pH-Responsive ß-Glucans-Complexed mRNA in LNPs as an Oral Vaccine for Enhancing Cancer Immunotherapy.

mRNA vaccines for cancer immunotherapy are commonly delivered using lipid nanoparticles (LNPs), which, when administered intravenously, may accumulate in the liver, potentially limiting their therapeutic efficacy. To overcome this challenge, the study introduces an oral mRNA vaccine formulation tailored for efficient uptake by immune cells in the gastrointestinal (GI) tract, known for its high concentration of immune cells, including dendritic cells (DCs). This formulation comprises mRNA complexed with ß-glucans (ßGlus), a potential adjuvant for vaccines, encapsulated within LNPs (ßGlus/mRNA@LNPs). The ßGlus/mRNA complexes within the small compartments of LNPs demonstrate a distinctive ability to partially dissociate and reassociate, responding to pH changes, effectively shielding mRNA from degradation in the harsh GI environment. Upon oral administration to tumor-bearing mice, ßGlus/mRNA@LNPs are effectively taken up by intestinal DCs and local nonimmune cells, bypassing potential liver accumulation. This initiates antigen-specific immune responses through successful mRNA translation, followed by drainage into the mesenteric lymph nodes to stimulate T cells and trigger specific adaptive immune responses, ultimately enhancing antitumor effects. Importantly, the vaccine demonstrates safety, with no significant inflammatory reactions observed. In conclusion, the potential of oral ßGlus/mRNA@LNPs delivery presents a promising avenue in cancer immunotherapy, offering needle-free and user-friendly administration for widespread adoption and self-administration.

STC1 competitively binding ßPIX enhances melanoma progression via YAP nuclear translocation and M2 macrophage recruitment through the YAP/CCL2/VEGFA/AKT feedback loop.

This study investigates the role of Stanniocalcin-1 (STC1) in melanoma progression, with a focus on its impact on metastasis, angiogenesis, and immune evasion. Systematic bioinformatics analysis revealed the potential influence of STC1 dysregulation on prognosis, immune cell infiltration, response to immune therapy, and cellular functions. In vitro assays were conducted to assess the proliferation, invasion, migration, and angiogenesis capabilities of A375 cells. In vivo experiments utilizing C57BL/6 J mice established a lung metastasis model using B16-F10 cells to evaluate macrophage infiltration and M2 polarization. A Transwell co-culture system was employed to explore the crosstalk between melanoma and macrophages. Molecular interactions among STC1, YAP, ßPIX, and CCL2 are investigated using mass spectrometry, Co-Immunoprecipitation, Dual-Luciferase Reporter Assay, and Chromatin Immunoprecipitation experiments. STC1 was found to enhance lung metastasis by promoting the recruitment and polarization of M2 macrophages, thereby fostering an immunosuppressive microenvironment. Mechanistically, STC1 competes with YAP for binding to ßPIX within the KER domain in melanoma cells, leading to YAP activation and subsequent CCL2 upregulation. CCL2-induced M2 macrophages secrete VEGFA, which enhances tumor vascularization and increases STC1 expression via the AKT signaling pathway in melanoma cells, establishing a pro-metastatic feedback loop. Notably, STC1-induced YAP activation increases PD-L1 expression, promoting immune evasion. Silencing STC1 enhances the efficacy of PD-1 immune checkpoint therapy in mice. This research elucidates STC1's role in melanoma metastasis and its complex interactions with tumor-associated macrophages, proposing STC1 as a potential therapeutic target for countering melanoma metastasis and augmenting the efficacy of PD-1 immunotherapy.

Determinants of hand pulse wave velocity and hand pulse transit time in healthy adults.

