Early determination of potential critical quality attributes of therapeutic antibodies in developability studies through surface plasmon resonance-based relative binding activity assessment.

Precise measurement of the binding activity changes of therapeutic antibodies is important to determine the potential critical quality attributes (CQAs) in developability assessment at the early stage of antibody development. Here, we report a surface plasmon resonance (SPR)-based relative binding activity method, which incorporates both binding affinity and binding response and allows us to determine relative binding activity of antibodies with high accuracy and precision. We applied the SPR-based relative binding activity method in multiple forced degradation studies of antibody developability assessment. The current developability assessment strategy provided comprehensive, precise characterization of antibody binding activity in the stability studies, enabling us to perform correlation analysis and establish the structure-function relationship between relative binding activity and quality attributes. The impact of a given quality attribute on binding activity could be confidently determined without isolating antibody variants. We identified several potential CQAs, including Asp isomerization, Asn deamidation, and fragmentation. Some potential CQAs affected binding affinity of antibody and resulted in a reduction of binding activity. Certain potential CQAs impaired antibody binding to antigen and led to a loss of binding activity. A few potential CQAs could influence both binding affinity and binding response and cause a substantial decrease in antibody binding activity. Specifically, we identified low abundance Asn33 deamidation in the light chain complementarity-determining region as a potential CQA, in which all the stressed antibody samples showed Asn33 deamidation abundances ranging from 4.2% to 27.5% and a mild binding affinity change from 1.76 nM to 2.16 nM.

Frailty and post-transplant adverse outcomes among kidney transplant recipients: A systematic review and meta-analysis.

INTRODUCTION: Frailty is a good predictor of adverse outcomes among older patients, especially those who have undergone surgery. The prevalence of frailty among kidney transplant candidates is higher than the general population. This study aimed to explore the predictive value of frailty on post-transplant adverse outcomes among kidney recipients. METHODS: A systematic review was performed for relevant studies until May 20, 2022, using four databases (Embase, Medline, Cochrane, and PsycINFO) for prospective design studies (PROSPERP: CRD42022331022). Random-effect meta-analysis modeling was undertaken in RevMan 5.3 to estimate the predicting value of frailty on adverse outcomes after kidney transplant. RESULTS: This systematic review included 14 studies, eight of which were suitable for meta-analysis. Frailty increased the risk of mortality (pooled hazard ratio [HR] 1.98, 95% confidence interval [CI] 1.48-2.64), surgical complications (risk ratio [RR] 2.14, 95% CI 1.01-4.54), death-censored graft failure (DCGF) (pooled HR 3.31, 95% CI 1.27-8.62), length of stay (LOS) (pooled RR 1.59, 95% CI 1.05-2.39), length of stay ≥2 weeks (pooled odds ratio [OR] 1.72, 95% CI 1.26-2.35). and other common adverse outcomes among kidney transplant recipients. CONCLUSIONS: Frailty is associated with adverse outcomes after kidney transplant. This systematic review suggests the importance of assessing frailty among kidney transplant candidates prior to transplantation. Further research focusing on pretransplant assessment combined with frailty is warranted to improve kidney transplant management.

Effects of low-dose methotrexate with MMI in patients with Graves' disease: results of a randomized clinical trial.

CONTEXT: Supplemental methotrexate (MTX) may affect the clinical course of Graves' disease (GD). OBJECTIVE: Evaluate efficacy of add-on MTX on medical treatment in GD. DESIGN: Prospective, open-label, randomized supplementation controlled trial. SETTING: Academic endocrine outpatient clinic. PATIENTS: One hundred and fifty-three untreated hyperthyroid patients with GD. INTERVENTION: Patients received MTX 10 mg/d with methimazole (MMI) or MMI only. MTX and MMI were discontinued at months 12-18 in euthyroid patients. MAIN OUTCOME MEASURES: Discontinuation rate at months 18 in each group. RESULTS: In the MTX with MMI group, the discontinuation rate was higher than the MMI group at months 15-18 (50.0 vs. 33.3%, P=0.043, 95% CI 1.020 to 3.922; and 55.6 vs 38.9%, P=0.045, 95%CI 1.011 to 3.815, respectively). The decrease in TRAb levels in the MTX with MMI group was significant from baseline to months 6 compared to the MMI alone group [MTX+MMI 67.22% (43.12-80.32), MMI 54.85% (33.18-73.76), P= 0.039) and became more significant from months 9 [MTX+MMI 77.79% (62.27-88.18), MMI 69.55% (50.50-83.22), P= 0.035] to months 18 (P < 0.01 in 15-18 months). A statistically significant difference between the levels of TRAb in the MTX with MMI group and the MMI group at 9-18 months. There were no significant differences in the levels of FT3, FT4 and TSH between two groups. No serious drug-related adverse events were observed in both groups(P=0.771). CONCLUSIONS: Supplemental MTX with MMI resulted in higher discontinuation rate and improvement in decreased TRAb levels to homeostatic levels faster than methimazole treatment alone at months 12-18.

