Gut-brain bidirectional determination in regulating the residual feed intake of small-sized meat ducks.

The gut-brain axis is essential in maintaining the homeostasis of neuronal system, endocrine system, and intestinal microbiota in both the afferent and efferent directions. This axis is considered to be a key mechanism that regulates feed efficiency (FE). This study aimed to investigate the regulatory mechanisms of gut-brain axis-related genes on the residual feed intake (RFI) in H-strain small-sized meat ducks. A total of 500 ducks with similar initial BW (635.2 ± 15.1 g) were selected and reared in the same experimental facility until slaughter at 42 d of age. RFI was calculated from the average daily gain (ADG), average daily feed intake (ADFI), and metabolic body weight (MBW0.75). Thirty high-RFI (H-RFI) and 30 low-RFI (L-RFI) birds were selected for further evaluation of growth performance, carcass characteristics, and blood biochemical parameter measurements. Six L-RFI and 6 H-RFI birds were then subjected to hypothalamic transcriptomic and cecal microbial sequencing analyses. Results indicated that L-RFI birds exhibited lower production performance (ADFI, FCR, and RFI) and blood biochemical indices (total cholesterol and ghrelin content) compared with H-RFI birds (P < 0.05). Gene expression differed significantly between the L-RFI and H-RFI birds, with 70 upregulated and 50 downregulated genes. The bacterial communities of L-RFI birds showed higher abundances of Bacteroides, Bifidobacterium, and Lactococcus, and lower abundances of Erysipelatoclostridium, Parasutterella, Fournierella, and Blautia compared with H-RFI birds (P < 0.05). Interactive analysis revealed bacterial communities associated with FE were significantly correlated with hypothalamic genes (P < 0.05), for example, Bacteroides was positively correlated with DGKH and LIPT2, while negatively correlated with CAPN9, GABRD, and PDE1A. Bifidobacterium showed significant correlations with ATP2A3, CALHM6, and TMEM121B. Overall, RFI was a crucial indicator of FE, regulated by interactions between brain gene expression and gut microbiota through cAMP signaling, neuroactive ligand-receptor interaction, and calcium signaling pathways. Notably, increased expression of hypothalamic genes and abundance of carbohydrate-utilization microbiota in L-RFI meat ducks improved FE by enhancing energy metabolism and volatile fatty acids absorption.

Metagenomic insights into the relationship between intestinal flora and residual feed intake of meat ducks.

In this study, we sought to determine the effects of intestinal flora on the feed efficiency of meat ducks by evaluating the correlation between intestinal flora and residual feed intake. The F2 generation of Cherry Valley ducks × Runzhou Crested White ducks was used as the study subjects, and feed consumption being recorded from d 21 to 42. RFI was calculated based on growth performance, and 20 low RFI and 20 high RFI ducks were randomly selected to characterize the effect of RFI on growth performance. To analyze the intestinal flora affecting RFI, 16s rDNA sequencing was performed on the contents of 5 intestinal segments from the HR and LR groups, and macrogenomic sequencing was performed on the cecal contents. Feed intake, average daily feed intake, feed conversion ratio, and residual feed intake were lower in low RFI. Analysis of the intestinal flora revealed the cecum to be more highly enriched in the carbohydrate metabolism pathway and less enriched with potentially pathogenic taxa than the other assessed intestinal regions. Further analysis of the cecal microbiota identified nine significantly differentially enriched intestinal flora. In this study, we accordingly identified a basis for the mechanisms underlying the effects of the intestinal flora on meat duck feed efficiency.

Association of the oxidative balance score with obesity and body composition among young and middle-aged adults.