Arterial pulse wave velocity (PWV) is recognized as a convenient method to assess peripheral vascular stiffness. This study explored the clinical characteristics of hand PWV (hPWV) and hand pulse transit time (hPTT) in healthy adults (sixty males = 42.4 ± 13.9 yrs; sixty-four females = 42.8 ± 13.9 yrs) voluntarily participated in this study. The arterial pulse waveform and the anatomical distance from the radial styloid process to the tip of the middle finger of both hands were recorded in the sitting position. The hPWV was calculated as the traversed distance divided by hPTT between those two points. Male subjects showed significantly greater hPWV, systolic blood pressure, and pulse pressure than age-matched female subjects, while the hPTT was not significantly different between genders. Multiple linear regression analysis showed that gender is a common determinant of hPWV and hPTT, and that age and heart rate (HR) were negatively correlated with hPWV and hPTT, respectively. We conclude that male subjects have greater hPWV than female subjects. Ageing is associated with decreased hPWV, while increased HR is associated with a smaller hPTT. The hPWV and hPTT might be used as non-invasive indices to characterise the ageing and arterial stiffness of peripheral blood vessels.

Mechanisms of the effect of fertility policies on the labor-capital income gap.

This paper investigates the impact mechanism by which an incentive-based fertility policy may reduce the labor income share. First, the specific paths through which this impact mechanism is realized are analyzed using the production function. It is found that an incentive-based fertility policy triggers high savings, which implies more, cheaper, and more readily available capital to be invested in production. A distribution system that earns income based on factor contributions results in more gains for capital than labor, i.e., a lower share of labor income and a wider income gap between labor and capital. Second, the impact mechanism includes three theoretical hypotheses. They are that an encouraging fertility policy is negatively related to labor income share; this relationship is valid provided that the study subject is in a closed economy; and that capital intensification is a mediator variable of fertility policy affecting labor income share. Finally, to further corroborate the impact mechanism in this paper, a Hansen threshold panel model is applied to verify that the effect of fertility policy on labor income share has a threshold effect. This indicates that the effect of the former on the latter changes significantly before and after the change in fertility policy, confirming the existence of an impact mechanism. The established literature has paid little attention to the impact of incentivised fertility policies on the labour income gap. Using capital intensification as the mediating variable, this paper demonstrates the existence of the former effect on the latter. In view of this, under the encouraged fertility policy, this paper proposes specific measures to enhance the labor income share in order to narrow the income gap between labor and capital.

Knockout of formyl peptide receptor 1 reduces osteogenesis and bone healing.

AIMS: Formyl peptide receptor 1 (FPR1), from a G-protein coupled receptor family, was previously well-characterized in immune cells. But the function of FPR1 in osteogenesis and fracture healing was rarely reported. This study, using the FPR1 knockout (KO) mouse, is one of the first studies that try to investigate FPR1 function to osteogenic differentiation of bone marrow-derived stem cells (BMSCs) in vitro and bone fracture healing in vivo. MATERIALS AND METHODS: Primary BMSCs were isolated from both FPR1 KO and wild type (WT) mice. Cloned mouse BMSCs (D1 cells) were used to examine role of FoxO1 in FPR1 regulation of osteogenesis. A closed, transverse fracture at the femoral midshaft was created to compare bone healing between KO and WT mice. Biomechanical and structural properties of femur were compared between healthy WT and KO mice. KEY FINDINGS: FPR1 expression increased significantly during osteogenesis of both primary and cloned BMSCs. Compared to BMSCs from FPR1 KO mice, WT BMSCs displayed considerably higher levels of osteogenic markers as well as mineralization. Osteogenesis by D1 cells was inhibited by either an FPR1 antagonist cFLFLF or a specific inhibitor of FoxO1, AS1842856. In addition, the femur from WT mice had better biomechanical properties than FPR1 KO mice. Furthermore, bone healing in WT mice was remarkably improved compared to FPR1 KO mice analyzed by X-ray and micro-CT. SIGNIFICANCE: These findings indicated that FPR1 played a vital role in osteogenic differentiation and regenerative capacity of fractured bone, probably through the activation of FoxO1 related signaling pathways.

Silicone rubber sealed channel induced self-healing of large bone defects: Where is the limit of self-healing of bone?

