Atomically Engineered Chlorine Coordination of Iron in Active Centers for Selectively Catalytic H2O2 Decomposition Toward Efficient Antitumor-Specific Therapy.

The intervention of endogenous H2O2 via nanozymes provides a potential antitumor-specific therapy; however, the role of the nanozyme structure in relation to the selective decomposition of H2O2 to hydroxyl radicals (•OH) is yet to be fully understood, which limits the development of this therapeutic approaches. Herein, an iron single-atom nanozyme (Fe─N2Cl2─C SAzyme) is reported, which is prepared through precise Fe─Cl coordination based on the construction of a characteristic Fe-containing molecule. Fe─N2Cl2─C exhibits efficient catalytic H2O2 decomposition (2.19 × 106 mm-1 s-1), which is the highest among reported SAzymes. More importantly, it is found that H2O2 selectively decomposed into •OH on the Fe─N2Cl2─C surface, which is attributable to the d orbitals of the Fe active center matching the O-2p electrons of the adsorbed hydroxide (*OH) intermediate. Fe─N2Cl2─C is strongly cytotoxic toward a variety of cancer-cell lines in vitro but not to normal cells. Furthermore, Fe─N2Cl2─C shows an outstanding specific therapeutic effect in vivo; it efficiently destroys solid malignant tumors without injuring normal tissue. Altogether, these findings highlight the selective catalytic decomposition of H2O2 to •OH, which is achieved by engineering the active center on the atomic level, thereby providing an avenue for the development of specific nanomedicines with efficient antitumor activities.

Biodegradable copper-iodide clusters modulate mitochondrial function and suppress tumor growth under ultralow-dose X-ray irradiation.

Both copper (Cu2+/+) and iodine (I-) are essential elements in all living organisms. Increasing the intracellular concentrations of Cu or I ions may efficiently inhibit tumor growth. However, efficient delivery of Cu and I ions into tumor cells is still a challenge, as Cu chelation and iodide salts are highly water-soluble and can release in untargeted tissue. Here we report mitochondria-targeted Cu-I cluster nanoparticles using the reaction of Cu+ and I- to form stable bovine serum albumin (BSA) radiation-induced phosphors (Cu-I@BSA). These solve the stability issues of Cu+ and I- ions. Cu-I@BSA exhibit bright radioluminescence, and easily conjugate with the emission-matched photosensitizer and targeting molecule using functional groups on the surface of BSA. Investigations in vitro and in vivo demonstrate that radioluminescence under low-dose X-ray irradiation excites the conjugated photosensitizer to generate singlet oxygen, and combines with the radiosensitization mechanism of the heavy atom of iodine, resulting in efficient tumor inhibition in female mice. Furthermore, our study reveals that BSA protection causes the biodegradable Cu-I clusters to release free Cu and I ions and induce cell death by modulating mitochondrial function, damaging DNA, disrupting the tricarboxylic acid cycle, decreasing ATP generation, amplifying oxidative stress, and boosting the Bcl-2 pathway.

Effect of modified Ca-Al adsorbents on heavy metal fixation during co-combustion of coal and coconut shells: Experiments and simulations.

As an alternative fuel, bio-waste coconut shells have shown promise in reducing pollution during the co-combustion process. In this study, a novel metal-mineral adsorbent, Ca-Al (Ca5Al6O14), was prepared and physically (ultrasonic) and chemically (ethylene glycol) modified to enhance its adsorption properties. Thermal adsorption experiments investigated the effect of the adsorbents on the fixation of six heavy metals (HMs): Cr, Cu, Mn, Ni, Pb, and Zn. XRD, SEM, BET, and XPS were used to analyze the adsorbents and the adsorption mechanism was investigated by combining lattice oxygen concentration and Factsage simulation calculations. The ecological risk assessment of heavy metals was used to comprehensively evaluate the fixation effects of the three Ca-Al adsorbents at different additive levels. The results showed that the modification significantly changed the morphological characteristics and oxygen activity of the Ca-Al adsorbents, increased the lattice oxygen and chemisorbed oxygen concentration, and laid the foundation for promoting the chemisorption process in the fixation of heavy metals. In combination with the Er (environmental risk factors), adding all three adsorbents reduced Ri (Risk index). Among them, Ca-Al (EG) at 3% had the best effect on Ri. 3% Ca-Al (EG) reduced the Er value of Ni by 49.02%. 5% Ca-Al (EG) reduced the Er value of Cr by 86.01%. 5% Ca-Al (UM) had the best effect on Mn, with a reduction of 46.13%. The addition of 10% Ca-Al (UM) reduced Er of Ni by 50.43%. Considering the practical application in coal-fired power plants, Ca-Al(EG), which exhibits a higher fixation rate at small additions, is more suitable.

