Inherited KDM6AA649T facilitates tumor-immune escape and exacerbates colorectal signet-ring cell carcinoma outcomes.

Childhood onset of colorectal signet-ring cell carcinoma (CR-SRCC) is extremely rare and featured as highly malignant with poor prognosis. Here we reported a CR-SRCC case of 11-year-old boy with a novel inherited X-linked KDM6AA694T mutation. The H3K27me3 demethylase KDM6A was frequently mutated in varieties of tumors and acts as a tumor suppressor. In vivo H3K27me3 demethylation assay demonstrated that KDM6AA694T had dampened H3K27me3 demethylase activity. Overexpression of KDM6AA694T in SRCC cell line KATO3 promoted cell proliferation, invasion and migration, which were further confirmed in vivo by constructing orthotopic tumor growth and lung metastasis model. Besides, expression of KDM6AA694T in immune cells suppresses inflammatory macrophage response and effector T cell response. In conclusion, we characterized a novel inherited KDM6AA694T mutant from a childhood-onset SRCC case and demonstrated that the mutant with impaired H3K27me3 demethylase activity could potentiate tumor malignancy and suppress antitumor immunity.

Atomic-Level Matching Metal-Ion Organic Hybrid Interface to Enhance Energy Storage of Polymer-Based Composite Dielectrics.

In this work, a distinctive "metal-ion organic hybrid interface" (MOHI) between polyimide (PI) and calcium niobate (CNO) nanosheets is designed. The metal ions in the MOHI can achieve atomic-level matching not only with the inorganic CNO, but also with the PI chains, forming uniform and strong chemical bonds. These results are demonstrated by experiment and theory calculations. Significantly, the MOHI reduces the free volume and introduces deep traps across the filler-matrix interfacial area, thus suppressing the electric field distortion in PI-based composite dielectrics. Consequently, PI-based dielectric containing the MOHI exhibits excellent energy storage performance. The energy storage densities (Ue) of the composite dielectric reach 9.42 J cm-3 and 4.75 J cm-3 with energy storage efficiency (η) of 90% at 25 °C and 150 °C respectively, which are 2.6 and 11.6 times higher than those of pure PI. This study provides new ideas for polymer-based composite dielectrics in high energy storage.

Serratia marcescens LYGN1 Reforms the Rhizosphere Microbial Community and Promotes Cucumber and Pepper Growth in Plug Seedling Cultivation.

The vegetable plug seedling plays an important role in improving vegetable production. The process of plug seedling contributes to high-quality vegetable seedlings. The substrate composition and chemical fertilizer are widely studied to promote seedling growth. However, little is known about the effect of beneficial bacteria in the rhizosphere microbial community and vegetables' growth during plug seedling. The use of beneficial microbes to promote vegetable seedling growth is of great potential. In this study, we showed that the Serratia marcescens strain LYGN1 enhanced the growth of cucumber and pepper seedlings in plug seedling cultivation. The treatment with LYGN1 significantly increased the biomass and the growth-related index of cucumber and pepper, improving the seedling quality index. Specifically, LYGN1 also improved the cucumber and pepper root system architecture and increased the root diameter. We applied high-throughput sequencing to analyze the microbial community of the seedlings' rhizosphere, which showed LYGN1 to significantly change the composition and structure of the cucumber and pepper rhizosphere microbial communities. The correlation analysis showed that the Abditibacteriota and Bdellovibrionota had positive effects on seedling growth. The findings of this study provide evidence for the effects of Serratia marcescens LYGN1 on the cucumber and pepper rhizosphere microbial communities, which also promoted seedling quality in plug seedling cultivation.

Poly (ADP-ribose) Polymerase Inhibitors in Patients with Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis of Randomized Controlled Trials.