Background: Large defects of long tubular bones due to severe trauma, bone tumor resection, or osteomyelitis debridement are challenging in orthopedics. Bone non-union and other complications often lead to serious consequences. At present, autologous bone graft is still the gold standard for the treatment of large bone defects. However, autologous bone graft sources are limited. Silicon rubber (SR) materials are widely used in biomedical fields, due to their safety and biocompatibility, and even shown to induce nerve regeneration. Materials and methods: We extracted rat bone marrow mesenchymal stem cells (BMMSCs) in vitro and verified the biocompatibility of silicone rubber through cell experiments. Then we designed a rabbit radius critical sized bone defect model to verify the effect of silicone rubber sealed channel inducing bone repair in vivo. Results: SR sealed channel could prevent the fibrous tissue from entering the fracture end and forming bone nonunion, thereby inducing self-healing of long tubular bone through endochondral osteogenesis. The hematoma tissue formed in the early stage was rich in osteogenesis and angiogenesis related proteins, and gradually turned into vascularization and endochondral osteogenesis, and finally realized bone regeneration. Conclusions: In summary, our study proved that SR sealed channel could prevent the fibrous tissue from entering the fracture end and induce self-healing of long tubular bone through endochondral osteogenesis. In this process, the sealed environment provided by the SR channel was key, and this might indicate that the limit of self-healing of bone exceeded the previously thought. The translational potential of this article: This study investigated a new concept to induce the self-healing of large bone defects. It could avoid trauma caused by autologous bone extraction and possible rejection reactions caused by bone graft materials. Further research based on this study, including the innovation of induction materials, might invent a new type of bone inducing production, which could bring convenience to patients. We believed that this study had significant meaning for the treatment of large bone defects in clinical practice.

COX5A as a potential biomarker for disease activity and organ damage in lupus.

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease with limited therapeutic targets or clinical outcome predictors. This study aimed to gain more insights into the underlying immunological pathways and prognostic biomarkers of SLE. Integrated analyses of RNA-seq data from 64 SLE and 62 healthy controls, examining 27 immune cell types to explore the key pathways and driver genes in SLE pathogenesis. Single-cell RNA sequencing data from the skin and kidney were used to determine the association of COX5A expression with organ damage. The associations of COX5A with SLE phenotypes were further evaluated in two independent cohorts, and receiver operating characteristic (ROC) curves were constructed to assess the value of COX5A as a biomarker for disease activity and organ damage in SLE. We found that oxidative phosphorylation (OXPHOS) is the most significantly altered metabolic pathway in SLE, especially in effector T cells. Notably, we identified an OXPHOS-related enzyme, COX5A, whose expression was significantly higher in effector T cells than in naïve T cells and showed associations with disease activity, organ damage, and steroid treatment of SLE. Furthermore, ROC curves showed that COX5A is a robust biomarker for disease activity, kidney involvement, and new-onset skin lesions, with the area under the curve (AUC) values of 0.880, 0.801, and 0.805, respectively. Our results identified the OXPHOS signature as a prominent feature in SLE T cells, and COX5A as a potential candidate biomarker for disease activity and organ damage in SLE.

A low-energy emulsification platform based on a Diet Coke-Mentos reaction-derived bubbly flow for formulating various emulsions as drug carriers.

The formulation of a drug using high-energy emulsification commonly causes drug deterioration. Exploiting the well-known Diet Coke-Mentos reaction (DCMR), a U-shaped tube reactor that can generate an eruption of bubbly flow that can serve as a low-energy emulsification platform, is proposed. The liquid in the U-tube reactor is a supersaturated solution of aqueous CO2, which mimics Diet Coke. When glass beads with rough surfaces, mimicking Mentos, are dropped into the carbonated water, an eruptive bubbly flow is spontaneously created, mediating effective emulsification at a compound water-oil interface. Experimental results demonstrate that DCMR-mediated bubbly flow may provide a versatile platform for the production of "oil-in-water" or "water-in-oil" droplets and Pickering emulsion composite particles as drug carriers. The DCMR-derived bubbly flow is generated without significant temperature elevation, so the activity of the drug to be emulsified is unaffected. In vivo results reveal the feasibility of using this low-energy emulsification platform to formulate an emulsion system that contains catalase, a temperature-sensitive oxidoreductase, to mitigate an experimentally formed paw inflammation in mice. The as-proposed emulsification platform is attractive for formulating numerous drug delivery systems on a small-scale in a customized manner to meet the needs of each individual for personalized medicine.