Clinical and pathological characteristics of and predictive model for colorectal neuroendocrine tumors.

Background: The incidence of colorectal neuroendocrine tumors (NETs) is increasing, causing a social burden. At present, there is no specific prognostic model for colorectal NETs. Thus, an accurate model is needed to predict the prognosis of patients with colorectal NETs. Aim: We aimed to create a new nomogram to predict the prognosis of patients with colorectal NETs. Furthermore, we compared nomogram we established and the 8th edition of the AJCC TNM staging system in terms of prediction ability and accuracy. Methods: A total of 3353 patients with colorectal NETs were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier analyses were used to assess overall survival (OS) and cancer-specific survival (CSS). Additionally, LASSO regression was used to select variables for constructing the nomogram. Furthermore, the C-index and time-dependent receiver operating characteristic (tdROC) curve were used to evaluate the nomogram. Decision curve analysis (DCA) was performed to compare the clinical utility of the nomogram with that of the TNM system. An external validation cohort (N = 61) was established to evaluate the nomogram's prediction accuracy. Results: A total of 9 factors (age, sex, marital status, tumor size, T stage, M stage, N stage, grade, and surgery) were selected based on the results of LASSO analysis. The C-indexes of the nomogram in the training and validation sets were 0.807 and 0.775, respectively, which indicated that the nomogram had better prediction accuracy than TNM staging (C-index = 0.700 in the training set and 0.652 in the validation set). The C-index of the nomogram in the external validation cohort was 0.954, indicating that the nomogram had satisfactory prediction accuracy. The results of DCA revealed that the survival nomogram possessed greater utility in clinical practice. Conclusion: We determined the OS and CSS of patients with colorectal NETs and developed a robust and clinically useful survival nomogram.

Natural variation in the Tn1a promoter regulates tillering in rice.

Rice tillering is an important agronomic trait that influences plant architecture and ultimately affects yield. This can be genetically improved by mining favourable variations in genes associated with tillering. Based on a previous study on dynamic tiller number, we cloned the gene Tiller number 1a (Tn1a), which encodes a membrane-localised protein containing the C2 domain that negatively regulates tillering in rice. A 272 bp insertion/deletion at 387 bp upstream of the start codon in the Tn1a promoter confers a differential transcriptional response and results in a change in tiller number. Moreover, the TCP family transcription factors Tb2 and TCP21 repress the Tn1a promoter activity by binding to the TCP recognition site within the 272 bp indel. In addition, we identified that Tn1a may affect the intracellular K+ content by interacting with a cation-chloride cotransporter (OsCCC1), thereby affecting the expression of downstream tillering-related genes. The Tn1a+272 bp allele, associated with high tillering, might have been preferably preserved in rice varieties in potassium-poor regions during domestication. The discovery of Tn1a is of great significance for further elucidating the genetic basis of tillering characteristics in rice and provides a new and favourable allele for promoting the geographic adaptation of rice to soil potassium.

Creatine Promotes Endometriosis by Inducing Ferroptosis Resistance via Suppression of PrP.

