Bonding affinity and durability of recycled zirconia.

STATEMENT OF PROBLEM: While repurposing waste materials into zirconia blocks presents a promising avenue, uncertainty remains regarding whether the bonding properties of recycled zirconia align with those of commercially available zirconia. PURPOSE: The purpose of this in vitro study was to evaluate the bonding affinity and durability of composite resin to recycled zirconia. MATERIAL AND METHODS: A series of processing steps were performed with recycled zirconia residuals (Lava Plus; 3M Oral Care), including pulverization, sieving, heating, compaction, isostatic pressing, and presintering. The presintered blocks of recycled zirconia (Group R) and commercially available zirconia (Group C) were sectioned and sintered to create test specimens (10×10×1.5 mm). After polishing and airborne-particle abrasion, specimens within each group were bonded to composite resin cylinders using a resin cement (Multilink Speed; Ivoclar AG). The specimens were then divided into 3 subgroups for shear bond strength (SBS) testing: no further treatment, 10 000 thermocycles, and 30 000 thermocycles (n=10). X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectrometry (EDS), surface roughness, and contact angle were used to analyze the surface physicochemical differences between Groups C and R. Data were analyzed with 2-way ANOVA followed by the Tukey post hoc test for SBS values, Pearson chi-squared test for failure modes, and independent t test for grain size, surface roughness, and wettability (α=.05). RESULTS: No significant difference was found in the SBS values between Group R and Group C (P=.403), while thermocycling significantly affected the SBS values (P<.05). Group R showed significantly greater Ra, Rz, and Rq values (P<.05) than did Group C. SEM analysis revealed that Group R exhibited more prominent grooves than Group C, while the XRD and EDS patterns exhibited similarities in both the crystalline phase and elemental composition. No significant difference was observed in the water contact angle between the 2 groups (P=.196). CONCLUSIONS: The bonding protocol established for commercially available zirconia was comparable with that of recycled zirconia, but both decreased after thermocycling. The recycling process did not affect the crystalline phase or elemental composition of the zirconia, but it induced alterations in the surface roughness.

New application of intestinal obstruction catheter in enterocutaneous fistula: A case report.

BACKGROUND: Enterocutaneous fistula (ECF) is an abnormal connection between the gastrointestinal tract and the skin. ECF can lead to massive body fluid loss, hypercatabolism, and malnutrition. Therefore, nutritional support plays a crucial role in managing ECFs and promoting the healing of fistulas. For nutritional support, enteral nutrition (EN) is the preferred method when gastrointestinal function is recovering. Currently, various EN approaches have been applied for different anatomical positions of the ECF. However, the effectiveness of administering EN support for treating lower ECFs still needs further exploration and improvement. CASE SUMMARY: We present the case of a 46-year-old male who underwent gastrointestinal stromal tumour resection. Six days after the surgery, the patient presented with fever, fatigue, severe upper abdominal pain, and septic shock. Subsequently, lower ECFs were diagnosed through laboratory and imaging examinations. In addition to symptomatic treatment for homeostasis, total parenteral nutrition support was administered in the first 72 h due to dysfunction of the intestine. After that, we gradually provided EN support through the intestinal obstruction catheter in consideration of the specific anatomic position of the fistula instead of using the nasal jejunal tube. Ultimately, the patient could receive optimal EN support via the catheter, and no complications were found during the treatment. CONCLUSION: Nutritional support is a crucial element in ECF management, and intestinal obstruction catheters could be used for early EN administration.

Predictive value of intracranial high-density areas in neurological function.