Role of the tumor microenvironment in malignant melanoma organoids during the development and metastasis of tumors.

Malignant melanoma (MM) is the most metastatic and aggressive form of skin cancer, and carries a high risk of death. Immune-checkpoint inhibitor therapy and molecular-targeted therapy can prolong the survival of patients with advanced MM significantly. However, the low response rate and inevitable drug resistance prevent further improvements in efficacy, which is closely related to the tumor microenvironment (TME). The TME refers to the tumor stroma, including fibroblasts, keratinocytes, immune cells, soluble molecules, and extracellular matrix (ECM). The dynamic interaction between the TME and tumor cells is very important for the growth, local invasion, and metastatic spread of tumor cells. A patient-derived organoid (PDO) model involves isolation of tumor tissue from patients with MM and culturing it in vitro in a three-dimensional pattern. Compared with traditional cultivation methods, the PDO model preserves the heterogeneity of the tissue structure of MM and demonstrates the interaction between MM cells and the TME. It can reproduce the characteristics of proliferation, migration, and invasion of MM cells, and better simulate the structural function of MM in vivo. This review explores the role of each TME component in development of the PDO model. This review will provide a reference for research on the drug screening and targeted treatment using PDOs, particularly for the immunotherapy of MM.

P2X7R Mediates the Synergistic Effect of ATP and MSU Crystals to Induce Acute Gouty Arthritis.

Activation of the nod-like receptor protein 3 (NLRP3) inflammasome by monosodium urate (MSU) crystals has been identified as the molecular basis for the acute inflammatory response in gouty arthritis. However, MSU crystals alone are not sufficient to induce acute gouty arthritis (AGA). Adenosine triphosphate (ATP) is an endogenous signaling molecule involved in the NLRP3 inflammasome activation. We aimed to explore the role of ATP in MSU crystal-induced AGA development. In peripheral blood mononuclear cell-derived macrophages obtained from gout patients, we observed a synergistic effect of ATP on MSU crystal-induced IL-1ß release. Furthermore, in a rat model of spontaneous gout, we demonstrated that a synergistic effect of ATP and MSU crystals, but not MSU crystals alone, is essential for triggering AGA. Mechanistically, this synergistic effect is achieved through the purinergic receptor P2X7 (P2X7R). Blockade of P2X7R prevented AGA induction in rats after local injection of MSU crystals, and carrying the mutant hP2X7R gene contributed to the inhibition of NLRP3 inflammasome activation induced by costimulation of MSU crystals and ATP in vitro. Taken together, these results support the synergistic effect of ATP on MSU crystal-induced NLRP3 inflammasome activation facilitating inflammatory episodes in AGA. In this process, P2X7R plays a key regulatory role, suggesting targeting P2X7R to be an attractive therapeutic strategy for the treatment of AGA.

Chitosan targets PI3K/Akt/FoxO3a axis to up-regulate FAM172A and suppress MAPK/ERK pathway to exert anti-tumor effect in osteosarcoma.

Osteosarcoma (OS) is a serve and the most frequent primary malignant tumor of bone. Chitosan was reported to have anti-tumor effect on human cancers including OS. However, the molecular mechanism by which chitosan suppresses tumor growth is not fully illustrated. In this study, human OS cell lines, including both Saos-2 and U2OS cells, were used to dissect the underlying mechanisms. RNA sequencing results show that a candidate biomarker family with sequence similarity 172 member A (FAM172A) was up-regulated in both of the two cell lines treated with chitosan. We observed that the mitogen-activated protein kinase (MAPK) signaling pathway could be inactivated by chitosan, and the MAPK inhibition caused by chitosan was reversed by FAM172A knockdown. Moreover, we uncovered a direct interaction between C-terminal domain of FAM172A (311-415) and mitogen-activated protein kinase kinase 1 (MEK1) (270-307) by immunoprecipitation assay. Finally, we also found that chitosan could bind with subunit p85 of PI3K to further inactivate the PI3K/Akt pathway. Taken together, our study demonstrates that chitosan binds with PI3K p85 subunit to suppress the activity of PI3K/Akt pathway to up-regulate the expression of FAM172A, and which exerts its function by suppressing phosphorylation of MEK1/2 and blocking the activity of MAPK/ERK signaling pathway. Taken together, our study deepens the understanding of the molecular mechanism of MAPK/ERK pathway inhibition induced by chitosan, and provides insights into the development of new targets to enhance the pharmacological effect of chitosan against OS.