Context: Several recent randomized controlled trials (RCTs) have reported on the survival benefits of poly (ADP-ribose) polymerase inhibitors (PARPi) compared to standard-of-care (SOC) treatment (enzalutamide, abiraterone, or docetaxel) in patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is a limited integrated analysis of high-quality evidence comparing the efficacy and safety of PARPi and SOC treatments in this context. Objective: This study aims to comprehensively analyze the survival benefits and adverse events associated with PARPi and SOC treatments through a head-to-head meta-analysis in mCRPC. Evidence acquisition: A systematic review search was conducted in PubMed, Embase, Clinical trials, and the Central Cochrane Registry in July 2023. RCTs were assessed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The systematic review was prospectively registered on PROSPERO (CRD42023441034). Evidence synthesis: A total of 8 studies, encompassing 2341 cases in the PARPi treatment arm and 1810 cases in the controlled arm, were included in the qualitative synthesis. The hazard ratio (HR) for radiographic progression-free survival (rPFS) and overall survival (OS) were 0.74 (95% CI, 0.61-0.90) and 0.89 (95% CI, 0.80-0.99), respectively, in the intention-to-treatment patients. For subgroup analysis, HRs for rPFS and OS in the BRCA-mutated subgroup were 0.39 (95% CI, 0.28-0.55) and 0.62 (95% CI, 0.38-0.99), while in the HRR-mutated subgroup, HR for rPFS was 0.57 (95% CI, 0.48-0.69) and for OS was 0.77 (95% CI, 0.64-0.93). The odds ratio (OR) for all grades of adverse events (AEs) and AEs with severity of at least grade 3 were 3.86 (95% CI, 2.53-5.90) and 2.30 (95% CI, 1.63-3.26), respectively. Conclusions: PARP inhibitors demonstrate greater effectiveness than SOC treatments in HRR/BRCA-positive patients with mCRPC. Further research is required to explore ways to reduce adverse event rates and investigate the efficacy of HRR/BRCA-negative patients.

Unobstructed orthopaedic surgical robot assisted percutaneous iliosacral screw fixation of sacral brittle fractures.

Pelvic fractures mostly result from high-energy injuries in life; the longitudinal fracture of the sacrum is the most common type of sacrum fracture. This study was designed to evaluate the accuracy, safety, and efficacy of percutaneous sacroiliac joint screw placement in the treatment of longitudinal sacrum fractures with the assistance of unobstructed orthopaedic surgery robots. According to different surgical methods, 32 patients were divided into robot group and free hand group, with 16 patients in each group. The operation time, intra-operative blood loss, intra-operative fluoroscopy times, screw placement angle deviation were collected. There were statistically significant differences in terms of angle deviation of screw placement (1.96 ± 0.75° vs. 2.87 ± 1.03°; p = 0.0145), deviation of the guide needle (1.92 ± 0.93 mm vs. 2.91 ± 1.22 mm; p = 0.0209), intra-operative fluoroscopy time (7.25 ± 1.72 s vs. 20.93 ± 5.64 s; p = 0.0000), insertion time of each sacroiliac joint screw (14.72 ± 2.66 min vs. 29.21 ± 5.18 min; p = 0.0000). There was no statistically significant difference in terms of blood loss (100.21 ± 7.37 mL vs. 102.52 ± 8.15 mL; p = 0.4136). These results suggest that orthopaedic surgery robot for the treatment of longitudinal sacrum fracture is safer and provides less irradiation than the traditional freehand methods.

DSE inhibits melanoma progression by regulating tumor immune cell infiltration and VCAN.

Dermatan sulfate epimerase (DSE) is a C5 epiminase that plays a key role in converting chondroitin sulfate into dermal sulfate. DSE is often upregulated during carcinogenesis of some types of cancer and can regulate growth factor signaling in cancer cells. However, the expression and function of DSE in human melanoma have not been reported. In this study, we investigated the influence of tumor-derived DSE in melanoma progression and the potential mechanism of their action. First, proteomic analysis of collected melanoma tissues revealed that DSE was significantly down-regulated in melanoma tissues. DSE silenced or overexpressed melanoma cells were constructed to detect the effect of DSE on melanoma cells, and it was found that the up-regulation of DSE significantly inhibited the proliferation, migration and invasion of melanoma cells. Data analysis and flow cytometry were used to evaluate the immune subpopulations in tumors, and it was found that the high expression of DSE was closely related to the invasion of killer immune cells. Mechanistically, DSE promoted the expression of VCAN, which inhibited the biological activity of melanoma cells. Together, these results suggest that DSE is downregulated in melanoma tissues, and that high expression of DSE can promote melanoma progression by inducing immune cell infiltration and VCAN expression.

Effects of Thermal-Strain-Induced Atomic Intermixing on the Interfacial and Photoluminescence Properties of InGaAs/AlGaAs Multiple Quantum Wells.