Objective: The oxidative balance score (OBS) is important for determining the cause of obesity and its complications. We aimed to evaluate the association between OBS and obesity and other segmental body composition parameters among young and middle-aged U.S. adults. Methods: 9,998 participants from the National Health and Nutrition Examination Survey 2011-2018 were included. Lean mass percentage (LM%) and FM% were evaluated by dual-energy x-ray absorptiometry. Obesity was defined as body FM% ≥25% in men and ≥ 35% in women. The OBS was scored by 5 pro-oxidant and 21 antioxidant factors. Associations of quartiles of OBS with obesity risk were estimated using multivariable logistic regression models. Multivariable linear regression was conducted to estimate the association between OBS and segmental body composition measures including the arm LM%, leg LM%, torso LM%, whole LM%, arm FM%, leg FM%, torso FM% and total FM%. Results: Compared to participants in the lowest quartile of OBS, those in the highest quartile of OBS were associated with a lower risk of BMI-defined obesity BMI-defined obesity [0.43 (0.36, 0.50)] and FM%-related obesity [0.43 (0.35, 0.52)]. Additionally, OBS was negatively associated with FM% of the limb and torso but positively associated with the percentage of lean mass (LM%) of the limb and trunk. Conclusion: OBS was negatively associated with the risk of obesity and segmental FM%, but was positively associated with segmental LM% among US adults, indicating that adhering to an anti-oxidative diet and lifestyle management may be beneficial for preventing segmental obesity.

Innovative Approach to Chiral Polyurethanes: Asymmetric Copolymerization with Isocyanates.

The introduction of nitrogen-containing functional groups to chiral polymer backbones enables the tailoring of physical properties and offers opportunities for further post-polymerization modification. However, the substrate scope of such polymers is extremely limited because monomers having nitrogen-containing groups can change coordination state with respect to the metal centers, thus decreasing the activity and enantioselectivity and even poisoning the catalyst completely. In this paper, we report our attempts to carry out the asymmetric copolymerization of meso-epoxide with highly reactive isocyanates. In particular, we found that biphenol-linked bimetallic Co(III) complexes with multiple chiral centers are very efficient in catalyzing this asymmetric copolymerization reaction, affording optically active polyurethanes with a completely alternating nature and a high enantioselectivity of up to 94% ee. Crucially, we identified that the steric hindrance at the phenolate ortho position of the ligand strongly influences the catalytic activity and product enantioselectivity. In addition, density functional theory calculations revealed that the highly sterically bulky substituents change the mechanism from bimetallic to monometallic, and result in the unexpected inversion of the chiral induction direction. Moreover, the high stereoregularity of the produced polyurethanes enhances their thermal stability. This study offers a versatile methodology for the synthesis of chiral polymers containing nitrogen functionalities.

Clinical efficacy and pathological outcomes of transanal endoscopic intersphincteric resection for low rectal cancer.

BACKGROUND: Transanal endoscopic intersphincteric resection (ISR) surgery currently lacks sufficient clinical research and reporting. AIM: To investigate the clinical effectiveness of transanal endoscopic ISR, in order to promote the clinical application and development of this technique. METHODS: This study utilized a retrospective case series design. Clinical and pathological data of patients with lower rectal cancer who underwent transanal endoscopic ISR at the First Affiliated Hospital of Xiamen University between May 2018 and May 2023 were included. All patients underwent transanal endoscopic ISR as the surgical approach. We conducted this study to determine the perioperative recovery status, postoperative complications, and pathological specimen characteristics of this group of patients. RESULTS: This study included 45 eligible patients, with no perioperative mortalities. The overall incidence of early complications was 22.22%, with a rate of 4.44% for Clavien-Dindo grade ≥ III events. Two patients (4.4%) developed anastomotic leakage after surgery, including one case of grade A and one case of grade B. Postoperative pathological examination confirmed negative circumferential resection margins and distal resection margins in all patients. The mean distance between the tumor lower margin and distal resection margin was found to be 2.30 ± 0.62 cm. The transanal endoscopic ISR procedure consistently yielded high quality pathological specimens. CONCLUSION: Transanal endoscopic ISR is safe, feasible, and provides a clear anatomical view. It is associated with a low incidence of postoperative complications and favorable pathological outcomes, making it worth further research and application.

Optimal configuration method of demand-side flexible resources for enhancing renewable energy integration.

Demand-side flexible load resources, such as Electric Vehicles (EVs) and Air Conditioners (ACs), offer significant potential for enhancing flexibility in the power system, thereby promoting the full integration of renewable energy. To this end, this paper proposes an optimal allocation method for demand-side flexible resources to enhance renewable energy consumption. Firstly, the adjustable flexibility of these resources is modeled based on the generalized energy storage model. Secondly, we generate random scenarios for wind, solar, and load, considering variable correlations based on non-parametric probability predictions of random variables combined with Copula function sampling. Next, we establish the optimal allocation model for demand-side flexible resources, considering the simulated operation of these random scenarios. Finally, we optimize the demand-side resource transformation plan year by year based on the growth trend forecast results of renewable energy installed capacity in Jiangsu Province from 2025 to 2031.