BACKGROUND: Intracranial high-density areas (HDAs) have attracted considerable attention for predicting clinical outcomes; however, whether HDAs predict worse neurological function and mental health remains controversial and unclear, which requires further investigation. AIM: To investigate the predictive value of intracranial HDAs for neurological function and mental health after endovascular treatment. METHODS: In this prospective study, 96 patients with acute ischemic stroke (AIS) who accepted endovascular mechanical thrombectomy (EMT) were included. The enrolled patients underwent cranial computed tomography (CT) examination within 24 hours after EMT. Clinical data in terms of National Institutes of Health Stroke Scale (NIHSS), the 3-month modified Rankin Scale (mRS), self-rating depression scale (SDS), and self-rating anxiety scale (SAS) scores were collected and compared between patients with HDAs and non-HDAs and between patients with good and poor clinical prognosis. RESULTS: Compared to patients without HDAs, patients with HDAs presented severe neurological deficits (admission NIHSS score: 18 ± 3 vs 19 ± 4), were more likely to have post-stroke disabilities (mRS < 3: 35% vs 62%), and suffered more severe depression (SDS score: 58 ± 16 vs 64 ± 13) and anxiety disorder (SAS score: 52 ± 8 vs 59 ± 10). Compared to patients with a good prognosis, patients with a poor prognosis presented severe neurological deficits (admission NIHSS score: 17 ± 4 vs 20 ± 3), were more likely to have HDAs on CT images (64% vs 33%), and suffered more severe depression (SDS score: 55 ± 19 vs 65 ± 11) and anxiety (SAS score: 50 ± 8 vs 58 ± 12). Multivariate analysis revealed that HDAs were independent negative prognostic factors. CONCLUSION: In conclusion, HDAs on CT images predicted poor prognosis and severe depressive and anxiety symptoms in patients with AIS who underwent EMT.

Depletion-assisted multiplexed cell-free RNA sequencing reveals distinct human and microbial signatures in plasma versus extracellular vesicles.

BACKGROUND: Cell-free long RNAs in human plasma and extracellular vesicles (EVs) have shown promise as biomarkers in liquid biopsy, despite their fragmented nature. METHODS: To investigate these fragmented cell-free RNAs (cfRNAs), we developed a cost-effective cfRNA sequencing method called DETECTOR-seq (depletion-assisted multiplexed cell-free total RNA sequencing). DETECTOR-seq utilised a meticulously tailored set of customised guide RNAs to remove large amounts of unwanted RNAs (i.e., fragmented ribosomal and mitochondrial RNAs) in human plasma. Early barcoding strategy was implemented to reduce costs and minimise plasma requirements. RESULTS: Using DETECTOR-seq, we conducted a comprehensive analysis of cell-free transcriptomes in both whole human plasma and EVs. Our analysis revealed discernible distributions of RNA types in plasma and EVs. Plasma exhibited pronounced enrichment in structured circular RNAs, tRNAs, Y RNAs and viral RNAs, while EVs showed enrichment in messenger RNAs (mRNAs) and signal recognition particle RNAs (srpRNAs). Functional pathway analysis highlighted RNA splicing-related ribonucleoproteins (RNPs) and antimicrobial humoral response genes in plasma, while EVs demonstrated enrichment in transcriptional activity, cell migration and antigen receptor-mediated immune signals. Our study indicates the comparable potential of cfRNAs from whole plasma and EVs in distinguishing cancer patients (i.e., colorectal and lung cancer) from healthy donors. And microbial cfRNAs in plasma showed potential in classifying specific cancer types. CONCLUSIONS: Our comprehensive analysis of total and EV cfRNAs in paired plasma samples provides valuable insights for determining the need for EV purification in cfRNA-based studies. We envision the cost effectiveness and efficiency of DETECTOR-seq will empower transcriptome-wide investigations in the fields of cfRNAs and liquid biopsy. KEYPOINTS: DETECTOR-seq (depletion-assisted multiplexed cell-free total RNA sequencing) enabled efficient and specific depletion of sequences derived from fragmented ribosomal and mitochondrial RNAs in plasma. Distinct human and microbial cell-free RNA (cfRNA) signatures in whole Plasma versus extracellular vesicles (EVs) were revealed. Both Plasma and EV cfRNAs were capable of distinguishing cancer patients from normal individuals, while microbial RNAs in Plasma cfRNAs enabled better classification of cancer types than EV cfRNAs.

Unmasking Spatial Heterogeneity in Phytotoxicology Mechanisms Induced by Carbamazepine by Mass Spectrometry Imaging and Multiomics Analyses.