Endometriosis, a chronic inflammatory disease, significantly impairs the quality of life of women in their reproductive years; however, its pathogenesis remains poorly understood. The accumulation of retrograde menstruation and recurrent bleeding fosters a high-iron environment in ectopic lesions, triggering ferroptosis in ectopic endometrial stromal cells (EESCs), thereby hindering the establishment of endometriosis. However, abnormal EESCs demonstrate resistance to ferroptosis in high-iron environments, promoting the progression of this disease. Here, novel findings on the accumulation of creatine, derived from endogenous synthesis, in both peritoneal fluid and EESCs of patients with endometriosis are presented. Creatine supplementation reduces cellular iron concentrations, mitigating oxidative stress and lipid peroxidation, thereby enhancing cell viability and preventing ferroptosis under high-iron conditions. Utilizing the drug affinity-responsive target stabilization (DARTS) assay, prion protein (PrP) as a potential creatine-sensing protein is identified. Mechanistically, creatine binds to the active site of PrP, inhibits the conversion of trivalent iron to divalent iron, and decreases iron uptake, promoting the tolerance of EESCs to ferroptosis. This interaction contributes to the development of endometriosis. The novel association between creatine and ferroptosis provides valuable insights into the role of creatine in endometriosis progression and highlights its potential as a therapeutic target for endometriosis.

ZMAT2 condensates regulate the alternative splicing of TRIM28 to reduce cellular ROS accumulation, thereby promoting the proliferation of HCC cells.

Dysregulation of splicing factor expression plays a crucial role in the progression of hepatocellular carcinoma (HCC). Our research found that the expression level of splicing factor ZMAT2 was increased in HCC, promoting the proliferation of HCC cells. RNAseq data indicated that the absence of ZMAT2 induced skipping exon of mRNA, while RIPseq data further revealed the mRNA binding motifs of ZMAT2. A comprehensive analysis of RNAseq and RIPseq data indicateed that ZMAT2 played a crucial role in the maturation process of TRIM28 mRNA. Knocking down of ZMAT2 led to the deletion of 25 bases in exon 11 of TRIM28, ultimately resulting in nonsense-mediated decay (NMD). Our data revealed that ZMAT2 could regulate TRIM28 to reduce the accumulation of ROS in HCC cells, thereby promoting their proliferation. Our research also discovered that ZMAT2 was capable of undergoing phase separation, resulting in the formation of liquid droplet condensates within HCC cells. Additionally, it was found that ZMAT2 was able to form protein-nucleic acid condensates with TRIM28 mRNA. In summary, this study is the first to reveal that ZMAT2 and TRIM28 mRNA form protein-nucleic acid condensates, thereby regulating the splicing of TRIM28 mRNA. The increased expression of ZMAT2 in HCC leads to upregulated TRIM28 expression and reduced ROS accumulation, ultimately accelerating the proliferation of HCC cells.

Analyzing performance and microbial mechanisms in an incineration leachate treatment after waste separation: Integrated metagenomic and metaproteomic analyses.

The absence of food waste after separation poses a significant challenge to incineration leachate treatment, as it decreases the C/N ratio and COD of leachate, greatly impacting the biological treatment process. A one-year in-situ study was systematically conducted in an incineration leachate treatment plant that experienced waste separation, focusing on the variations in carbon and nitrogen removal performance as well as the involved microbial mechanism of the "anaerobic digestion (AD) + two-stage A/O" process. Results indicated that the biodegradability of leachate significantly decreased over time, with COD concentration decreasing by 10 times and the average C/N ratio decreasing from 12.3 to 1.4. The AD process was maintained stable, achieving a COD removal efficiency exceeding 92 %. The nitrification process also remained stable; while the denitrification process was significantly affected, and a nine-fold increase in external glucose addition was required to achieve a nitrogen removal efficiency of 85 %. Metagenomic analysis indicated that comammox Nitrospira (contributing 90 % to ammonia monooxygenase) occupied the dominant position over Nitrosomonas for nitrification due to the low NH4+-N concentration in A/O tanks (<35 mg/L), and Methanothrix was substituted by Methanosarcina for methanogenesis in AD unit. Metaproteomic results further elucidated that the expression of enzymes responsible for denitrification process, i.e., Nir, Nor, Nos (convert NO2- to N2), was decreased significantly, although the expression of enzymes related to glycolysis and TCA cycle were stimulated by glucose addition. The expression of Nar (convert NO3--N to NO2--N) remained stable, while the imbalance expression within denitrifying enzymes might have facilitated occurrence of partial denitrification, attributed to the low C/N ratio. The results prove that the function robustness and metabolic versatility were achieved in leachate treatment plant after waste separation but at the cost of the high external carbon resource addition, highlighting the urgent requirement for low-carbon nitrogen removal technologies.