Causal effects of systemic lupus erythematosus on endometrial cancer: A univariable and multivariable Mendelian randomization study.

Objective: Systemic lupus erythematosus (SLE) has been observationally associated with endometrial cancer, but the causality remains unclear. Here, we investigated for the first time the causal links between SLE and endometrial cancer risk. Methods: Univariable and multivariable Mendelian randomization (MR) analyses were conducted to disentangle the causality of SLE with endometrial cancer. Apart from the inverse-variance weighted (IVW) method as the primary MR estimate, three complementary MR techniques including weighted median, weighted mode, and MR-Egger regression in univariable MR were conducted to clarify the robustness of the causal estimate and mediation effects of the body mass index (BMI) and were investigated within multivariable MR-IVW and MR-Egger analyses. Results: All univariable MR analyses consistently suggested that SLE has a protective effect on the risk of overall endometrial cancer (IVW: OR = 0.956, 95% CI = 0.932-0.981, P = 0.001) and endometrioid endometrial cancer (IVW: OR = 0.965, 95% CI = 0.933-0.999, P = 0.043). More compelling, after adjustment for BMI within the multivariable MR setting, the association between SLE and decreased risk of overall endometrial cancer was significantly stronger (IVW: OR = 0.952, 95% CI = 0.931-0.973, P = 9.58E-06). Conclusions: Our findings provide evidence of a significant causal relationship between SLE and decreased endometrial cancer risk. Further understanding of the underlying mechanisms linking SLE with endometrial cancer is therefore needed.

Bioinformatics methods in biomarkers of preeclampsia and associated potential drug applications.

BACKGROUND: Preeclampsia is a pregnancy-related condition that causes high blood pressure and proteinuria after 20 weeks of pregnancy. It is linked to increased maternal mortality, organ malfunction, and foetal development limitation. In this view, there is a need critical to identify biomarkers for the early detection of preeclampsia. The objective of this study is to discover critical genes and explore medications for preeclampsia treatment that may influence these genes. METHODS: Four datasets, including GSE10588, GSE25906, GSE48424 and GSE60438 were retrieved from the Gene Expression Omnibus database. The GSE10588, GSE25906, and GSE48424 datasets were then removed the batch effect using the "sva" R package and merged into a complete dataset. The differentially expressed genes (DEGs) were identified using the "limma" R package. The potential small-molecule agents for the treatment of PE was further screened using the Connective Map (CMAP) drug database based on the DEGs. Further, Weight gene Co-expression network (WGNCA) analysis was performed to identified gene module associated with preeclampsia, hub genes were then identified using the logistic regression analysis. Finally, the immune cell infiltration level of genes was evaluated through the single sample gene set enrichment analysis (ssGSEA). RESULTS: A total of 681 DEGs (376 down-regulated and 305 up-regulated genes) were identified between normal and preeclampsia samples. Then, Dexamethasone, Prednisone, Rimexolone, Piretanide, Trazodone, Buflomedil, Scoulerin, Irinotecan, and Camptothecin drugs were screened based on these DEGs through the CMAP database. Two modules including yellow and brown modules were the most associated with disease through the WGCNA analysis. KEGG analysis revealed that the chemokine signaling pathway, Th1 and Th2 cell differentiation, B cell receptor signalling pathway and oxytocin signalling pathway were significantly enriched in these modules. Moreover, two key genes, PLEK and LEP were evaluated using the univariate and multivariate logistic regression analysis from the hub modules. These two genes were further validated in the external validation cohort GSE60438 and qRT-PCR experiment. Finally, we evaluated the relationship between immune cell and two genes. CONCLUSION: In conclusion, the present study investigated key genes associated with PE pathogenesis that may contribute to identifying potential biomarkers, therapeutic agents and developing personalized treatment for PE.