Previous studies have highlighted the toxicity of pharmaceuticals and personal care products (PPCPs) in plants, yet understanding their spatial distribution within plant tissues and specific toxic effects remains limited. This study investigates the spatial-specific toxic effects of carbamazepine (CBZ), a prevalent PPCP, in plants. Utilizing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), CBZ and its transformation products were observed predominantly at the leaf edges, with 2.3-fold higher concentrations than inner regions, which was confirmed by LC-MS. Transcriptomic and metabolic analyses revealed significant differences in gene expression and metabolite levels between the inner and outer leaf regions, emphasizing the spatial location's role in CBZ response. Notably, photosynthesis-related genes were markedly downregulated, and photosynthetic efficiency was reduced at leaf edges. Additionally, elevated oxidative stress at leaf edges was indicated by higher antioxidant enzyme activity, cell membrane impairment, and increased free fatty acids. Given the increased oxidative stress at the leaf margins, the study suggests using in situ Raman spectroscopy for early detection of CBZ-induced damage by monitoring reactive oxygen species levels. These findings provide crucial insights into the spatial toxicological mechanisms of CBZ in plants, forming a basis for future spatial toxicology research of PPCPs.

EBF1-COX4I2 signaling axis promotes a myofibroblast-like phenotype in cancer-associated fibroblasts (CAFs) and is associated with an immunosuppressive microenvironment.

Immunotherapy has limited response rates in colorectal cancer (CRC) due to an immunosuppressive tumor microenvironment (TME). Combining transcriptome sequencing, clinical specimens, and functional experiments, we identified a unique group of CAF subpopulations (COX4I2 + ) with inhibited mitochondrial respiration and enhanced glycolysis. Through bioinformatics predictions and luciferase reporter assays, we determined that EBF1 can upstreamly regulate COX4I2 transcription. COX4I2 + CAFs functionally and phenotypically resemble myofibroblasts, are important for the formation of the fibrotic TME, and are capable of activating the M2 phenotype of macrophages. In vitro experiments demonstrated that COX4I2 + CAFs promote immunosuppressive TME by blocking CD8 + T cell infiltration and inducing CD8 + T cell dysfunction. Using multiple independent cohorts, we also found a strong correlation between the immunotherapy response rate of CRC patients and COX4I2 expression in their tumors. Our results identify a CAF subpopulation characterized by activation of the EBF1-COX4I2 axis, and this group of CAFs can be targeted to improve cancer immunotherapy outcomes.

Copper-Based Composites Nanoparticles Improve Triple-Negative Breast Cancer Treatment with Induction of Apoptosis-Cuproptosis and Immune Activation.

The synergistic effect of apoptosis and cuproptosis, along with the activation of the immune system, presents a promising approach to enhance the efficacy against triple-negative breast cancer (TNBC). Here, two prodrugs are synthesized: a reactive oxygen species (ROS)-responsive prodrug PEG-TK-DOX and a glutathione (GSH)-responsive prodrug PEG-DTPA-SS-CPT. These prodrugs are self-assembled and chelated Cu2+ to prepare nanoparticle PCD@Cu that simultaneously loaded doxorubicin (DOX), camptothecin (CPT), and Cu2+. The elevated levels of ROS and GSH in TNBC cells disrupted the PCD@Cu structure, leading to the release of Cu+, DOX, and CPT and the depletion of GSH. DOX and CPT triggered apoptosis with immunogenic cell death (ICD) in TNBC cells. Simultaneously, PCD@Cu downregulated the expression of copper transporting ATPase 2 (ATP7B), causing a significant accumulation of copper ions in TNBC cells. This further induced the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and downregulation of iron-sulfur (Fe-S) cluster proteins, ultimately leading to cuproptosis and ICD in TNBC. In vitro and in vivo experiments confirmed that PCD@Cu induced apoptosis and cuproptosis in TNBC and activated the immune system, demonstrating strong anti-tumor capabilities. Moreover, PCD@Cu exhibited an excellent biosafety profile. Overall, this study provides a promising strategy for effective TNBC therapy.

Development and Validation of an Interpretable Machine Learning Model for Early Prognosis Prediction in ICU Patients with Malignant Tumors and Hyperkalemia.