An acid-activatable fluorouracil prodrug for colorectal cancer synergistic therapy.

5-Fluorouracil has demonstrated certain efficiency in patients with colorectal cancer. However, significant side effects of use by injection are common. To address this issue defects, a reengineered 5'-deoxy-5-fluorocytidine (DFCR) based drug delivery system (POACa) is developed as a prominent tumor-selective nano-activator. Investigations demonstrate that the constructed nano-activator exhibits good biocompatibility and high therapeutic efficiency in mice with subcutaneous and orthotopic SW-480 colorectal tumors, as its activity is strictly dependent on the tumor-associated acid environment and thymidine phosphorylase. These strategies diminish the off-target toxicity and improve the specificity and sensitivity of human colorectal cancer cells to 5-Fu, obtaining potent efficiency by the combination of H2O2 mediated oxidative stress, calcium overload and 5-Fu-induced chemotherapy (the combination index is 0.11). Overall, the engineered nano-activator exhibits a high therapeutic index in vitro and in vivo. STATEMENT OF SIGNIFICANCE: In this study, we designed and prepared a pH-responsive polymer to synchronously deliver DFCR (5'-deoxy-5-fluorocytidine, a prodrug of 5-Fu), Ca2+ and H2O2. The constructed nano-activator was denoted as POACa. (1) To address the problem of premature leakage of cargo by physical embedding, our research modified the inactive prodrug DFCR through chemical bonding. (2) The activation of the prepared nano-activator was strictly dependent on the tumor-associated acid environment and thymidine phosphorylase, providing the drug delivery system with inherent safety. (3) A distinctly low combination index value (0.11) of CaO2 and DFCR indicated that POACa has a prominent tumor suppression effect by tumor calcium overload sensitized chemotherapy and H2O2 mediated cytotoxicity.

Functional and structural abnormalities of thalamus in individuals at early stage of schizophrenia.

BACKGROUND: Thalamic abnormalities in schizophrenia are recognized, alongside cognitive deficits. However, the current findings about these abnormalities during the prodromal period remain relatively few and inconsistent. This study applied multimodal methods to explore the alterations in thalamic function and structure and their relationship with cognitive function in first-episode schizophrenia (FES) patients and ultra-high-risk (UHR) individuals, aiming to affirm the thalamus's role in schizophrenia development and cognitive deficits. METHODS: 75 FES patients, 60 UHR individuals, and 60 healthy controls (HC) were recruited. Among the three groups, gray matter volume (GMV) and functional connectivity (FC) were evaluated to reflect the structural and functional abnormalities in the thalamus. Pearson correlation was used to calculate the association between these abnormalities and cognitive impairments. RESULTS: No significant difference in GMV of the thalamus was found among the abovementioned three groups. Compared with HC individuals, FES patients had decreased thalamocortical FC mostly in the thalamocortical triple network, including the default mode network (DMN), salience network (SN), and executive control network (ECN). UHR individuals had similar but milder dysconnectivity as the FES group. Furthermore, FC between the left thalamus and right putamen was significantly correlated with execution speed and attention in the FES group. CONCLUSIONS: Our findings revealed decreased thalamocortical FC associated with cognitive deficits in FES and UHR subjects. This improves our understanding of the functional alterations in thalamus in prodromal stage of schizophrenia and the related factors of the cognitive impairment of the disease. TRIAL REGISTRATION: ClinicalTrials.govNCT03965598; https://clinicaltrials.gov/ct2/show/NCT03965598.