Molecular Dynamics and Experimental Investigation on the Interfacial Binding Mechanism in the Fe/Cu1-x-Nix Bimetallic Interface.

To systematically investigate the diffusion behavior of Fe/Cu bimetallic materials and the influence of the Ni element on the diffusion and mechanical properties of the Fe/Cu bimetallic interface, the diffusion distance, diffusion coefficient, and strain-stress process based on molecular dynamics (MD) calculations and experimental testing were analyzed. All simulation results indicated that the liquid Cu matrix had a higher diffusion coefficient but hardly diffused into the Fe matrix, and the solid Fe matrix had a smaller diffusion coefficient but diffused deep into the Cu matrix at the same temperature. Compared with the initial state, the addition of nickel atoms to the Cu matrix favored the improvement of the diffusion coefficient and the diffusion distance of Fe/Cu bimetallic materials. Moreover, we found that the diffusion distance and the yield strength simultaneously increased and then decreased with the increase in Ni atoms, which is in agreement with the experimental test results. These improvements in the diffusion and mechanical properties were attributed to the enrichment of Ni atoms at the interface, but excessive Ni content resulted in deteriorated properties. Finally, our research described the enhancement mechanism of the addition of nickel atoms to the Fe/Cu bimetallic diffusion system. An analysis of the contributions of the diffusion distance, the diffusion coefficient, and the yield strength revealed that the diffusion properties of nickel atoms play an important role in Fe/Cu bimetallic materials.

Effect of Two-Stage Cooling on the Microstructure and Tribological Properties of Steel-Copper Bimetals.

In this paper, the solid-liquid composite method is used to prepare the steel-copper bimetal sample through two-stage cooling process (forced air cooling and oil cooling). The relationship between the different microstructures and friction properties of the bimetal copper layer is clarified. The results show that: the friction and wear parameters are 250 N, the speed is 1500 r/min (3.86 m/s), the friction coefficient fluctuates in the range of 0.06-0.1, and the lowest point is 0.06 at 700 °C. The microstructure of the copper layer was α-Cu, δ, Cu3P, and Pb phases, and Pb was free between α-Cu dendrites. When the solidification temperature is 900 °C, the secondary dendrite of α-Cu develops. With the decrease temperature, the growth of primary and secondary dendrites gradually tends to balance at 700 °C. During the wear process, Pb forms a self-lubricating film uniformly distributed on the surface of α-Cu, and the Cu3P and δ phases are distributed in the wear mark to increase α-Cu wear resistance.

Association of Fpr1 gene expression with osteogenesis and adipogenesis of adipose derived stem cells.

Formyl peptide receptors (Fprs) play fundamental roles in multiple cell functions including promotion of osteogenesis and bone fracture healing. In this study, the role of Fpr1 gene in osteogenic and adipogenic differentiation of adipose derived stem cells (ADSCs) was investigated. Primary ADSCs (mADSCs) from either Fpr1 knockout (KO) or wild type (WT) mice and human ADSCs (hADSCs) were treated by osteogenic (OM) or adipogenic (AM) medium, with basal medium as control. Osteogenesis and adipogenesis were measured by histological and biochemical methods. In both hADSCs and mADSCs, Fpr1 gene expression, osteogenic gene expression, as well as mineralization were increased after osteogenic induction. The osteogenic capacity of KO ADSCs was remarkably reduced compared to WT ADSCs, with decreased levels of expression of osteogenic markers, alkaline phosphatase activity, and mineralization. In contrast, the adipogenesis of KO ADSCs was remarkably enhanced compared with WT ADSCs, forming more lipid droplets, and increasing expression of adipogenic markers PPARγ and aP2. Expression of the nuclear transcription factor Forkhead box protein O1 (FoxO1) was decreased in KO ADSCs, while OM and AM caused increase and decrease in FoxO1 expression, respectively. The current study revealed a correlation of Fpr1 gene expression with osteogenesis and adipogenesis of mADSCs, underlying a mechanism involving FoxO1. Our present research suggests that targeting Fpr1 might be a novel strategy to enhance osteogenesis of ADSCs.