This study aims to develop and validate a machine learning (ML) predictive model for assessing mortality in patients with malignant tumors and hyperkalemia (MTH). We extracted data on patients with MTH from the Medical Information Mart for Intensive Care-IV, version 2.2 (MIMIC-IV v2.2) database. The dataset was split into a training set (75%) and a validation set (25%). We used the Least Absolute Shrinkage and Selection Operator (LASSO) regression to identify potential predictors, which included clinical laboratory indicators and vital signs. Pearson correlation analysis tested the correlation between predictors. In-hospital death was the prediction target. The Area Under the Curve (AUC) and accuracy of the training and validation sets of 7 ML algorithms were compared, and the optimal 1 was selected to develop the model. The calibration curve was used to evaluate the prediction accuracy of the model further. SHapley Additive exPlanations (SHAP) and Local Interpretable Model-agnostic Explanations (LIME) enhanced model interpretability. 496 patients with MTH in the Intensive Care Unit (ICU) were included. After screening, 17 clinical features were included in the construction of the ML model, and the Pearson correlation coefficient was <0.8, indicating that the correlation between the clinical features was small. eXtreme Gradient Boosting (XGBoost) outperformed other algorithms, achieving perfect scores in the training set (accuracy: 1.000, AUC: 1.000) and high scores in the validation set (accuracy: 0.734, AUC: 0.733). The calibration curves indicated good predictive calibration of the model. SHAP analysis identified the top 8 predictive factors: urine output, mean heart rate, maximum urea nitrogen, minimum oxygen saturation, minimum mean blood pressure, maximum total bilirubin, mean respiratory rate, and minimum pH. In addition, SHAP and LIME performed in-depth individual case analyses. This study demonstrates the effectiveness of ML methods in predicting mortality risk in ICU patients with MTH. It highlights the importance of predictors like urine output and mean heart rate. SHAP and LIME significantly enhanced the model's interpretability.

CMPK2 Promotes CD4+ T Cell Activation and Apoptosis through Modulation of Mitochondrial Dysfunction in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a classic autoimmune disease characterized by abnormal autoantibodies, immune complex deposition, and tissue inflammation. Despite extensive research, the exact etiology and progression of SLE remain elusive. Cytidine/uridine monophosphate kinase 2 (CMPK2), a mitochondrial nucleoside monophosphate kinase, has garnered attention for its potential involvement in the development of various diseases, including SLE, where it has been observed to be dysregulated in affected individuals. However, the specific involvement of CMPK2 in the pathogenesis of SLE remains unclear. This study aims to clarify the expression level of CMPK2 in SLE CD4+ T cells and explore its impact on CD4+ T cells. The expression levels of the CMPK2 gene and the corresponding CMPK2 protein in CD4+ T cells of SLE patients were quantified using RT-qPCR and Western blot, respectively. Immunofluorescence and RT-qPCR were used to assess the mitochondrial function of SLE CD4+ T cells. Flow cytometry was used to assess CD4+ T cell activation and apoptosis levels. The impact of CMPK2 on CD4+ T cells was investigated by gene transfection experiment. We found that CMPK2 was significantly upregulated in SLE CD4+ T cells at both gene and protein levels. These cells demonstrated aberrant mitochondrial function, as evidenced by elevated mitochondrial reactive oxygen species (mtROS) levels, mitochondrial membrane potential, and mitochondrial DNA (mtDNA) copy number. Flow cytometry revealed a notable increase in both apoptosis and activation levels of CD4+ T cells in SLE patients. Gene transfection experiments showed that suppressing CMPK2 led to a significant improvement in these conditions. These findings suggest that CMPK2 may be involved in the pathogenesis of SLE by regulating mitochondrial dysfunction in CD4+ T cells and thus affecting CD4+ T cell activation and apoptosis. Our study may provide a new target for the treatment of SLE.

Dietary inflammatory index, mediating biomarkers and incident frailty in Chinese community-dwelling older adults.