Transcriptomic Analysis Reveals the Flavonoid Biosynthesis Pathway Involved in Rhizome Development in Polygonatum cyrtonema Hua.

Polygonatum cyrtonema Hua (P. cyrtonema) rhizomes are rich in flavonoids and other secondary metabolites, exhibiting remarkable antioxidant, anti-tumor, and immunomodulatory effects. Polygonatum flavonoid-biosynthesis-related genes have been characterized already. However, a comprehensive overview of Polygonatum flavonoid biosynthesis pathways is still absent. To articulate the accumulation of the flavonoid biosynthesis pathways, we examined transcriptome changes using Illumina HiSeq from five different tissues and the RNA-seq of 15 samples had over 105 Gb of a clean base, generating a total of 277,955 unigenes. The cDNA libraries of the fruits (F), leaves (L), roots (R), stems (S), and rhizomes (T) of three-year-old P. cyrtonema plants generated 57,591, 53,578, 60,321, 51,530, and 54,935 unigenes. Comparative transcriptome analysis revealed that 379 differentially expressed genes (DEGs) were in the group of F _vs_ T, L _vs_ T, R _vs_ T, and S _vs_ T, and the transcripts of flavonoid-biosynthesis-related DEGs were principally enriched in rhizomes. In addition, combined with WGCNA and the FPKM of five tissues' transcription, nine differentially expressed transcription factor families (MYB, WRKY, AP2/ERF, etc.) were characterized in the red module, the red module positively correlated with rhizome flavonoid accumulation. Quantitative real-time PCR (qRT-PCR) further indicated that BZIP1, C3H31, ERF114, and DREB21 are differentially expressed in rhizomes, accompanied in rhizome development in P. cyrtonema. Therefore, this study provides a foundation for further research into uncovering the accumulation of flavonoid biosynthesis in the rhizomes of P. cyrtonema.

In vitro generation of trophoblast like stem cells from goat pluripotent stem cells.

Since the first mouse induced pluripotent stem cells (iPSCs) was derived, the in vitro culture of domestic iPSCs functionally and molecularly comparable with mouse iPSCs has been a challenge. Here, we established dairy goat iPSCs (giPSCs) from goat ear fibroblast cells with mouse iPSCs morphology, the expression of pluripotent markers and differentiation ability in vitro delivered by piggyBac transposon with nine Dox-inducible exogenous reprogramming factors. These reprogramming factors were bOMSK (bovine OCT4, CMYC, SOX2, and KLF4), pNhL (porcine NANOG and human LIN28), hRL (human RARG and LRH1), and SV40 Large T. Notably, AF-giPSCs (induced in activin A and bFGF condition) were capable of differentiation in embryoid bodies in vitro and could contribute to interspecies chimerism in mouse E6.5 embryos in vitro, demonstrating that AF-giPSCs have the developmental capability to generate some embryonic cell lineages. Moreover, Wnt/ß-catenin signaling has an important role in driving goat induced trophoblast-like stem cells (giTLSCs) from Dox-independent giPSCs. This study will support further establishment of the stable giPSC lines without any integration of exogenous genes.

Optimizing Geriatric Venipuncture: A DRG-Compatible Team-Based Reengineering Strategy.

