Fast fabrication of a hierarchical nanostructured multifunctional ferromagnet.

Materials with multifunctionality affect society enormously. However, the inability to surmount multiple functionality trade-offs limits the discovery of next-generation multifunctional materials. Departing from conventional alloying design philosophy, we present a hierarchical nanostructure (HNS) strategy to simultaneously break multiple performance trade-offs in a material. Using a praseodymium-cobalt (PrCo5) ferromagnet as a proof of concept, the resulting HNS outperforms contemporary high-temperature ferromagnets with a 50 to 138% increase in electrical resistivity while achieving their highest energy density. Our strategy also enables an exceptional thermal stability of coercivity (-0.148%/°C)-a key characteristic for device accuracy and reliability-surpassing that of existing commercial rare-earth magnets. The multifunctionality stems from the deliberately introduced nanohierarchical structure, which activates multiple micromechanisms to resist domain wall movement and electron transport, offering an advanced design concept for multifunctional materials.

Ubiquitin-induced RNF168 condensation promotes DNA double-strand break repair.

Rapid accumulation of repair factors at DNA double-strand breaks (DSBs) is essential for DSB repair. Several factors involved in DSB repair have been found undergoing liquid-liquid phase separation (LLPS) at DSB sites to facilitate DNA repair. RNF168, a RING-type E3 ubiquitin ligase, catalyzes H2A.X ubiquitination for recruiting DNA repair factors. Yet, whether RNF168 undergoes LLPS at DSB sites remains unclear. Here, we identified K63-linked polyubiquitin-triggered RNF168 condensation which further promoted RNF168-mediated DSB repair. RNF168 formed liquid-like condensates upon irradiation in the nucleus while purified RNF168 protein also condensed in vitro. An intrinsically disordered region containing amino acids 460-550 was identified as the essential domain for RNF168 condensation. Interestingly, LLPS of RNF168 was significantly enhanced by K63-linked polyubiquitin chains, and LLPS largely enhanced the RNF168-mediated H2A.X ubiquitination, suggesting a positive feedback loop to facilitate RNF168 rapid accumulation and its catalytic activity. Functionally, LLPS deficiency of RNF168 resulted in delayed recruitment of 53BP1 and BRCA1 and subsequent impairment in DSB repair. Taken together, our finding demonstrates the pivotal effect of LLPS in RNF168-mediated DSB repair.

Identification of immune- and oxidative stress-related signature genes as potential targets for mRNA vaccines for pancreatic cancer patients.

Adenocarcinoma of the pancreas (PAAD) is one of the deadliest malignant tumors, and messenger ribonucleic acid vaccines, which constitute the latest generation of vaccine technology, are expected to lead to new ideas for the treatment of pancreatic cancer. The Cancer Genome Atlas-PAAD and Genotype-Tissue Expression data were merged and analyzed. Weighted gene coexpression network analysis was used to identify gene modules associated with tumor mutational burden among the genes related to both immunity and oxidative stress. Differentially expressed immune-related oxidative stress genes were screened via univariate Cox regression analysis, and these genes were analyzed via nonnegative matrix factorization. After immune infiltration analysis, least absolute shrinkage and selection operator regression combined with Cox regression was used to construct the model, and the usefulness of the model was predicted based on the receiver operating characteristic curve and decision curve analysis curves after model construction. Finally, metabolic pathway enrichment was analyzed using gene set enrichment analysis combined with Kyoto Encyclopedia of Genes and Genomes and gene ontology biological process analyses. This model consisting of the ERAP2, mesenchymal-epithelial transition factor (MET), CXCL9, and angiotensinogen (AGT) genes can be used to help predict the prognosis of pancreatic cancer patients more accurately than existing models. ERAP2 is involved in immune activation and is important in cancer immune evasion. MET binds to hepatocyte growth factor, leading to the dimerization and phosphorylation of c-MET. This activates various signaling pathways, including MAPK and PI3K, to regulate the proliferation, invasion, and migration of cancer cells. CXCL9 overexpression is associated with a poor patient prognosis and reduces the number of CD8 + cytotoxic T lymphocytes in the PAAD tumor microenvironment. AGT is cleaved by the renin enzyme to produce angiotensin 1, and AGT-converting enzyme cleaves angiotensin 1 to produce angiotensin 2. Exposure to AGT-converting enzyme inhibitors after pancreatic cancer diagnosis is associated with improved survival. The 4 genes identified in the present study - ERAP2, MET, CXCL9, and AGT - are expected to serve as targets for messenger ribonucleic acid vaccine development and need to be further investigated in depth.