Quantum-well intermixing (QWI) technology is commonly considered as an effective methodology to tune the post-growth bandgap energy of semiconductor composites for electronic applications in diode lasers and photonic integrated devices. However, the specific influencing mechanism of the interfacial strain introduced by the dielectric-layer-modulated multiple quantum well (MQW) structures on the photoluminescence (PL) property and interfacial quality still remains unclear. Therefore, in the present study, different thicknesses of SiO2-layer samples were coated and then annealed under high temperature to introduce interfacial strain and enhance atomic interdiffusion at the barrier-well interfaces. Based on the optical and microstructural experimental test results, it was found that the SiO2 capping thickness played a positive role in driving the blueshift of the PL peak, leading to a widely tunable PL emission for post-growth MQWs. After annealing, the blueshift in the InGaAs/AlGaAs MQW structures was found to increase with increased thickness of the SiO2 layer, and the largest blueshift of 30 eV was obtained in the sample covered with a 600 nm thick SiO2 layer that was annealed at 850 °C for 180 s. Additionally, significant well-width fluctuations were observed at the MQW interface after intermixing, due to the interfacial strain introduced by the thermal mismatch between SiO2 and GaAs, which enhanced the inhomogeneous diffusion rate of interfacial atoms. Thus, it can be demonstrated that the introduction of appropriate interfacial strain in the QWI process is of great significance for the regulation of MQW band structure as well as the control of interfacial quality.

Fatty Acids Support the Fitness and Functionality of Tumor-Resident CD8+ T Cells by Maintaining SCML4 Expression.

CD8+ tissue-resident memory T (Trm) cells and tumor-infiltrating lymphocytes (TIL) regulate tumor immunity and immune surveillance. Characterization of Trm cells and TILs could help identify potential strategies to boost antitumor immunity. Here, we found that the transcription factor SCML4 was required for the progression and polyfunctionality of Trm cells and was associated with a better prognosis in patients with cancer. Moreover, SCML4 maintained multiple functions of TILs. Increased expression of SCML4 in CD8+ cells significantly reduced the growth of multiple types of tumors in mice, while deletion of SCML4 reduced antitumor immunity and promoted CD8+ T-cell exhaustion. Mechanistically, SCML4 recruited the HBO1-BRPF2-ING4 complex to reprogram the expression of T cell-specific genes, thereby enhancing the survival and effector functions of Trm cells and TILs. SCML4 expression was promoted by fatty acid metabolism through mTOR-IRF4-PRDM1 signaling, and fatty acid metabolism-induced epigenetic modifications that promoted tissue-resident and multifunctional gene expression in Trm cells and TILs. SCML4 increased the therapeutic effect of anti-PD-1 treatment by elevating the expression of effector molecules in TILs and inhibiting the apoptosis of TILs, which could be further enhanced by adding an inhibitor of H3K14ac deacetylation. These results provide a mechanistic perspective of functional regulation of tumor-localized Trm cells and TILs and identify an important activation target for tumor immunotherapy. SIGNIFICANCE: SCML4 upregulation in CD8+ Trm cells and tumor-infiltrating lymphocytes induced by fatty acid metabolism enhances antitumor immune responses, providing an immunometabolic axis to target for cancer treatment. See related commentary by Chakraborty et al., p. 3321.

The "Hand as Foot" teaching method in calcaneal skeletal traction nursing.

OBJECTIVE: To introduce the application of "Hand as Foot" teaching method in calcaneal skeletal traction nursing.

m6A methylation regulates hypoxia-induced pancreatic cancer glycolytic metabolism through ALKBH5-HDAC4-HIF1α positive feedback loop.

Pancreatic cancer (PC) is the most hypoxic cancer type among solid tumors. The dynamic changes of RNA N6-methyl-adenosine (m6A) contribute to tumor cells adaption to hypoxic microenvironmental. However, the regulatory mechanisms of hypoxia response in PC remains elusive. Here, we reported that the m6A demethylase ALKBH5 mediated a decrease of total mRNA m6A modification during hypoxia. Subsequently, methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq) revealed transcriptome-wide gene expression alteration and identified histone deacetylase type 4 (HDAC4) as a key target gene of m6A modification under hypoxic conditionds. Mechanistically, m6A methylation recognized by m6A reader-YTHDF2 enhanced the stability of HDAC4, and then promoted glycolytic metabolism and migration of PC cells. Our assays also demonstrated that hypoxia-induced HDAC4 enhanced HIF1a protein stability, and overexpressed HIF1a promoted transcription of ALKBH5 in hypoxic pancreatic cancer cells. Together, these results found a ALKBH5/HDAC4/HIF1α positive feedback loop for cellular response to hypoxia in pancreatic cancer. Our studies uncover the crosstalk between histone acetylation and RNA methylation modification on layer of epigenetic regulation.

Atomic-scale insights into the interfacial charge transfer in a NiO/CeO2 heterostructure for electrocatalytic hydrogen evolution.

