encouragingly, multiple sequence alignment of 273 CEP domains showed that Ser10 residue was evolutionarily conserved in monocot and eudicot plants. MdCEP derivative (Ser to Cys) lost the ability to inhibit the root growth of Nicotiana benthamiana, Setaria italic, Samolous parviflorus, and Raphanus sativus L. and up-regulate the NO3− importer gene NRT2.1. Conclusion: Taken together, Ser10 residue is crucial for CEP function exertion in higher land plants, at least in apple.

To explore the effects of multi-cutting and sheep excrement on greenhouse gas (GHG) emissions from grassland ecosystems which simulate grazing livestock to a certain extent, spring wheat (Triticum aestivum L., var. Yongliang 15) and common vetch (Vicia sativa L., var. Lanjian 3) were planted in pot experiments in an inland arid region in 2019. Four treatments were conducted with eight replicates: plants without sheep excrement and cutting (CK), plants with multi-cutting (MC), plants with sheep excrement (SE), and plants with multi-cutting and sheep excrement (CE). The results showed that the carbon dioxide (CO2) emission of common vetch with CE significantly was higher than that with MC at the earlier and later branching stages (p < 0.05). That of spring wheat with CE was significantly higher than that with MC at the later tillering stage (p < 0.05). Nitrogen oxide (N2O) emissions of the two forage crops with SE rose significantly more than those with MC at both stages (p < 0.05). Methane (CH4) of both forage crops with SE changed from absorption to emission (p < 0.05). Soil NO3−-N content of both forages significantly increased with SE compared with MC (p < 0.05), while soil NH4+-N content did not change significantly. Sheep excrement changed the CH4 sink into a CH4 source of the soil growing the two forage crops and increased the emissions of CO2 and N2O, whereas multi-cutting significantly reduced the GHG intensity of forage crops mostly by promoting the growth of the two forage crops. Future studies are suggested to identify the spatiotemporal effects of cutting and sheep excrement on GHG emissions to improve the prediction of future climate impacts from grazing activities.