Dehydroepiandrosterone promotes ovarian angiogenesis and improves ovarian function in a rat model of premature ovarian insufficiency by up-regulating HIF-1α/VEGF signalling.

RESEARCH QUESTION: What impact does dehydroepiandrosterone (DHEA) have on ovarian angiogenesis and function in a rat model of with premature ovarian insufficiency (POI), and what are the potential mechanisms of action? DESIGN: DHEA was added to a culture of human microvascular endothelial cells (HMEC-1) to investigate its effects on cell proliferation, migration and tube formation. A rat model of POI was established by intraperitoneal injection of cyclophosphamide, followed by continuous oral administration of DHEA or vehicle for 28 days. Ovarian angiogenesis, follicular growth and granulosa cell survival in ovarian tissues were assessed through haematoxylin and eosin staining, immunohistochemistry and TdT (terminal deoxynucleotidyl transferase)-mediated dUTP nick-end labelling (TUNEL). The effect of DHEA on the fertility of rats with POI was evaluated in pregnant animals. The expression levels of characteristic genes and proteins in the hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) pathway was determined using quantitative reverse transcription PCR and western blotting. RESULTS: In-vitro experiments revealed that DHEA stimulated the proliferation, migration and tube formation of HMEC-1. In in-vivo studies, DHEA treatment improved the disruption of the oestrous cycle and hormone imbalances in POI rats. Key genes in the HIF-1α/VEGF pathway exhibited up-regulated expression, promoting ovarian angiogenesis in POI rats, and enhancing follicular development and granulosa cell survival, thereby restoring fertility in rats. CONCLUSIONS: DHEA can potentially restore ovarian function in rats with cyclophosphamide-induced POI by up-regulating HIF-1α/VEGF signalling, which promotes the growth of blood vessels in the ovaries.

The impact of thyroid autoimmunity on pregnancy outcomes in women with unexplained infertility undergoing intrauterine insemination: a retrospective single-center cohort study and meta-analysis.

Introduction: Infertility affects 8-12% of couples worldwide, with 15-30% classified as unexplained infertility (UI). Thyroid autoimmunity (TAI), the most common autoimmune disorder in women of reproductive age, may impact fertility and pregnancy outcomes. However, the underlying mechanism is unclear. This study focuses on intrauterine insemination (IUI) and its potential association with TAI in UI patients. It is the first meta-analysis following a comprehensive literature review to improve result accuracy and reliability. Methods: Retrospective cohort study analyzing 225 women with unexplained infertility, encompassing 542 cycles of IUI treatment. Participants were categorized into TAI+ group (N=47, N= 120 cycles) and TAI- group (N=178, N= 422 cycles). Additionally, a systematic review and meta-analyses following PRISMA guidelines were conducted, incorporating this study and two others up to June 2023, totaling 3428 IUI cycles. Results: Analysis revealed no significant difference in independent variables affecting reproductive outcomes. However, comparison based on TAI status showed significantly lower clinical pregnancy rates (OR: 0.43, P= 0.028, 95%CI: 0.20-0.93) and live birth rate (OR: 0.20, P= 0.014, 95%CI: 0.05 ~ 0.71) were significantly lower than TAI- group. There was no significant difference in pregnancy rate between the two groups (OR: 0.61, P= 0.135, 95%CI: 0.32-1.17). However, the meta-analysis combining these findings across studies did not show statistically significant differences in clinical pregnancy rates (OR:0.77, P=0.18, 95%CI: 0.53-1.13) or live birth rates (OR: 0.68, P=0.64, 95%CI: 0.13-3.47) between the TAI+ and TAI- groups. Discussion: Our retrospective cohort study found an association between TAI and reduced reproductive outcomes in women undergoing IUI for unexplained infertility. However, the meta-analysis incorporating other studies did not yield statistically significant associations. Caution is required in interpreting the relationship between thyroid autoimmunity and reproductive outcomes. Future studies should consider a broader population and a more rigorous study design to validate these findings. Clinicians dealing with women with unexplained infertility and TAI should be aware of the complexity of this field and the limitations of available evidence.