To understand the underlying mechanism of the interfacial charge transfer and local chemical state variation in the nonprecious-based hydrogen evolution reaction (HER) electrocatalysts, a model system of the NiO/CeO2 heterostructure was chosen for investigation using a combination of the advanced electron microscopic characterization and first-principles calculations. The results directly proved that interfacial charge transfer occurs from Ni to Ce, leading to reduction in the valence state of Ce and increased formation of VO. This would optimize ΔGH* and facilitate the hydrogen evolution process, resulting in outstanding HER performance in 1 M KOH with a low overpotential of 99 mV at the current density of 10 mA•cm-2 and a modest Tafel slope of 78.4 mV•dec-1 for the NiO/CeO2 heterostructure sample. Therefore, the improved HER performance could be attributed to the synergistic coupling interactions and electron redistribution at the interface of NiO and CeO2. These results concretely demonstrate the direct determination of the interfacial structure of the heterostructure and provide atomistic insights to unravel the underlying mechanism of interfacial charge transfer induced HER performance improvement.

Self-Adaptive Electronic Structure of Amphoteric Conjugated Ligand-Modified 3 d Metal-C3 N4 Smart Electrocatalyst by pH Self-Response Realizing Electrocatalytic Self-Adjustment.

Constructing pH-responsive smart material provides a new opportunity to address the problem that traditional electrocatalysts cannot achieve both alkaline oxygen evolution reaction (OER) and acidic hydrogen evolution reaction (HER) activities. In this study, amphoteric conjugated ligand (2-aminoterephthalic acid, BDC-NH2 )-modified 3d metal-anchored graphitic carbon nitride (3d metal-C3 N4 ) smart electrocatalysts are constructed, and self-adaptation of the electronic structure is realized by self-response to pH stimulation, which results in self-adjustment of alkaline OER and acidic HER. Specifically, the amino and carboxyl functional groups in BDC-NH2 undergo protonation and deprotonation respectively under different pH stimulation to adapt to environmental changes. Through DFT calculations, the increase or decrease of electron delocalization range brought by the self-response characteristic is found to lead to redistribution of the Bader charge around the modified active sites. The OER and HER activities are greatly promoted roughly 4.8 and 8.5 times over Co-C3 N4 after BDC-NH2 -induced self-adaptive processes under different environments, arising from the reduced energy barrier of O* to OOH* and ΔGH* . Impressively, the proposed BDC-NH2 -induced smart regulation strategy is applicable to a series of 3d metal anchors for C3 N4 , including Co, Ni and Fe, providing a general structural upgrading method for constructing smart electrocatalytic systems.

USP48 Stabilizes Gasdermin E to Promote Pyroptosis in Cancer.

Pyroptosis is a type of programmed cell death characterized by the activation of inflammatory caspases and the cleavage of gasdermin proteins. Pyroptosis can suppress tumor development and induce antitumor immunity, and activating pyroptosis is a potential treatment strategy for cancer. To uncover approaches to harness the anticancer effects of pyroptosis, we aimed to identify regulators of pyroptosis in cancer. A CRISPR-Cas9 screen identified that loss of USP48, a deubiquitinating enzyme, significantly inhibited cell pyroptosis. USP48 promoted pyroptosis by stabilizing gasdermin E (GSDME). USP48 bound GSDME and removed K48-linked ubiquitination at positions K120 and K189. Clinical tissue testing confirmed that the expression of USP48 positively correlated with GSDME and pyroptosis-related factors. Single-cell sequencing showed that the functions of T cells and tumor-associated macrophages in the tumor microenvironment were inhibited after USP48 knockout. Finally, overexpression of USP48 enhanced the therapeutic efficacy of programmed cell death protein 1 inhibitors in tumors in mouse models. Together, these findings define a pyroptosis regulation pathway and indicate that pharmacologic activation of USP48 may provide an effective strategy to sensitize cancer cells to pyroptosis and improve response to immunotherapy. SIGNIFICANCE: USP48 promotes pyroptosis by deubiquitinating GSDME and enhances antitumor immunity, indicating that increasing USP48 activity may be a future therapeutic strategy for treating cancer.

Development and Validation of the Prediction Model of Sepsis in Patients After Percutaneous Nephrolithotomy and Sepsis Progresses to Septic Shock.