A national-scale assessment of land subsidence in China's major cities.

China's massive wave of urbanization may be threatened by land subsidence. Using a spaceborne synthetic aperture radar interferometry technique, we provided a systematic assessment of land subsidence in all of China's major cities from 2015 to 2022. Of the examined urban lands, 45% are subsiding faster than 3 millimeters per year, and 16% are subsiding faster than 10 millimeters per year, affecting 29 and 7% of the urban population, respectively. The subsidence appears to be associated with a range of factors such as groundwater withdrawal and the weight of buildings. By 2120, 22 to 26% of China's coastal lands will have a relative elevation lower than sea level, hosting 9 to 11% of the coastal population, because of the combined effect of city subsidence and sea-level rise. Our results underscore the necessity of enhancing protective measures to mitigate potential damages from subsidence.

miR-92a-3p regulates ethanol-induced apoptosis in H9c2 cardiomyocytes.

The role of miR-92a-3p in the ethanol-induced apoptosis of H9c2 cardiomyocytes remains unclear. In this study, we explored the role of miR-92a-3p in the ethanol-induced apoptosis of H9c2 cardiomyocytes and identified its target genes and signaling pathways. H9c2 cells were cultured with or without 100 mM ethanol for 24 h. The differential expression of miR-92a-3p was verified in H9c2 cells through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). To manipulate the expression of miR-92a-3p, both a mimic and an inhibitor were transfected into H9c2 cells. An Annexin V-fluorescein isothiocyanate/propidium iodide apoptosis detection kit and apoptosis-related antibodies were used for apoptosis detection through flow cytometry and Western blotting, respectively. Target genes were verified through RT-qPCR, Western blotting, and double luciferase reporter gene assays. miR-92a-3p was significantly overexpressed in ethanol-stimulated H9c2 cardiomyocytes (P < 0.001). After ethanol stimulation, H9c2 myocardial cells exhibited increased apoptosis. The apoptosis rate was higher in the miR-92a-3p mimic group than in the control group. However, the apoptosis rate was lower in the miR-92a-3p inhibitor group than in the control group, indicating that miR-92a-3p promotes the ethanol-induced apoptosis of H9c2 myocardial cells. RT-qPCR and Western blotting revealed that the miR-92a-3p mimic and inhibitor significantly regulated the mRNA and protein expression levels of mitogen- and stress-activated protein kinase 2 and cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2), suggesting that miR-92a-3p promotes the apoptosis of H9c2 cardiomyocytes by inhibiting the MSK2/CREB/Bcl-2 pathway. Therefore, the apoptosis of H9c2 cardiomyocytes increases after ethanol stimulation, and miR-92a-3p can directly target MSK2 and CREB3L2, thereby promoting the ethanol-induced apoptosis of H9c2 myocardial cells.

Closed-loop recycling of sulfur-rich polymers with tunable properties spanning thermoplastics, elastomers, and vitrimers.

The development of closed-loop recycling polymers that exhibit excellent performance is of great significance. Sulfur-rich polymers possessing excellent optical, thermal, and mechanical properties are promising candidates for chemical recycling but lack efficient synthetic strategies for achieving diverse structures. Herein, we report a universal synthetic strategy for producing polytrithiocarbonates, a class of sulfur-rich polymers, via the polycondensation of dithiols and dimethyl trithiocarbonate. This strategy has excellent compatibility with a wide range of monomers, including aliphatic, heteroatomic, and aromatic dithiols enabling the synthesis of polytrithiocarbonates with diverse structures. The present synthesis strategy offers a versatile platform for the construction of thermoplastics, elastomers, and vitrimers. Notably, these polytrithiocarbonates can be easily depolymerized via solvolysis into the corresponding monomers, which can be repolymerized to virgin polymers without changing the material properties.