MoMkk1 and MoAtg1 dichotomously regulating autophagy and pathogenicity through MoAtg9 phosphorylation in Magnaporthe oryzae.

Autophagy is a central biodegradation pathway critical in eliminating intracellular cargo to maintain cellular homeostasis and improve stress resistance. At the same time, the key component of the mitogen-activated protein kinase cascade regulating cell wall integrity signaling MoMkk1 has an essential role in the autophagy of the rice blast fungus Magnaporthe oryzae. Still, the mechanism of how MoMkk1 regulates autophagy is unclear. Interestingly, we found that MoMkk1 regulates the autophagy protein MoAtg9 through phosphorylation. MoAtg9 is a transmembrane protein subjected to phosphorylation by autophagy-related protein kinase MoAtg1. Here, we provide evidence demonstrating that MoMkk1-dependent MoAtg9 phosphorylation is required for phospholipid translocation during isolation membrane stages of autophagosome formation, an autophagic process essential for the development and pathogenicity of the fungus. In contrast, MoAtg1-dependent phosphorylation of MoAtg9 negatively regulates this process, also impacting growth and pathogenicity. Our studies are the first to demonstrate that MoAtg9 is subject to MoMkk1 regulation through protein phosphorylation and that MoMkk1 and MoAtg1 dichotomously regulate autophagy to underlie the growth and pathogenicity of M. oryzae.IMPORTANCEMagnaporthe oryzae utilizes multiple signaling pathways to promote colonization of host plants. MoMkk1, a cell wall integrity signaling kinase, plays an essential role in autophagy governed by a highly conserved autophagy kinase MoAtg1-mediated pathway. How MoMkk1 regulates autophagy in coordination with MoAtg1 remains elusive. Here, we provide evidence that MoMkk1 phosphorylates MoAtg9 to positively regulate phospholipid translocation during the isolation membrane or smaller membrane structures stage of autophagosome formation. This is in contrast to the negative regulation of MoAtg9 by MoAtg1 for the same process. Intriguingly, MoMkk1-mediated MoAtg9 phosphorylation enhances the fungal infection of rice, whereas MoAtg1-dependant MoAtg9 phosphorylation significantly attenuates it. Taken together, we revealed a novel mechanism of autophagy and virulence regulation by demonstrating the dichotomous functions of MoMkk1 and MoAtg1 in the regulation of fungal autophagy and pathogenicity.

Impact of oil-based contrast agents in hysterosalpingography on fertility outcomes in endometriosis: a retrospective cohort study.

BACKGROUND: Previous studies have suggested that oil-based contrast agents used during hysterosalpingography (HSG) in infertile patients can enhance fertility. However, limited research has investigated the effect of oil-based contrast medium specifically in individuals with endometriosis-related infertility. OBJECTIVE: This study aims to explore the impact of oil-based contrast medium on fertility outcomes in women with endometriosis-related infertility. METHODS: Conducted at the First Affiliated Hospital of Guangxi Medical University (January 2020 to June 2022), the study included 512 patients undergoing HSG. Patients were categorized into oil-based and non-oil-based groups, and after propensity score matching, demographic characteristics were compared. Main outcomes included clinical pregnancy rates, live birth rates, early miscarriage rates, and ectopic pregnancy rates. RESULTS: In our analysis, the Oil-based group showed significantly better outcomes compared to the Non-oil-based group. Specifically, the Oil-based group had higher clinical pregnancy rates (51.39% vs. 27.36%) and increased live birth rates (31.48% vs. 19.93%). This trend held true for expectant treatment, IUI, and IVF/ICSI, except for surgical treatment where no significant difference was observed. After adjusting for various factors using propensity score matching, the Non-oil-based group consistently exhibited lower clinical pregnancy rates compared to the Oil-based group. The Odds Ratio (OR) was 0.38 (95%CI: 0.27-0.55) without adjustment, 0.34 (0.22-0.51) in multivariable analysis, 0.39 (0.27-0.57) using inverse probability of treatment weighting (IPTW), and 0.22 (0.14-0.35) in propensity score matching. CONCLUSION: Oil-based contrast medium used in HSG for women with endometriosis-related infertility is associated with higher clinical pregnancy rates and live birth rates compared to Non-oil-based contrast medium.