OBJECTIVES: Diet can modulate systemic inflammation, while inflammation is a critical contributory factor of frailty. However, longitudinal data on the association between dietary inflammatory index (DII) and frailty are limited, and the intermediate mechanisms remain unclear. This study aimed to examine the association between DII and incident frailty and the potential mediating roles of frailty-related biomarkers. DESIGN: Prospective cohort study. SETTING: The Mr. OS and Ms. OS (Hong Kong) study. PARTICIPANTS: A total of 3,035 community-dwelling men and women aged above 65 years without frailty at baseline were included. MEASUREMENTS: DII scores were calculated using the locally validated food frequency questionnaire. Incident frailty at year four was defined using the Fried frailty phenotype. Logistic regression was used to examine the association between DII and frailty onset. Mediation analysis was used to explore the mediating roles of frailty-related biomarkers in the DII-frailty association. RESULTS: During four years of follow-up, 208 individuals developed frailty. Compared with the lowest tertile of DII, the highest tertile was associated with an increased risk of incident frailty (OR: 1.82; 95% CI: 1.17-2.82; p = 0.008) after adjustment for relevant confounders. The DII-frailty association was significant in men but not in women. Furthermore, increasing serum homocysteine, decreasing serum folate, and reducing estimated glomerular filtration rate (eGFR) mediated 11.6%, 7.1%, and 9.6 % of the total relation between DII and frailty onset, respectively. CONCLUSION: In this cohort study, a pro-inflammatory diet was associated with a higher risk of frailty onset, mediated by homocysteine, folate, and renal function.

Spatiotemporal heterogeneity of LMOD1 expression summarizes two modes of cell communication in colorectal cancer.

Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial-mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity.

Efficient high-resolution fluorescence projection imaging over an extended depth of field through optical hardware and deep learning optimizations.

Optical microscopy has witnessed notable advancements but has also become more costly and complex. Conventional wide field microscopy (WFM) has low resolution and shallow depth-of-field (DOF), which limits its applications in practical biological experiments. Recently, confocal and light sheet microscopy become major workhorses for biology that incorporate high-precision scanning to perform imaging within an extended DOF but at the sacrifice of expense, complexity, and imaging speed. Here, we propose deep focus microscopy, an efficient framework optimized both in hardware and algorithm to address the tradeoff between resolution and DOF. Our deep focus microscopy achieves large-DOF and high-resolution projection imaging by integrating a deep focus network (DFnet) into light field microscopy (LFM) setups. Based on our constructed dataset, deep focus microscopy features a significantly enhanced spatial resolution of ∼260 nm, an extended DOF of over 30 µm, and broad generalization across diverse sample structures. It also reduces the computational costs by four orders of magnitude compared to conventional LFM technologies. We demonstrate the excellent performance of deep focus microscopy in vivo, including long-term observations of cell division and migrasome formation in zebrafish embryos and mouse livers at high resolution without background contamination.

Sodium Octahydridotriborate as a Solid Electrolyte with Excellent Stability Against Sodium-Metal Anode.

Solid-state sodium metal batteries have been extensively investigated because of their potential to improve safety, cost-effectiveness, and energy density. The development of such batteries urgently required a solid-state electrolyte with fast Na-ion conduction and favorable interfacial compatibility. Herein, the progress on developing the NaB3H8 solid-state electrolytes is reported, which show a liquid-like ionic conductivity of 0.05 S cm-1 at 56 °C with an activation energy of 0.35 eV after an order-disorder phase transformation, matching or surpassing the best single-anion hydridoborate conductors investigated up to now. The steady polarization voltage and significantly decreased resistance are achieved in the symmetric Na/NaB3H8/Na cell, indicating the great electrochemical stability and favorable interfacial contact with the Na metal of NaB3H8. Furthermore, a Na/NaB3H8/TiS2 battery, the first high-rate (up to 1 C) solid-state sodium metal battery using the single-anion hydridoborate electrolyte, is demonstrated, which exhibits superior rate capability (168.2 mAh g-1 at 0.1 C and 141.2 mAh g-1 at 1 C) and long-term cycling stability (70.9% capacity retention at 1 C after 300 cycles) at 30 °C. This work may present a new possibility to solve the interfacial limitations and find a new group of solid-state electrolytes for high-performance sodium metal batteries.

Co4+ in porous ZIF-67-derives intercalating-bridging adsorption of 2-reaction sites for simultaneous 2-electron transfer toward sensitive detection of uric acid.