Background: To study the predictors of sepsis and the progression of sepsis to septic shock in patients after percutaneous nephrolithotomy (PCNL) and to establish and validate predictive models. Methods: The patients were assigned to either the development cohort or the validation cohort depending on their hospital. In the development cohort, univariate and multivariate logistic regression analyses were used to screen independent risk factors for sepsis after PCNL and sepsis progression to septic shock. Nomogram prediction models were established according to the related independent risk factors. Areas under the receiver operating characteristic curves, calibration plots, and decision curve analysis (DCA) were used to estimate the discrimination, calibration, and clinical usefulness of the prediction models, respectively. The two sets of models were further validated on the validation cohort. Results: In the development cohort, the risk factors for sepsis after PCNL were diabetes, urine nitrite, staghorn calculi, HU value, albumin-globulin ratio, and high-sensitivity C-reactive protein/albumin ratio. The pre- and postoperative white blood cell counts were risk factors for the progression of sepsis to septic shock. The area under the ROC curve value for predicting sepsis risk was 0.891 and that for predicting septic shock risk was 0.981 in the development cohort; in the validation cohort, these values were 0.893 and 0.996, respectively. In the development cohort, the calibration test p values in the sepsis and septic shock cohorts were 0.946 and 0.634, respectively; in the validation cohort, these values were 0.739 and 0.208, respectively. DCA of the model in the sepsis and septic shock cohorts showed threshold probabilities of 10%-90% in the development cohort; in the validation cohort, these values were 10%-90%. Conclusion: The individualized nomogram prediction models can help improve the early identification of patients who are at higher risk of developing sepsis after PCNL and the progression of sepsis to septic shock to avoid further damage.

Synthesis of Fibrous Phosphorus Micropillar Arrays with Pyro-Phototronic Effects.

The bottom-up preparation of two-dimensional material micro-nano structures at scale facilitates the realisation of integrated applications in optoelectronic devices. Fibrous Phosphorus (FP), an allotrope of black phosphorus (BP), is one of the most promising candidate materials in the field of optoelectronics with its unique crystal structure and properties.[1] However, to date, there are no bottom-up micro-nano structure preparation methods for crystalline phosphorus allotropes.[1c, 2] Herein, we present the bottom-up preparation of fibrous phosphorus micropillar (FP-MP) arrays via a low-pressure gas-phase transport (LP-CVT) method that controls the directional phase transition from amorphous red phosphorus (ARP) to FP. In addition, self-powered photodetectors (PD) of FP-MP arrays with pyro-phototronic effects achieved detection beyond the band gap limit. Our results provide a new approach for bottom-up preparation of other crystalline allotropes of phosphorus.

Atomic-Scale Insights into the Interfacial Polarization Effect in the InGaN/GaN Heterostructure for Solar Cells.

The model system of the InGaN/GaN quantum wells (QWs), based on the first principles calculation, was chosen to understand the underlying mechanism of interfacial polarization and its synergic effect with the built-in electric field (Bef) at the p-n junction in solar cells (SLs). The polarized electric field (Pef) was generated due to the redistribution of electrons and holes at the interface; moreover, the Pef of InGaN/GaN heterostructure on the semipolar (01-11) GaN surface was consistent with that of on the N-polar (000-1) surface, which is on the lines of the Bef and favors the electron-hole separation efficiency in SLs. Furthermore, the growth of high-quality InGaN/GaN QWs on the semipolar (01-11) GaN surface was achieved. Such an atomic-scale investigation provides a fundamental understanding of the polarization charge-induced Pef and its interaction coupling with Bef at the p-n junction, which could be generalized to polar material-based SLs.

Mixed-Dimensional van der Waals Heterostructure for High-Performance and Air-Stable Perovskite Nanowire Photodetectors.

An organic-inorganic hybrid perovskite nanowire (NW), CH3NH3PbI3, shows great potential for high-performance photodetectors due to its excellent photoresponse. However, the inefficient carrier collection between the one-dimensional (1D) NWs and metallic electrodes, as well as degradation of the perovskite, limits the viability of the CH3NH3PbI3 NWs for commercial production. Here, we demonstrate a photodetector with a mixed-dimensional van der Waals heterostructure of hexagonal boron nitride (hBN)/graphene (Gr)/1D CH3NH3PbI3, which exhibits excellent responsivity and specific detectivity of up to 558 A/W and 2.3 × 1012 Jones, owing to the improved carrier extraction at the electrical contact between Gr and the NW. As for the atomic encapsulation of hBN, the device is extremely robust and maintains its outstanding performance for more than 2 months when exposed to air. Moreover, benefitting from the 1D geometry of the CH3NH3PbI3 NW, our device is highly sensitive to polarized light. The mixed-dimensional van der Waals heterostructure, hBN/Gr/1D CH3NH3PbI3, would provide a novel idea and protocol for fabricating high-performance and air-stable photoelectronic devices based on organic-inorganic hybrid perovskite NWs.