Precision USPIO-PEG-SLex Nanotheranostic Agent Targeted Photothermal Therapy for Enhanced Anti-PD-L1 Immunotherapy to Treat Immunotherapy Resistance.

Background: The anti-Programmed Death-Ligand 1 (termed aPD-L1) immune checkpoint blockade therapy has emerged as a promising treatment approach for various advanced solid tumors. However, the effect of aPD-L1 inhibitors limited by the tumor microenvironment makes most patients exhibit immunotherapy resistance. Methods: We conjugated the Sialyl Lewis X with a polyethylene glycol-coated ultrasmall superparamagnetic iron oxide (USPIO-PEG) to form UPS nanoparticles (USPIO-PEG-SLex, termed UPS). The physicochemical properties of UPS were tested and characterized. Transmission electron microscopy and ICP-OES were used to observe the cellular uptake and targeting ability of UPS. Flow cytometry, mitochondrial membrane potential staining, live-dead staining and scratch assay were used to verify the in vitro photothermal effect of UPS, and the stimulation of UPS on immune-related pathways at the gene level was analyzed by sequencing. Biological safety analysis and pharmacokinetic analysis of UPS were performed. Finally, the amplification effect of UPS-mediated photothermal therapy on aPD-L1-mediated immunotherapy and the corresponding mechanism were studied. Results: In vitro experiments showed that UPS had strong photothermal therapy ability and was able to stimulate 5 immune-related pathways. In vivo, when the PTT assisted aPD-L1 treatment, it exhibited a significant increase in CD4+ T cell infiltration by 14.46-fold and CD8+ T cell infiltration by 14.79-fold, along with elevated secretion of tumor necrosis factor-alpha and interferon-gamma, comparing with alone aPD-L1. This PTT assisted aPD-L1 therapy achieved a significant inhibition of both primary tumors and distant tumors compared to the alone aPD-L1, demonstrating a significant difference. Conclusion: The nanotheranostic agent UPS has been introduced into immunotherapy, which has effectively broadened its application in biomedicine. This photothermal therapeutic approach of the UPS nanotheranostic agent enhancing the efficacy of aPD-L1 immune checkpoint blockade therapy, can be instructive to address the challenges associated with immunotherapy resistance, thereby offering potential for clinical translation.

Injectable collagen hydrogel combines human umbilical cord mesenchymal stem cells to promote endometrial regeneration in rats with thin endometrium.

The regeneration of thin endometrium still remains as a great challenge in the field of reproductive medicine. Stem cells-based therapy has been considered as a promising strategy for the restoration of thin endometrium. However, the low transplantation and retention rate of stem cells and loss of stemness due to in vitro expansion limits the therapeutic efficacy. In our study, we combined collagen hydrogel and human umbilical cord mesenchymal stem cells (uMSCs) for improving the regeneration of thin endometrium, by using the potent pluripotency and low immunogenicity of uMSCs and collagen hydrogel that promotes the anchorage and proliferation of stem cells. Results showed that collagen hydrogel has favorable biocompatibility and the capacity to enhance the cell viability and expression of stemness-associated genes (including organic cation/carnitine transporter4 (Oct-4), Nanog homeobox (Nanog) and SRY-box transcription factor 2 (SOX2)) of uMSCs. The combination of collagen hydrogel and uMSCs prolonged the retention time of the constructs in the uterine cavity and improved endometrial thickness compared with uMSCs alone, leading to increase the fertility of the rats with thin endometrium. These highlighted therapeutic prospects of collagen hydrogel combined with uMSCs for the minimally invasive therapy of thin endometrium in the clinic.