Metal-organic frameworks (MOFs) have been used to detect uric acid (UA), but still very challenging to achieve a low detection limit due to the low inferior conductivity of MOFs. Herein, three different N-doped ZIF-67-derived carbons were synthesized for the first time by one-step co-pyrolysis of 2-methylimidazole with cobalt nitrate (CN), cobalt acetate (CA) or cobalt chloride (CC) toward UA sensing. Afterwards, the cobalt nitrate-derived Co particle (Co/CN) supported by N-doped ZIF-67-derived carbon displays extremely low detection limit and high sensitivity for UA, outperformed all reported MOFs-based UA sensors. More interestingly, it was discovered that the high valence Co4+ within the Co/CN sample produced in high-acidic environment can intercalate in the frame for a bridge adsorption between two reaction sites, which boosted simultaneous 2-electron transfer, while Co3+ only allows an end-adsorption structure for one-electron transfer being the rate determining step. Furthermore, the bridge adsorption mode of UA on Co4+ -based catalyst was also verified by theoretical DFT calculations and XPS experiment. This work holds great promise for a selective and sensitive UA sensor for practical bioscience and clinic diagnostic applications while shedding lights in fundamental research for innovative designs and developments of high-sensitive electrochemical sensors.

Long-term intravital subcellular imaging with confocal scanning light-field microscopy.

Long-term observation of subcellular dynamics in living organisms is limited by background fluorescence originating from tissue scattering or dense labeling. Existing confocal approaches face an inevitable tradeoff among parallelization, resolution and phototoxicity. Here we present confocal scanning light-field microscopy (csLFM), which integrates axially elongated line-confocal illumination with the rolling shutter in scanning light-field microscopy (sLFM). csLFM enables high-fidelity, high-speed, three-dimensional (3D) imaging at near-diffraction-limit resolution with both optical sectioning and low phototoxicity. By simultaneous 3D excitation and detection, the excitation intensity can be reduced below 1 mW mm-2, with 15-fold higher signal-to-background ratio over sLFM. We imaged subcellular dynamics over 25,000 timeframes in optically challenging environments in different species, such as migrasome delivery in mouse spleen, retractosome generation in mouse liver and 3D voltage imaging in Drosophila. Moreover, csLFM facilitates high-fidelity, large-scale neural recording with reduced crosstalk, leading to high orientation selectivity to visual stimuli, similar to two-photon microscopy, which aids understanding of neural coding mechanisms.

Can pilot free trade zones policy force the green transformation of enterprises? Evidence from listed companies in China.

In order to reveal the impact of pilot free trade zones policy on green development, we use multi-period difference-in-difference estimation and fixed effect model to explore the impact and impact mechanism of the establishment of free trade zones on the green transformation of enterprises from the micro perspective, based on the panel data of China's A-share listed companies from 2009-2021, The results show that pilot free trade zones policy significantly improves the green transformation of enterprises in the zones. Pilot free trade zones policy affects the corporate green transformation through industrial agglomeration and financial constraints. The green transformation of state-owned enterprises, non-heavy polluting enterprises and high-tech enterprises are significantly impacted by pilot free trade zones policy. Urban innovation and green subsidies play a positive moderating role in the impact of free trade zones on enterprises' green transformation. The research conclusions provide a valuable policy basis for how to promote the green transformation of enterprises under the free trade zones policy.

Pathformer: a biological pathway informed transformer for disease diagnosis and prognosis using multi-omics data.

MOTIVATION: Multi-omics data provide a comprehensive view of gene regulation at multiple levels, which is helpful in achieving accurate diagnosis of complex diseases like cancer. However, conventional integration methods rarely utilize prior biological knowledge and lack interpretability. RESULTS: To integrate various multi-omics data of tissue and liquid biopsies for disease diagnosis and prognosis, we developed a biological pathway informed Transformer, Pathformer. It embeds multi-omics input with a compacted multi-modal vector and a pathway-based sparse neural network. Pathformer also leverages criss-cross attention mechanism to capture the crosstalk between different pathways and modalities. We first benchmarked Pathformer with 18 comparable methods on multiple cancer datasets, where Pathformer outperformed all the other methods, with an average improvement of 6.3%-14.7% in F1 score for cancer survival prediction, 5.1%-12% for cancer stage prediction, and 8.1%-13.6% for cancer drug response prediction. Subsequently, for cancer prognosis prediction based on tissue multi-omics data, we used a case study to demonstrate the biological interpretability of Pathformer by identifying key pathways and their biological crosstalk. Then, for cancer early diagnosis based on liquid biopsy data, we used plasma and platelet datasets to demonstrate Pathformer's potential of clinical applications in cancer screening. Moreover, we revealed deregulation of interesting pathways (e.g. scavenger receptor pathway) and their crosstalk in cancer patients' blood, providing potential candidate targets for cancer microenvironment study. AVAILABILITY AND IMPLEMENTATION: Pathformer is implemented and freely available at https://github.com/lulab/Pathformer.