Development of a risk prediction model for subsequent infection after colonization with carbapenem-resistant Enterobacterales: a retrospective cohort study.

BACKGROUND: Colonization of carbapenem-resistant Enterobacterale (CRE) is considered as one of vital preconditions for infection, with corresponding high morbidity and mortality. It is important to construct a reliable prediction model for those CRE carriers with high risk of infection. METHODS: A retrospective cohort study was conducted in two Chinese tertiary hospitals for patients with CRE colonization from 2011 to 2021. Univariable analysis and the Fine-Gray sub-distribution hazard model were utilized to identify potential predictors for CRE-colonized infection, while death was the competing event. A nomogram was established to predict 30-day and 60-day risk of CRE-colonized infection. RESULTS: 879 eligible patients were enrolled in our study and divided into training (n = 761) and validation (n = 118) group, respectively. There were 196 (25.8%) patients suffered from subsequent CRE infection. The median duration of subsequent infection after identification of CRE colonization was 20 (interquartile range [IQR], 14-32) days. Multisite colonization, polymicrobial colonization, catheterization and receiving albumin after colonization, concomitant respiratory diseases, receiving carbapenems and antimicrobial combination therapy before CRE colonization within 90 days were included in final model. Model discrimination and calibration were acceptable for predicting the probability of 60-day CRE-colonized infection in both training (area under the curve [AUC], 74.7) and validation dataset (AUC, 81.1). Decision-curve analysis revealed a significantly better net benefit in current model. Our prediction model is freely available online at https://ken-zheng.shinyapps.io/PredictingModelofCREcolonizedInfection/ . CONCLUSIONS: Our nomogram has a good predictive performance and could contribute to early identification of CRE carriers with a high-risk of subsequent infection, although external validation would be required.

Synthesis of Helical-Shaped Axially Chiral Bisoxime Ethers via Chiral Phosphoric-Acid-Catalyzed Sequential Enantioselective Condensations.

A successful synthesis of helical-shaped axially chiral bisoxime ethers is reported. This approach utilized symmetric L-shaped diketone scaffolds as carbonyl components for the enantioselective condensation with hydroxylamines, delivering dual axially chiral oxime ethers with up to 99% ee. Additionally, the axially chiral mono-oxime ethers of azabicyclic ketones with high ee's were also successfully produced. Various chiral bicyclic lactams can be readily synthesized via Beckmann rearrangement, demonstrating a potential application in organic synthetic chemistry.

Risk factors for hemorrhage in patients with long-term aspirin therapy undergoing emergency external ventricular drainage/intracranial pressure probe placement.

Background: Studies have been inconclusive on the risk for hemorrhage in patients with a history of aspirin use who underwent emergency external ventricular drainage (EVD)/intracranial pressure (ICP) probe placement. The aim of this study was to explore hemorrhage-related risk factors in order to reduce the risk for hemorrhage in these patients. Methods: Between July 2014 and July 2020, patients were retrospectively divided into EVD/ICP-related hemorrhage and non-hemorrhage groups. The collected data included age, gender, major diagnosis, medical history, imaging examinations, conventional coagulation test data, thromboelastography with platelet mapping (TEG-PM), surgical procedures and discharge conditions. Results: In total 94 patients, 21 in the hemorrhage group (15 males, 6 females) and 73 in the non-hemorrhage group (52 males, 21 females) were included. The majority of hemorrhages were recorded in EVD patients (19/21; 90.5%). Platelet AA pathway inhibition rate of ≥75% (sensitivity: 79.45% specificity: 52.38%) (P = 0.014) and SBP ≥125 mmHg (P = 0.006) were significantly related to hemorrhage. When the platelet AA pathway inhibition rate was ≥75% and the during-procedure SBP was ≥125 mmHg, the hemorrhage rate was significantly higher (83.3%) than with SBP <125 mmHg (6.7%) (P < 0.001). When the inhibition rate was <75%, there were no significant differences in the hemorrhage rates between the during-procedure SBP ≥125 mmHg group (17.2%) and the SBP <125 mmHg group (13.2%) (P > 0.05). Multivariate logistic regression analysis revealed that a platelet AA pathway inhibition rate ≥75% (OR = 5.183, 95% CI: 1.683-15.960) and during-procedure SBP ≥125 mmHg (OR = 4.609, 95% CI: 1.466-14.484) were independent risk factors for EVD/ICP-related hemorrhage. Conclusion: Patients with long-term aspirin therapy, a platelet AA pathway inhibition rate ≥75% and during-procedure SBP ≥125 mmHg had a significantly higher risk of hemorrhage, which could be reduced by adjusting the SBP to <125 mmHg.