Objective: This study evaluates a reengineered intervention aimed at improving the clinical management of intravenous indwelling needles in geriatric patients, focusing on cost-efficiency within the Diagnosis-Related Group (DRG) payment framework. Methods: The intervention was assessed through a comparative study involving 387 elderly patients in the Geriatric Department of Xuanwu Hospital, between June 2021 and March 2022. The study contrasted outcomes between patients treated before and after implementing a new team-based management protocol in November 2021. Results: Findings indicate enhanced first-attempt venipuncture success, reduced consumable costs, and decreased complication rates in the post-intervention group (P < 0.001), compared to controls. Conclusion: The intervention demonstrates significant benefits in venipuncture efficiency, cost reduction, and patient safety, suggesting its potential for broader adoption in geriatric care.

A dynamic online nomogram for predicting renal outcomes of idiopathic membranous nephropathy.

BACKGROUND: Because spontaneous remission is common in IMN, and there are adverse effects of immunosuppressive therapy, it is important to assess the risk of progressive loss of renal function before deciding whether and when to initiate immunosuppressive therapy. Therefore, this study aimed to establish a risk prediction model to predict patient prognosis and treatment response to help clinicians evaluate patient prognosis and decide on the best treatment regimen. METHODS: From September 2019 to December 2020, a total of 232 newly diagnosed IMN patients from three hospitals in Liaoning Province were enrolled. Logistic regression analysis selected the risk factors affecting the prognosis, and a dynamic online nomogram prognostic model was constructed based on extreme gradient boost, random forest, logistic regression machine learning algorithms. Receiver operating characteristic and calibration curves and decision curve analysis were utilized to assess the performance and clinical utility of the developed model. RESULTS: A total of 130 patients were in the training cohort and 102 patients in the validation cohort. Logistic regression analysis identified four risk factors: course ≥ 6 months, UTP, D-dimer and sPLA2R-Ab. The random forest algorithm showed the best performance with the highest AUROC (0.869). The nomogram had excellent discrimination ability, calibration ability and clinical practicability in both the training cohort and the validation cohort. CONCLUSIONS: The dynamic online nomogram model can effectively assess the prognosis and treatment response of IMN patients. This will help clinicians assess the patient's prognosis more accurately, communicate with the patient in advance, and jointly select the most appropriate treatment plan.

Unsuccessful laparoscopic resection of a large pelvic solitary fibrous tumor: A case report.

We present a rare case of a female pelvic solitary fibrous tumor unsuccessfully resected using single-port laparoscopy, requiring conversion to laparotomy. Although the resection was successful, the surgical approach could have been improved. For large tumors, minimally invasive results are possible with flexible choices of equipment and incision position.

[Mechanism of tetramethylpyrazine intervention with ischemia-reperfusion rats based on Nrf2/HO-1/CXCR4 pathway through regulating neural stem cell migration].

This study aims to decipher the mechanism of tetramethylpyrazine(TMP) in regulating the migration of neural stem cells(NSCs) in the rat model of middle cerebral artery occlusion(MCAO) via the nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)/C-X-C motif chemokine receptor 4(CXCR4) pathway. SD rats were randomized into sham, MCAO(model), and tetramethylpyrazine(TMP, 20 mg·kg~(-1) and 40 mg·kg~(-1)) groups. The neurological impairment was assessed by the modified neurological severity score(mNSS). The immunofluorescence assay was employed to detect the cells stained with both 5-bromodeoxyuridine(BrdU) and doublecortin(DCX) in the brain tissue. The effect of TMP on the migration of C17.2 cells was observed. Western blot was employed to determine the protein levels of Nrf2, HO-1, p62, NAD(P)H quinone oxidoreductase 1(NQO1), stromal cell-derived factor 1(SDF-1), and CXCR4 in the brain tissue and C17.2 cells. The results showed that after 7 days and 21 days of mode-ling, the mNSS and BrdU~+/DCX~+ cells were increased, and the expression of Nrf2 and CXCR4 in the brain tissue was up-regulated. Compared with the model group, TMP(40 mg·kg~(-1)) reduced the mNSS, increased the number of BrdU~+/DCX~+ cells, and up-regulated the expression of Nrf2, CXCR4, and SDF-1. In addition, TMP promoted the migration of C17.2 cells and up-regulated the expression of p62, Nrf2, HO-1, and NQO1 in a time-and dose-dependent manner. The expression was the highest at the time point of 12 h in the TMP(50 µg·mL~(-1)) group(P<0.01). In conclusion, TMP activates the Nrf2/HO-1/CXCR4 pathway to promote the migration of NSCs to the ischemic area, thus exerting the therapeutic effect on the ischemia-reperfusion injury. This study provides experimental support for the application of TMP in ischemic stroke.