Carbon dot/g-C3N4-mediated self-activated antimicrobial nanocomposite films for active packaging applications.

A novel carbon dot/g-C3N4 nanocomposite (CCN) exhibiting enhanced photocatalytic activity was developed and used as a photoactive nanofiller to construct corn starch/carboxymethyl cellulose (CS/CMC)-based functional films. The morphologies and structures of the CCN-CS/CMC composite films were investigated with scanning electron microscopy, Fourier transform infrared spectroscopy and X-ray diffraction. The effects of the CCN on the physicochemical properties and antibacterial activities of the films were analyzed. The properties of the films were optimized with the addition of CCN (0.20 mg/mL), and the tensile strength of the film was increased to 11.9 MPa and the water contact angle was increased to 103.39°. The optimal active film showed > 99.9 % antibacterial efficiencies against Escherichia coli and Staphylococcus aureus under visible light and prolonged the shelf lives of bananas for more than four days compared to the 4-day shelf life of the control. This work provides a novel route for developing antimicrobial active packaging.

Reinforcement Learning-Based Fractional-Order Adaptive Fault-Tolerant Formation Control of Networked Fixed-Wing UAVs With Prescribed Performance.

This article investigates the fault-tolerant formation control (FTFC) problem for networked fixed-wing unmanned aerial vehicles (UAVs) against faults. To constrain the distributed tracking errors of follower UAVs with respect to neighboring UAVs in the presence of faults, finite-time prescribed performance functions (PPFs) are developed to transform the distributed tracking errors into a new set of errors by incorporating user-specified transient and steady-state requirements. Then, the critic neural networks (NNs) are developed to learn the long-term performance indices, which are used to evaluate the distributed tracking performance. Based on the generated critic NNs, actor NNs are designed to learn the unknown nonlinear terms. Moreover, to compensate for the reinforcement learning errors of actor-critic NNs, nonlinear disturbance observers (DOs) with skillfully constructed auxiliary learning errors are developed to facilitate the FTFC design. Furthermore, by using the Lyapunov stability analysis, it is shown that all follower UAVs can track the leader UAV with predesigned offsets, and the distributed tracking errors are finite-time convergent. Finally, comparative simulation results are presented to show the effectiveness of the proposed control scheme.

Assessing the impact of transplant site on ovarian tissue transplantation: a single-arm meta-analysis.

BACKGROUND: Survival rates of young women undergoing cancer treatment have substantially improved, with a focus on post-treatment quality of life. Ovarian tissue transplantation (OTT) is a viable option to preserve fertility; however, there is no consensus on the optimal transplantation site. Most studies on OTT are nonrandomized controlled trials with limited sample sizes and uncontrolled statistical analyses, leaving the question of which transplant site yields the highest chance of achieving a live birth unanswered. OBJECTIVE: This meta-analysis aimed to assess the effect of different ovarian transplant sites on postoperative reproductive outcomes. METHODS: We adhered to the PRISMA Reporting Items for Systematic Reviews and Meta-Analyses recommendations. Systematic searches were conducted in PubMed, Embase, Web of Science, and the Cochrane Library from inception to September 17, 2023. The inclusion criteria were as follows: (1) women who underwent OTT with a desire for future childbirth, and (2) reports of specific transplant sites and corresponding pregnancy outcomes. The exclusion criteria included the inability to isolate or extract relevant outcome data, case reports, non-original or duplicate data, and articles not written in English. RESULTS: Twelve studies (201 women) were included in the meta-analysis of cumulative live birth rates (CLBR) after OTT. The CLBR, which encompasses both spontaneous pregnancies and those achieved through assisted reproductive technology (ART) following OTT to the ovarian site, was 21% (95% CI: 6-40, I2: 52.81%, random effect). For transplantation to the pelvic site, the live birth rate was 30% (95% CI: 20-40, I2: 0.00%, fixed effect). Combining transplantation to both the pelvic and ovarian sites resulted in a live birth rate of 23% (95% CI: 11-36, I2: 0.00%, fixed effect). Notably, heterotopic OTT yielded a live birth rate of 3% (95% CI: 0-17, I2: 0.00%, fixed effect). CONCLUSION: Pregnancy outcomes were not significantly different after orthotopic ovarian transplantation, and pregnancy and live birth rates after orthotopic OTT were significantly higher than those after ectopic transplantation. REGISTRATION NUMBER: INPLASY202390008.