Knockdown of NLE1 inhibits development of malignant melanoma in vitro and in vivo NLE1 promotes development of malignant melanoma.

Melanoma, which originates from neural crest derived melanocytes, causes severe pain and even death to numerous patients. Previous studies reported that Notchless Homolog 1 (NLE1) plays an important role in cell proliferation, transcription and signal transduction. However, the clinical significance and biological behavior of NLE1 in melanoma remain a mystery. Thus, the role of NLE1 in melanoma was investigated in vitro and in vivo. The expression of NLE1 in melanoma was elevated and the expression level was positively correlated with lymphatic metastasis and tumor stage. In addition, NLE1 knockdown by shRNA specifically inhibited proliferation, enhanced the apoptotic sensitivity and hindered migration of melanoma cells in vitro. Mice xenograft model further showed that NLE1 knockdown could inhibit the tumor formation of melanoma in vivo. Additionally, the induction of apoptosis of melanoma cells by NLE1 knockdown required the participation of a series of apoptosis-related proteins. Besides, NLE1 can activate the PI3K/AKT signaling pathway. In summary, NLE1 was involved in the development and progression of melanoma, which may be a novel potential target for molecular therapy of melanoma.

PGT or ICSI? The impression of NGS-based PGT outcomes in nonmosaic Klinefelter syndrome.

This retrospective study demonstrates the clinical outcomes of patients with nonmosaic Klinefelter's syndrome (KS) who underwent preimplantation genetic testing (PGT) with frozen-thawed testicular spermatozoa. Microdissection testicular sperm extraction (micro-TESE) was performed for sperm retrieval. Next-generation sequencing (NGS) was conducted for embryo analysis. A total of 18 couples aged ≤35 years were included, and 22 oocyte retrieval cycles were completed. Euploidy was detected in 29 of 45 (64.4%) embryos. Additionally, the numbers of aneuploid and mosaic embryos detected were 8 (17.8%) and 8 (17.8%), respectively, regardless of a lack of sex chromosome abnormalities. Finally, 13 couples with euploid embryos completed 14 frozen embryo transfer (FET) cycles. Ten couples had clinical pregnancies, and 6 of them had already delivered 5 healthy babies and 1 monozygotic twin. There were also 4 ongoing pregnancies and 2 biochemical pregnancies, but no early pregnancy loss was reported. Based on our results, we speculate that for KS patients, when sperm can be obtained by micro-TESE, the cryopreservation strategy makes the ovarian stimulation procedure more favorable for female partners. The paternal genetic risk of sex chromosome abnormalities in their offspring is extremely low in men with KS. In addition to PGT, the intracytoplasmic sperm injection (ICSI) procedure is comparably effective but more economical for young nonmosaic KS couples. ICSI should be offered as an option for such couples, but monitoring by prenatal genetic diagnosis is recommended.

Pollen-Mimetic Metal-Organic Frameworks with Tunable Spike-Like Nanostructures That Promote Cell Interactions to Improve Antigen-Specific Humoral Immunity.

The exine capsules of pollen particles exhibit a variety of characteristic surface morphologies that promote their cell interactions; their use as antigen carriers for vaccination has been proposed. However, the allergy-causing substances in pollen particles may not all be removed, even by vigorous chemical treatments. To resolve this issue, this work develops systemic approaches for synthesizing pollen-mimetic metal-organic frameworks (MOFs), which comprise aluminum (Al) ions and an organic linker (2-aminoterephthalic acid), with tunable spike-like nanostructures on their surfaces. The as-synthesized MOFs act not only as a delivery vehicle that carries a model antigen (ovalbumin, OVA) but also as an adjuvant (Al). Scanning and transmission electron microscopies images reveal that the aspect ratio of the nanospikes that are grown on the MOFs can be controlled. A higher aspect ratio of the nanospikes on the MOFs is associated with greater cell attachment and faster and more efficient phagocytosis in cells, which results in greater expressions of pro-inflammatory cytokines. Consequently, a more robust immune response against the antigen of interest is elicited. These findings have broad implications for the rational design of the future antigen/adjuvant-presenting particles for vaccination.