[Mechanism of tetramethylpyrazine combined with neural stem cells transplantation on cerebral ischemia-reperfusion rats].

This study aimed to investigate the intervention effect of tetramethylpyrazine(TMP) combined with transplantation of neural stem cells(NSCs) on middle cerebral artery occlusion(MCAO) rat model and to explore the mechanism of TMP combined with NSCs transplantation on ischemic stroke based on the regulation of stem cell biological behavior. MCAO rats were randomly divided into a model group, a TMP group, an NSCs transplantation group, and a TMP combined with NSCs transplantation group according to neurological function scores. A sham group was set up at the same time. The neurological function score was used to evaluate the improvement of neurological function in MCAO rats after TMP combined with NSCs transplantation. The proliferation, migration, and differentiation of NSCs were evaluated by BrdU, BrdU/DCX, BrdU/NeuN, and BrdU/GFAP immunofluorescence labeling. The protein expression of stromal cell-derived factor 1(SDF-1), C-X-C motif chemokine receptor 4(CXCR4), as well as oxidative stress pathway proteins nuclear factor erythroid 2-related factor 2(Nrf2), Kelch-like ECH-associated protein 1(KEAP1), heme oxygenase 1(HO-1), NAD(P)H quinone oxidoreductase 1(NQO1) was detected by Western blot to study the migration mechanism of TMP combined with NSCs. The results showed that TMP combined with NSCs transplantation significantly improved the neurological function score in MCAO rats. Immunofluorescence staining showed a significant increase in the number of BrdU~+, BrdU~+/DCX~+, BrdU~+/NeuN~+, and BrdU~+/GFAP~+ cells in the TMP, NSCs transplantation, and combined treatment groups, with the combined treatment group showing the most significant increase. Further Western blot analysis revealed significantly elevated expression of CXCR4 protein in the TMP, NSCs transplantation, and combined treatment groups, along with up-regulated protein expression of Nrf2, HO-1, and NQO1, and decreased KEAP1 protein expression. This study showed that both TMP and NSCs transplantation can promote the recovery of neurological function by promoting the proliferation, migration, and differentiation of NSCs, and the effect of TMP combined with NSCs transplantation is superior. The mechanism of action may be related to the activation of the Nrf2/HO-1/CXCR4 pathway.

Fully Floatable Mortise-and-Tenon Architecture for Synergistically Photo/Sono-Driven Evaporation Desalination and Plastic-Enabled Value-Added Co-Conversion of H2O and CO2.

Establishing an advanced ecosystem incorporating freshwater harvesting, plastic utilization, and clean fuel acquisition is profoundly significant. However, low-efficiency evaporation, single energy utilization, and catalyst leakage severely hinder sustainable development. Herein, a nanofiber-based mortise-and-tenon structural Janus aerogel (MTSJA) is strategically designed in the first attempt and supports Z-scheme catalysts. By harnessing of the upper hydrophilic layer with hydrophilic channels embedding into the hydrophobic bottom layer to achieve tailoring bottom wettability states. MTSJA is capable of a fully-floating function for lower heat loss, water supply, and high-efficiency solar-to-vapor conversion. Benefiting from the ultrasonic cavitation effect and high sensitivity of materials to mechanical forces, this is also the first demonstration of synergistic solar and ultrasound fields to power simultaneous evaporation desalination and waste plastics as reusable substrates generating fuel energy. The system enables persistent desalination with an exceptional evaporation rate of 3.1 kg m-2 h-1 and 82.3% efficiency (21 wt.% NaCl solution and 1 sun), and realizes H2, CO, and CH4 yields with 16.1, 9.5, and 3 µmol h-1 g-1, respectively. This strategy holds great potential for desalination and plastics value-added transformation toward clean energy and carbon neutrality.

Lysine-specific demethylase 1 (LSD1) participate in porcine early embryonic development by regulating cell autophagy and apoptosis through the mTOR signaling pathway.