LMP2 and TAP2 impair tumor growth and metastasis by inhibiting Wnt/ß-catenin signaling pathway and EMT in cervical cancer.

BACKGROUND: The roles of low molecular mass polypeptide 2 (LMP2) and transporter-associated with antigen processing (TAP2) in tumorigenesis are controversial. Here we aimed to explore the effect of LMP2 and TAP2 on the oncogenesis and metastasis of cervical cancer cells. METHODS: The expressions of LMP2 and TAP2 in cervical cancer and normal tissues were determined by qPCR. Plate colony formation, cell counting kit-8 analysis and in vivo tumor xenograft assays were used to detect the tumor growth. Wound healing and transwell assays were used to detect the metastasis of cervical cancer. Gelatin zymography and western blotting assays were used to detect the effect of LMP2 and TAP2 on the EMT and Wnt/ß-catenin pathway in cervical cancer cells. RESULTS: In the present study, we reported that LMP2 and TAP2 levels were overexpressed in cervical cancer. Overexpression of LMP2 and TAP2 impaired the proliferation of Hela cells. In vivo studies substantiated that LMP2 and TAP2 antagonized tumor growth. Likewise, LMP2 and TAP2 overexpression decreased the migration and invasion ability of Hela cells by regulating the process of epithelial-mesenchymal transition (EMT). Mechanically, LMP2 and TAP2 subverted the protein abundance of Wnt1 and ß-catenin, thereby downregulating their downstream targets Cyclin D1 and c-Myc. In addition, Wnt1 overexpression partially rescued the observed consequences of ectopic expression of LMP2 and TAP2 in cervical cancer cells. Taken together, our study revealed that LMP2 and TAP2 suppress the oncogenesis and metastasis of cervical cancer cells by Wnt/ß-catenin pathway and altering EMT. CONCLUSION: LMP2 and TAP2 may inhibit the oncogenesis and metastasis of cervical cancer cells by inhibiting the process of EMT and the Wnt/ß-catenin signaling pathway, which may provide important insight into prospective targets for the treatment of cervical cancer.

Eggshell waste act as multifunctional fillers overcoming the restrictions of starch-based films.

Starch has great potential to replace petroleum-based plastics in food packaging applications. However, starch films often exhibit poor mechanical and barrier properties, and are vulnerable to moisture and bacterial contamination. This study proved that the incorporation of eggshell powder (ES) enhanced the hydrogen bonding in starch-based films significantly, which contributed to improved tensile strength, Young's modulus, and water resistance of the films. The performance of ES-incorporated films could be optimized by adjusting the size, concentration, and surface property of ES in the film matrix. Notably, adsorbing epigallocatechin gallate (EGCG) on the surface of porous ES contributed to enhanced dispersibility of the fillers in the film matrix, which increased the tortuous path of light, water vapor, and oxygen have to take through the films, resulting in increased UV screening performance, water vapor and oxygen barrier property of the films by 60 %, 7.2 %, and 27.9 %, respectively. Meanwhile, loading EGCG in ES also enable superior antibacterial activity of the final films. This study suggests that eggshell fillers offer a sustainable means of improving the functional performance of starch-based films, which may increase their application as packaging materials in the food industry.

Dynamical analysis of a glucose-insulin regulatory system with insulin-degrading enzyme and multiple delays.

This paper investigates the dynamics of a glucose-insulin regulatory system model that incorporates: (1) insulin-degrading enzyme in the insulin equation; and (2) discrete time delays respectively in the insulin production term, hepatic glucose production term, and the insulin-degrading enzyme. We provide rigorous results of our model including the asymptotic stability of the equilibrium solution and the existence of Hopf bifurcation. We show that analytically and numerically at a certain value the time delays driven stability or instability occurs when the corresponding model has an interior equilibrium. Moreover, we illustrate the oscillatory regulation and insulin secretion via numerical simulations, which show that the model dynamics exhibit physiological observations and more information by allowing parameters to vary. Our results may provide useful biological insights into diabetes for the glucose-insulin regulatory system model.