An injectable, chitosan-based hydrogel prepared by Schiff base reaction for anti-bacterial and sustained release applications.

Injectable hydrogels, providing sustained release as implanted materials, have received tremendous attention. In this study, chitosan-based hydrogels were prepared via Schiff base reaction of the aldehyde groups on Poly(NIPAM-co-FBEMA) and the amine groups on chitosan. Owing to the dynamic covalent linkage, the SC/PNF hydrogels exhibit pH-responsive, reversible sol-gel transition, injectable, and self-healing capacity. The mechanical strength of SC/PNF hydrogels can be operated simply by switching the composition or solid content of Poly(NIPAM-co-FBEMA) copolymers. Rheological analyses, including frequency sweeps, strain sweep scanning, and dynamic time sweeps, were employed to demonstrate the relationship between storage modulus (G'), loss modulus (G″), and composition of the SC/PNF hydrogels. In vitro release behaviors reveal that vancomycin-loaded SC/PNF hydrogel could contribute to both the initial burst release (over 1000 ppm within 4 h) and the sustained release (3000 ppm for at least 30 days). Pristine SC/PNF hydrogel holds good biocompatibility toward L929 cells and S. aureus that it degrades as incubated with S. aureus. However, vancomycin-wrapped SC/PNF hydrogel possesses a rapid bacterial-killing effect with a clear inhibition zone. In short, the SC/PNF hydrogels deliver not only sustainable release ability but also tunable physical properties, which are expected to be an outstanding candidate for non-invasive, anti-infection applications.

Discovery and pharmacological characterization of 1,2,3,4-tetrahydroquinoline derivatives as RORγ inverse agonists against prostate cancer.

The retinoic acid receptor-related orphan receptor γ (RORγ) is regarded as an attractive therapeutic target for the treatment of prostate cancer. Herein, we report the identification, optimization, and evaluation of 1,2,3,4-tetrahydroquinoline derivatives as novel RORγ inverse agonists, starting from high throughput screening using a thermal stability shift assay (TSA). The representative compounds 13e (designated as XY039) and 14a (designated as XY077) effectively inhibited the RORγ transcriptional activity and exhibited excellent selectivity against other nuclear receptor subtypes. The structural basis for their inhibitory potency was elucidated through the crystallographic study of RORγ LBD complex with 13e. Both 13e and 14a demonstrated reasonable antiproliferative activity, potently inhibited colony formation and the expression of AR, AR regulated genes, and other oncogene in AR positive prostate cancer cell lines. Moreover, 13e and 14a effectively suppressed tumor growth in a 22Rv1 xenograft tumor model in mice. This work provides new and valuable lead compounds for further development of drugs against prostate cancer.

Nickel-Iron-Layered Double Hydroxide Electrocatalyst with Nanosheets Array for High Performance of Water Splitting.

Developing high-performance and cost-competitive electrocatalysts have great significance for the massive commercial production of water-splitting hydrogen. Ni-based electrocatalysts display tremendous potential for electrocatalytic water splitting. Herein, we synthesize a novel NiFe-layered double hydroxide (LDH) electrocatalyst in nanosheets array on high-purity Ni foam. By adjusting the Ni/Fe ratio, the microstructure, and even the behavior of the electrocatalyst in the oxygen evolution reaction (OER), changes significantly. The as-obtained material shows a small overpotential of 223 mV at 10 mAcm-2 as well as a low Tafel slope of 48.9 mV·dec-1 in the 1 M KOH electrolyte. In addition, it can deliver good stability for at least 24 h of continuous working at 10 mAcm-2. This work proposes a strategy for engineering catalysts and provides a method for the development of other Ni-based catalysts with excellent performance.