Mechanism of Salt Precipitation Blockage in Low-Producing Gas Wells and the Method of Acidification Blockage Removal.

In the Changqing area, over 23.6% of gas wells produce less than 0.1 × 104 m3/d of gas daily, posing a challenge to gas field sustainability. Laboratory analysis of scale samples from three wells and formation water analysis via inductively coupled plasma revealed soluble salt as the primary well blockage, with sodium chloride and calcium chloride comprising 48.0-81.2% of total content. The G3# well blockage contains a small amount of quartz from acid-insoluble components of carbonate acidification. Formation water from all wells exhibited high salinity (up to 153 g/L) with a calcium chloride water type. Scanning electron microscopy and EDS confirmed halite and quartz features in blockage samples. Theoretical calculations show salt crystallization when tubing pressure falls below 10 MPa and daily water production is <1.0 tons/day. Lower production leads to lower tubing pressure and higher salt precipitation at the bottom of the well. For G1# and G2# blockages, HCl dissolves >90%, and water >85%, making them suitable removal agents. For 3# blockage, mud acid with >80% dissolution is recommended. Chemical methods effectively clean the wellbore and formation. Optimized blockage removal measures increase tubing pressure and daily production by 2.18 and 4.05 times, respectively. This study offers insights into addressing well blockage challenges in low-producing gas wells.

Integrating Paper-Based Microfluidics and Lateral Flow Strip into Nucleic Acid Amplification Device toward Rapid, Low-Cost, and Visual Diagnosis of Multiple Mycobacteria.

Efficient diagnosis of mycobacterial infections can effectively manage and prevent the transmission of infectious diseases. Unfortunately, existing diagnostic strategies are challenged by long assay times, high costs, and highly specialized expertise to distinguish between pulmonary tuberculosis (PTB) and nontuberculous mycobacterial pulmonary diseases (NTM-PDs). Herein, in this study, an optimized 3D paper-based analytical device (µPAD) is incorporated with a closed lateral flow (LF) strip into a loop-mediated isothermal amplification (LAMP) device (3D-µPAD-LF-LAMP) for rapid, low-cost, and visual detection of pathogenic mycobacteria. The platform's microfluidic feature enhanced the nucleic acid amplification, thereby reducing the costs and time as compared to boiling, easyMAG, and QIAGEN techniques. Moreover, the LF unit is specifically designed to minimize aerosol contamination for a user-friendly and visual readout. 3D-µPAD-LF-LAMP is optimized and assessed using standard strains, demonstrating a limit of detection (LOD) down to 10 fg reaction-1 . In a cohort of 815 patients, 3D-µPAD-LF-LAMP displays significantly better sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and diagnostic accuracy than conventional bacterial culture and Xpert techniques. Collectively, 3D-µPAD-LF-LAMP demonstrates enhanced accessibility, efficiency, and practicality for the diagnosis of multiple pathogenic mycobacteria, which can be applied across diverse clinical settings, thereby ultimately improving public health outcomes.

Mechanically and Thermally Guided, Honeycomb-like Nanocomposites with Strain-Insensitive High Thermal Conductivity for Stretchable Electronics.

Thermal management materials have become increasingly crucial for stretchable electronic devices and systems. Drastically different from conventional thermally conductive materials, which are applied at static conditions, thermal management materials for stretchable electronics additionally require strain-insensitive thermal conductivity, as they generally undergo cyclic deformation. However, realizing such a property remains challenging mainly because conventional thermally conductive polymer composites generally lack a mechanically guided design. Here, we report a honeycomb-like nanocomposite with a three-dimensional (3D) thermally conductive network fabricated by an arrayed ice-templating technique followed by elastomer infiltration. The hexagonal honeycomb-like structure with thin, compact walls (≈ 40 µm) endows our composite with a high through-plane thermal conductivity (≈ 1.54 W m-1 K-1) at an ultralow boron nitride nanosheet (BNNS) loading (≈ 0.85 vol %), with an enhancement factor of thermal conductivity up to 820% and thermal-insensitive strain up to 200%, which are 2.7 and 2 times higher than those reported in the literature. We report an intelligent strategy for the development of advanced thermal management materials for high-performance stretchable electronics.