Characterization of site-specific N-glycosylation signatures of isolated uromodulin from human urine.

Uromodulin (Umod, Tamm-Horsfall protein) is the most abundant urinary N-glycoprotein produced exclusively by the kidney. It can form filaments to antagonize the adhesion of uropathogens. However, the site-specific N-glycosylation signatures of Umod in healthy individuals and patients with IgA nephropathy (IgAN) remain poorly understood due to the lack of suitable isolation and analytical methods. In this study, we first presented a simple and fast method based on diatomaceous earth adsorption to isolate Umod. These isolated glycoproteins were digested by trypsin and/or Glu-C. Intact N-glycopeptides with or without HILIC enrichment were analyzed using our developed EThcD-sceHCD-MS/MS. Based on the optimized workflow, we identified a total of 780 unique intact N-glycopeptides (7 N-glycosites and 152 N-glycan compositions) from healthy individuals. As anticipated, these glycosites exhibited glycoform heterogeneity. Almost all N-glycosites were modified completely by the complex type, except for one N-glycosite (N275), which was nearly entirely occupied by the high-mannose type for mediating Umod's antiadhesive activity. Then, we compared the N-glycosylation of Umod between healthy controls (n = 9) and IgAN patients (n = 9). The N-glycosylation of Umod in IgAN patients will drastically decrease and be lost. Finally, we profiled the most comprehensive site-specific N-glycosylation map of Umod and revealed its alterations in IgAN patients. Our method provides a high-throughput workflow for characterizing the N-glycosylation of Umod, which can aid in understanding its roles in physiology and pathology, as well as serving as a potential diagnostic tool for evolution of renal tubular function.

Aquaporin 9 causes recurrent spontaneous abortion by inhibiting trophoblast cell epithelial-mesenchymal transformation and invasion through the PI3K/AKT pathway†.

BACKGROUND: Invasion of the endometrium by trophoblast cells is a key event during pregnancy, although the underlying mechanism remains unclear. Aquaporin 9 (AQP 9) is expressed in many eukaryotes and is associated with cell invasion. The objective of this study was to evaluate the significance of AQP9 in recurrent spontaneous abortion. METHODS: We screened the GSE22490 dataset and further differentiated aquaporin 9 expression in villi. AQP9 was evaluated as one of the key factors in abortion by injecting AQP9 overexpressed plasmid into the uterus of CD1 mice. Trophoblast cells were transfected with AQP9-overexpressing plasmid or siAQP9 to measure cell proliferation, migration, invasion, and apoptosis. Western blot was used to measure changes in the expression of invasion, epithelial-mesenchymal transformation process, and PI3K/AKT pathway. Finally, the role of AQP9 in PI3K/AKT signaling pathway was determined using the PI3K/AKT inhibitor, LY294002, and activator, 740Y-P. RESULTS: AQP9 is highly expressed in recurrent spontaneous abortion villus. Intrauterine injections of AQP9-overexpressing plasmid into CD1 mice resulted in atrophy and blackness of the gestational sac and increased the absorption rate, it is the causative factor of abortion. AQP9 upregulation inhibited the proliferation, invasion, migration, and epithelial-mesenchymal transformation process in vitro of trophoblast cells and increased cell apoptosis. The opposite result was observed after silencing AQP9. AQP9 overexpression also inhibited the PI3K/AKT pathway. LY294002 and 740Y-P partially recovered AQP9-induced trophoblast invasion and migration via the PI3K/AKT pathway. CONCLUSIONS: AQP9 reduces the invasive ability of trophoblast cells by regulating PI3K/AKT signaling pathway, participating in recurrent spontaneous abortion.

Anatase TiO2-x and zwitterionic porphyrin polymer-based nanocomposite for enhanced cancer photodynamic therapy.