Lysine-specific demethylase 1 (LSD1) stands as the pioneering histone demethylase uncovered, proficient in demethylating H3K4me1/2 and H3K9me1/2, thereby governing transcription and participating in cell apoptosis, proliferation, or differentiation. Nevertheless, the complete understanding of LSD1 during porcine early embryonic development and the underlying molecular mechanism remains unclear. Thus, we investigated the mechanism by which LSD1 plays a regulatory role in porcine early embryos. This study revealed that LSD1 inhibition resulted in parthenogenetic activation (PA) and in vitro fertilization (IVF) embryo arrested the development, and decreased blastocyst quality. Meanwhile, H3K4me1/2 and H3K9me1/2 methylase activity was increased at the 4-cell embryo stage. RNA-seq results revealed that autophagy related biological processes were highly enriched through GO and KEGG pathway analyses when LSD1 inhibition. Further studies showed that LSD1 depletion in porcine early embryos resulted in low mTOR and p-mTOR levels and high autophagy and apoptosis levels. The LSD1 deletion-induced increases in autophagy and apoptosis could be reversed by addition of mTOR activators. We further demonstrated that LSD1 inhibition induced mitochondrial dysfunction and mitophagy. In summary, our research results indicate that LSD1 may regulate autophagy and apoptosis through the mTOR pathway and affect early embryonic development of pigs.

Chlorogenic acid improves the development of porcine parthenogenetic embryos by regulating oxidative stress and ameliorating mitochondrial function.

Chlorogenic acid (CGA) is an effective phenolic antioxidant that can scavenge hydroxyl radicals and superoxide anions. Herein, the protective effects and mechanisms leading to CGA-induced porcine parthenogenetic activation (PA) in early-stage embryos were investigated. Our results showed that 50 µM CGA treatment during the in vitro culture (IVC) period significantly increased the cleavage and blastocyst formation rates and improved the blastocyst quality of porcine early-stage embryos derived from PAs. Then, genes related to zygotic genome activation (ZGA) were identified and investigated, revealing that CGA can promote ZGA in porcine PA early-stage embryos. Further analysis revealed that CGA treatment during the IVC period decreased the abundance of reactive oxygen species (ROS), increased the abundance of glutathione and enhanced the activity of catalase and superoxide dismutase in porcine PA early-stage embryos. Mitochondrial function analysis revealed that CGA increased mitochondrial membrane potential and ATP levels and upregulated the mitochondrial homeostasis-related gene NRF-1 in porcine PA early-stage embryos. In summary, our results suggest that CGA treatment during the IVC period helps porcine PA early-stage embryos by regulating oxidative stress and improving mitochondrial function.

Correlation of Glycolysis-immune-related Genes in the Follicular Microenvironment of Endometriosis Patients with ART Outcomes.

Endometriosis (EMT) -related infertility has been a challenge for clinical research. Many studies have confirmed that abnormal alterations in the immune microenvironment and glycolysis are instrumental in causing EMT-related infertility. Recently, our research team identified several key glycolysis-immune-related genes in the endometrial cells of EMT patients. This study aimed to further investigate the expression patterns of pyruvate dehydrogenase kinase 3 (PDK3), glypican-3 (GPC3), and alcohol dehydrogenase 6 (ADH6), which are related to glycolysis and immunity, in the follicular microenvironment of infertile patients with EMT using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR) assays. According to the results, compared to the patients with tubal factor infertility, the concentrations of PDK3 and GPC3 were considerably increased in the follicular environment of EMT patients, while ADH6 expression was significantly reduced. The number of oocytes retrieved, the transferable embryo rate, and the cumulative clinical pregnancy rate of EMT patients were significantly reduced, and there was a correlation with the level of PDK3, GPC3, and ADH6 in Follicular Fluid (FF). The area under the receiver operating characteristic (ROC) curve for predicting clinical pregnancy in infertile patients with EMT for PDK3, GPC3, ADH6, and their combination was 0.732, 0.705, 0.855, and 0.879, respectively (P < 0.05). In conclusion, our research indicates that glycolysis-immune-related genes may contribute to infertility in EMT patients through immune infiltration, and disruption of mitochondrial and oocyte functions. The combined detection of PDK3, GPC3, and ADH6 in FF helps to predict clinical pregnancy outcomes in infertile patients with EMT.