Genetic mutation profiling reveals biomarkers for targeted therapy efficacy and prognosis in non-small cell lung cancer.

Introduction: The genetic heterogeneity of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations may affect clinical responses and outcomes to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study aims to investigate the genomic factors that influence the efficacy and clinical outcomes of first-line, second-line and third-line treatments in NSCLC and explore the heterogeneity of resistance mechanisms. Materials and methods: This real-world study comprised 65 patients with EGFR mutant NSCLC. Molecular alterations were detected using a customized DNA panel before and after administering targeted therapy. The efficacy and prognosis of each treatment line were evaluated. Results: In first-generation EGFR-TKIs treatment, gefitinib showed favorable efficacy compared to icotinib and erlotinib, particularly in patients with EGFR L858R mutations. The resistance mechanisms to first-generation EGFR-TKIs varied among different EGFR mutation cohorts and different first-generation EGFR-TKIs. In second-line EGFR-TKIs treatment, EPH receptor A3 (EPHA3), IKAROS family zinc finger 1 (IKZF1), p21 (RAC1) activated kinase 5 (PAK5), DNA polymerase epsilon, catalytic subunit (POLE), RAD21 cohesin complex component (RAD21) and RNA binding motif protein 10 (RBM10) mutations were markedly associated with poorer progression-free survival (PFS). Notably, EPHA3, IKZF1 and RBM10 were identified as independent predictors of PFS. The mechanisms of osimertinib resistance exhibited heterogeneity, with a higher proportion of non-EGFR-dependent resistant mutations. In third-line treatments, the combination of osimertinib and anlotinib demonstrated superior efficacy compared to other regimens. Glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) mutation was an independent risk indicator of shorter OS following third-line treatments. Conclusions: Comprehending the tumor evolution in NSCLC is advantageous for assessing the efficacy and prognosis at each stage of treatment, providing valuable insights to guide personalized treatment decisions for patients.

Resource utilization of stone waste and loess to prepare grouting materials.

Loess, a terrestrial clastic sediment, is formed essentially by the accumulation of wind-blown dust, while stone waste (SW) is an industrial waste produced during stone machining. Utilising loess and SW to prepare environmentally-friendly supplementary cementitious materials can not only address environmental issues caused by solid waste landfills but also meet the demand of reinforcement of coal-seam floor aquifer for grouting materials. In this paper, the effects of the loess/SW mass ratio and calcination temperature on the transformation of calcined products are investigated and their pozzolanic activities are evaluated. The workability, environmental impact and cost of grouting materials based on cement and calcined products are also assessed. Experimental results reveal that higher temperatures favour the formation of free lime and periclase, which tend to be involved in solid-state reactions. Higher temperature and loess/SW mass ratio strengthens the diffraction peaks of dodecalcium hepta-aluminate (C12A7), dicalcium ferrite (C2F) and dicalcium silicate (C2S). The clay minerals in loess become completely dehydroxylated before 825 °C, generating amorphous SiO2 and Al2O3. Covalent Si-O bonds are interrupted and that disordered silicate networks are generated in the calcined products, which is confirmed by the increased strength of the Si29 resonance region at -60 ppm to -80 ppm. Although co-calcined loess and SW contain the most four-fold aluminium at 950 °C, recrystallisation depresses the pozzolanic activity. Hence, the loess/SW sample designated LS2-825 exhibits the better hydration activity. Additionally, grouting materials composed of cement and LS2-825 exhibit good setting times, fluidity, strength and a low carbon footprint in practical engineering applications, and they also provide the additional benefit of being cost effective.

A Powerful Strategy for Synthesizing Block Copolymers via Bimetallic Synergistic Catalysis.