Photodynamic therapy has been used as a treatment option for cancer; however, the existing TiO2 photosensitizer does not have the ability to specifically target cancer cells. This lack of selectivity reduces its effectiveness in overcoming cancer resistance. To improve photodynamic therapy outcomes, an innovative solution is proposed. In this study, we report on the compounding of a zwitterionic covalent organic polymer (COP) with a TiO2 photosensitizer for the first time. The aim is to overcome cancer cellular resistance. A one-pot synthetic strategy, which includes the construction of a porphyrin-based COP has been employed. This strategy has also been applied to the rapid preparation of anatase defective TiO2 (TiO2-x). To improve the hydrophilic and antifouling properties of the polymer, zwitterion L-cysteine has been conjugated with a porphyrin-based COP using a thiol-ene "click chemistry" reaction. The novel zwitterionic porphyrin-based COP has the ability to trigger biodegradation under the acid microenvironment due to the presence of acid-sensitive ß-thioether esters. When combined with TiO2-x, the resultant nanocomposite produces an enhanced photodynamic therapy effect for drug-resistant cancer cells under NIR laser irradiation. This is due to the strong mutual sensitization of zwitterionic porphyrin-based COP and TiO2-x. Importantly, the nanocomposite delivery system exhibits excellent cytocompatibility in the dark and has the potential to improve the accuracy of cancer diagnosis through fluorescence imaging. The results of this study demonstrate the potential application of this alternative nanocomposite delivery system for remote-controllable photodynamic therapy of tumors.

Field-free spin-orbit torque switching in interlayer exchange coupled Co/Ta/CoTb.

This study investigates a T-type field-free spin-orbit torque device with an in-plane magnetic layer coupled to a perpendicular magnetic layer via a non-magnetic spacer. The device utilizes a Co/Ta/CoTb structure, in which the in-plane Co layer and the perpendicular CoTb layer are ferromagnetically (FM) coupled through the Ta spacer. 'T-type' refers to the magnetization arrangement in the FM/spacer/FIM structure, where the magnetization in FM is in-plane, while in FIM, it is out-of-plane. This configuration forms a T-shaped arrangement for the magnetization of the two magnetic layers. Additionally, 'interlayer exchange coupling (IEC)' denotes the interaction between the two magnetic layers, which is achieved by adjusting the material and thickness of the spacer. Our results show that an in-plane effective field from the IEC enables deterministic current-induced magnetization switching of the CoTb layer. The field-driven and the current-driven asymmetric domain wall motion are observed and characterized by magneto-optic Kerr effect measurements. The functionality of multistate synaptic plasticity is demonstrated by understanding the relationship between the anomalous Hall resistance and the applied current pulses, indicating the potential for the device in spintronic memory and neuromorphic computing.

Combined oral antibiotics and intrauterine perfusion can improve in vitro fertilization and embryo transfer pregnancy outcomes in patients with chronic endometritis and repeated embryo implantation failure.

BACKGROUND: The aim of this retrospective study was to investigate whether oral antibiotics (doxycycline and metronidazole) combined with intrauterine perfusion (gentamicin and dexamethasone) are beneficial for patients with repeated implantation failure (RIF) and chronic endometritis (CE) to improve clinical pregnancy outcomes. METHODS: Patients with RIF and CE were diagnosed using hysteroscopy and histology together. A total of 42 patients were enrolled in the study. All patients received oral antibiotics (doxycycline combined with metronidazole) and 22 patients underwent intrauterine perfusion (gentamicin combined with dexamethasone) immediately after the end of oral antibiotic therapy. Pregnancy outcomes were evaluated during the first in vitro fertilization (IVF) and embryo transfer (ET) cycle. RESULTS: For the first D3 ET after treatment with oral antibiotics (doxycycline and metronidazole) combined with intrauterine perfusion (gentamicin and dexamethasone), higher embryo implantation rate (30.95% vs. 26.67%, P = 0.0308), clinical pregnancy rate (30% vs. 50%, P < 0.001), live birth rate (33.33% vs. 45.45%, P < 0.0001). No fetal malformations or ectopic pregnancies were observed. CONCLUSION: We report oral antibiotics (doxycycline and metronidazole) combined with intrauterine perfusion (gentamicin and dexamethasone) as a novel treatment for CE to improve the outcomes of successful pregnancy compared with those of oral antibiotics alone.