The Inflammatory State of Follicular Fluid Combined with Negative Emotion Indicators can Predict Pregnancy Outcomes in Patients with PCOS.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder syndrome with an incidence of 6% to 10% in women of reproductive age. Women with PCOS not only exhibit abnormal follicular development and fertility disorders, but also have a greater tendency to develop anxiety and depression. Our aim was to evaluate the ability of inflammatory factors in follicular fluid to predict embryonic developmental potential and pregnancy outcome and to construct a machine learning model that can predict IVF pregnancy outcomes based on indicators such as basic sex hormones, embryonic morphology, the follicular microenvironment, and negative emotion. In this study, inflammatory factors (CRP, IL-6, and TNF-α) in follicular fluid samples obtained from 225 PCOS and 225 non-PCOS women were detected via ELISA. For patients with PCOS, the levels of CRP and IL-6 in the follicular fluid in the pregnant group were significantly lower than those in the nonpregnant group. For non-patients with PCOS, only the level of IL-6 in the follicular fluid was significantly lower in the pregnant group than in the nonpregnant group. In addition, for both PCOS and non-patients with PCOS, compared with those in the pregnant group, patients in the nonpregnant group showed more pronounced signs of anxiety and depression. Finally, the factors that were significantly different between the two subgroups (pregnancy and nonpregnancy) of patients with or without PCOS were identified by an independent sample t test first and further analysed by multilayer perceptron (MLP) and random forest (RF) models to distinguish the two clinical pregnancy outcomes according to the classification function. The accuracy of the RF model in predicting pregnancy outcomes in patients with or without PCOS was 95.6% and 91.1%, respectively. The RF model is more suitable than the MLP model for predicting pregnancy outcomes in IVF patients. This study not only identified inflammatory factors that can affect embryonic development and assessed the anxiety and depression tendencies of PCOS patients, but also constructed an AI model that predict pregnancy outcomes through machine learning methods, which is a beneficial clinical tool.

Prevalence of sarcopenic obesity in the older non-hospitalized population: a systematic review and meta-analysis.

BACKGROUND: Sarcopenic obesity emerges as a risk factor for adverse clinical outcomes in non-hospitalized older adults, including physical disabilities, metabolic diseases, and even mortality. In this systematic review and meta-analysis, we investigated the overall SO prevalence in non-hospitalized adults aged ≥ 65 years and assessed the sociodemographic, clinicobiological, and lifestyle factors related to SO. METHODS: We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for studies reporting the prevalence of SO from database inception to October 2023. Two researchers independently screened the literature, evaluated the study quality, and extracted the data. Both fixed- and random-effects models were used in the meta-analysis to estimate the pooled SO prevalence and perform subgroup analyses. Publication and sensitivity bias analyses were performed to test the robustness of the associations. RESULTS: Among 46 studies eligible for review and a total of 71,757 non-hospitalized older adults, the combined prevalence of SO was 14% (95% CI:11-17%, I2 = 99.5%, P < 0.01). Subgroup analysis according to lifestyle factors demonstrated that the SO prevalence was 17% (95% CI: 8-29%, I2 = 99.5%, P < 0.01) in older adults without exercise habits. Regarding clinicobiological factors, older adults with a history of falls (15% [95% CI: 10-22%, I2 = 82%, P < 0.01]), two or more chronic diseases (19% [95% CI: 10-29%, I2 = 97%, P < 0.01]), functional impairment (33% [95% CI: 29-37%, I2 = 0%, P = 0.95]), cognitive impairment (35% [95% CI: 9-65%, I2 = 83%, P = 0.02]), osteoporosis (20% [95% CI: 8-35%, I2 = 96%, P < 0.01]), high fasting glucose level (17% [95% CI: 1-49%, I2 = 98%, P < 0.01]), or the use of antipsychotics (13% [95% CI: 2-28%, I2 = 0%, P = 0.32]) exhibited a higher SO prevalence. CONCLUSION: SO prevalence is high among non-hospitalized older adults, especially those with functional and cognitive impairments. Thus, SO is a potential problem for the aging population; implementation of planned interventions in the community is needed to reduce the prevalence and adverse outcomes of SO.