Block copolymers, comprising polyether and polyolefin segments, are an important and promising category of functional materials. However, the lack of efficient strategies for the construction of polyether-b-polyolefin block copolymers have hindered the development of these materials. Herein, we propose a simple and efficient method to obtain various block copolymers through the copolymerization of epoxides and acrylates via bimetallic synergistic catalysis. The copolymerization of epoxides and acrylates proceeds in a sequence-controlled manner, where the epoxides-involved homo- or copolymerization occurs first, followed by the homopolymerization of acrylates initiated by the alkoxide species from the propagating polymer chain, thus yielding copolymers with a block structure. Notably, the high monomer compatibility of this powerful strategy provides a platform for synthesizing various polyacrylate-based block copolymers comprising polyether, polycarbonate, polythiocarbonate, polyester, and polyurethane segments, respectively.

Genetic alterations predict poor efficacy, outcomes and resistance to second-line osimertinib treatment in non-small cell lung cancer.

The genetic heterogeneity of non-small cell lung cancer (NSCLC) may impact clinical response and outcomes to targeted therapies. In second-line osimertinib treatment for NSCLC, real-world data on genetic biomarkers for treatment efficacy and prognosis remain incomplete. This real-world study involved 68 NSCLC patients receiving first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). All of these patients developed resistance, and 49 of them subsequently underwent second-line osimertinib treatment. A 639-gene DNA panel was employed to assess the impact of molecular alterations on treatment efficacy, clinical outcomes and resistance. The findings showed that the median progression-free survival (PFS) for second-line osimertinib therapy was 13.3 months. Genes alterations such as P21 (RAC1) activated kinase 5 (PAK5), RNA binding motif protein 10 (RBM10), and EPH receptor A3 (EPHA3) mutations were associated with significantly shorter PFS in osimertinib therapy. At multivariate analysis, they were all independent risk predictors of shorter PFS. Additionally, the median overall survival (OS) for osimertinib was 26.2 months. Glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A), hepatocyte growth factor (HGF), and RBM10 mutations were significantly associated with poorer OS in osimertinib treatment. The multivariate analysis demonstrated that only RBM10 mutation emerged as an independent risk predictor of shorter OS. In vitro experiments showed that RBM10 mutations could promote the proliferation and migration ability of NSCLC cells and reduced cell apoptosis. The resistance mechanisms to osimertinib were heterogeneous. Histone cluster 1 H2B family member D (HIST1H2BD) acted as a novel resistance mechanism to osimertinib. Previously unreported HIST1H2BD mutations (p.K25Q and p.E36D) were detected in the NSCLC tissues. In vitro experiments confirmed that HIST1H2BD mutations led to resistance to osimertinib. In summary, we demonstrate that genetic biomarkers, such as PAK5, RBM10, and EPHA3, are independent predictors of PFS in second-line osimertinib treatment, with RBM10 emerging as an independent predictor of OS. Additionally, HIST1H2BD represents a novel resistance mutation to osimertinib. All of these findings offer valuable insights for making personalized treatment strategies for NSCLC patients.

Iron-Confined CRISPR/Cas9-Ribonucleoprotein Delivery System for Redox-Responsive Gene Editing.

Clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) is a promising gene editing tool to treat diseases at the genetic level. Nonetheless, the challenge of the safe and efficient delivery of CRISPR/Cas9 to host cells constrains its clinical applicability. In the current study, a facile, redox-responsive CRISPR/Cas9-Ribonucleoprotein (RNP) delivery system by combining iron-coordinated aggregation with liposomes (Fe-RNP@L) is reported. The Fe-RNP is formed by the coordination of Fe3+ with amino and carboxyl groups of Cas9, which modifies the lipophilicity and surface charge of RNP and alters cellular uptake from primary endocytosis to endocytosis and cholesterol-dependent membrane fusion. RNP can be rapidly and reversibly released from Fe-RNP in response to glutathione without loss of structural integrity and enzymatic activity. In addition, iron coordination also improves the stability of RNP and substantially mitigates cytotoxicity. This construct enabled highly efficient cytoplasmic/nuclear delivery (≈90%) and gene-editing efficiency (≈70%) even at low concentrations. The high payload content, high editing efficiency, good stability, low immunogenicity, and ease of production and storage, highlight its potential for diverse genome editing and clinical applications.