Mechanically Robust Hemostatic Hydrogel Membranes with Programmable Strain-Adaptive Microdomain Entanglement for Wound Treatment in Dynamic Tissues.

Supramolecular hydrogels emerge as a promising paradigm for sutureless wound management. However, their translation is still challenged by the insufficient mechanical robustness in the context of complex wounds in dynamic tissues. Herein, we report a tissue-adhesive supramolecular hydrogel membrane based on biocompatible precursors for dressing wounds in highly dynamic tissues, featuring robust mechanical resilience through programmable strain-adaptive entanglement among microdomains. Specifically, the hydrogels are synthesized by incorporating a long-chain polyurethane segment into a Schiff base-ligated short-chain oxidized cellulose/quaternized chitosan network via acylhydrazone bonding, which readily establishes interpenetrating entangled microdomains in dynamic cross-linked hydrogel matrices to enhance their tear and fatigue resistance against extreme mechanical stresses. After being placed onto dynamic tissues, the hydrogel dressing could efficiently absorb blood to achieve rapid hemostasis. Moreover, metal ions released from ruptured erythrocytes could be scavenged by the Schiff base linkers to form additional ionic bonds, which would trigger the cross-linking of the short-chain components and establish abundant crystalline microdomains, eventually leading to the in situ stiffening of the hydrogels to endure heavy mechanical loads. Benefiting from its hemostatic capacity and strain adaptable mechanical performance, this hydrogel wound dressing shows promise for the clinical management of various traumatic wounds.

Deep learning on tertiary lymphoid structures in hematoxylin-eosin predicts cancer prognosis and immunotherapy response.

Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13, a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models' discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis.

Sustainable conversion of alkaline nitrate to ammonia at activities greater than 2 A cm-2.

Nitrate (NO3‒) pollution poses significant threats to water quality and global nitrogen cycles. Alkaline electrocatalytic NO3‒ reduction reaction (NO3RR) emerges as an attractive route for enabling NO3‒ removal and sustainable ammonia (NH3) synthesis. However, it suffers from insufficient proton (H+) supply in high pH conditions, restricting NO3‒-to-NH3 activity. Herein, we propose a halogen-mediated H+ feeding strategy to enhance the alkaline NO3RR performance. Our platform achieves near-100% NH3 Faradaic efficiency (pH = 14) with a current density of 2 A cm-2 and enables an over 99% NO3--to-NH3 conversion efficiency. We also convert NO3‒ to high-purity NH4Cl with near-unity efficiency, suggesting a practical approach to valorizing pollutants into valuable ammonia products. Theoretical simulations and in situ experiments reveal that Cl-coordination endows a shifted d-band center of Pd atoms to construct local H+-abundant environments, through arousing dangling O-H water dissociation and fast *H desorption, for *NO intermediate hydrogenation and finally effective NO3‒-to-NH3 conversion.

TSLP enhances progestin response in endometrial cancer via androgen receptor signal pathway.

BACKGROUND: The enriched proteins within in vitro fertilisation (IVF)-generated human embryonic microenvironment could reverse progestin resistance in endometrial cancer (EC). METHODS: The expression of thymic stromal lymphopoietin (TSLP) in EC was evaluated by immunoblot and IHC analysis. Transcriptome sequencing screened out the downstream pathway regulated by TSLP. The role of TSLP, androgen receptor (AR) and KANK1 in regulating the sensitivity of EC to progestin was verified through a series of in vitro and in vivo experiments. RESULTS: TSLP facilitates the formation of a BMP4/BMP7 heterodimer, resulting in activation of Smad5, augmenting AR signalling. AR in turn sensitises EC cells to progestin via KANK1. Downregulation of TSLP, loss of AR and KANK1 in EC patients are associated with tumour malignant progress. Moreover, exogenous TSLP could rescue the anti-tumour effect of progestin on mouse in vivo xenograft tumour. CONCLUSIONS: Our findings suggest that TSLP enhances the sensitivity of EC to progestin through the BMP4/Smad5/AR/KANK1 axis, and provide a link between embryo development and cancer progress, paving the way for the establishment of novel strategy overcoming progestin resistance using embryo original factors.