Metal-Carbon Bond Heterolysis Energy Scale for Model Palladium Catalysts.

Thermodynamic studies of transition-metal intermediates are crucial for understanding of metal-catalyzed transformations. Herein, a series of arylpalladium cyanomethanides were synthesized and characterized. Their palladium-carbon bond heterolysis energies (ΔGhet(Pd-C)) were determined in DMSO for the first time by equilibrium methods. ΔGhet(Pd-C) values of 7.9-19.1 kcal/mol, located between the ΔGhet(Pd-O) and ΔGhet(Pd-N) scales previously established, are much smaller than the corresponding ΔGhet(C-H)s of phenylacetonitrile (30.0 kcal/mol). Linear free energy relationship (LEFR) analysis reveals insights into the structure-property relationship and the factor dictating the thermodynamics of metalation. These ΔGhet(Pd-X)s in combination with ΔGhet(X-H)s are successfully used to diagnose the reaction feasibility and selectivity of X-H bond activation.

Progression from cardiomyopathy to heart failure with reduced ejection fraction: A CORIN deficient course.

Cardiomyopathies, encompassing hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), constitute a diverse spectrum of heart muscle diseases that often culminating in heart failure (HF). The inherent molecular heterogeneity of these conditions has implications for prognosis and therapeutic strategies. Publicly available microarray and RNA sequencing (RNA-seq) data sets of HCM (n = 106 from GSE36961) and DCM (n = 18 from GSE135055 and 166 from GSE141910) patients were employed for our analysis. The Non-negative Matrix Factorization (NMF) algorithm was applied to explore the molecular stratification within HCM and DCM, and enrichment analysis was performed to delineate their biological characteristics. By integrating bulk and single-nucleus RNA-seq (snRNA-seq) data, we identified a potential biomarker for HCM progression and cardiac fibrosis, which was subsequently validated using mendelian randomization and in vitro. Our application of NMF identified two distinct molecular clusters. Particularly, a profibrotic, heart failure with reduced ejection fraction (HFrEF)-resembling Cluster 1 emerged, characterized by diminished expression of CORIN and a high degree of fibroblast activation. This cluster also exhibited lower left ventricular ejection fraction (LVEF) and worse prognostic outcomes, establishing the significance of this molecular subclassification. We further found that overexpression of CORIN could mitigate TGFß1-induced expression of col1a1 and α-SMA in neonatal rat cardiac fibroblasts. Our results indicated the heterogeneity of HCM population, and further evidenced the participation of corin in the progression of HCM, DCM and HFrEF. Nevertheless, our study is constrained by the lack of corresponding clinical data and experimental validation of the identified subtypes. Therefore, further studies are warranted to elucidate the downstream pathways of corin and to validate these findings in independent patient cohorts.

The Role of ADCY1 in Regulating the Sensitivity of Platinum-Based Chemotherapy in NSCLC.

Lung cancer has the highest fatality rate among malignant tumors in the world. Finding new biomarkers of drug resistance is of great importance in the prognosis of lung cancer patients. We found that the polymorphisms of Adenylate Cyclase 1 (ADCY1) are significantly associated with platinum-based chemotherapy resistance in lung cancer patients in our previous research. In this study, we wanted to identify the mechanism of ADCY1 affecting platinum resistance. We used an MTT assay to find if the expression of ADCY1 is associated with the sensitivity of cisplatin in A549, H1299, and A549-DDP cells. Then, we performed CCK-8 tests to detect the absorbance of these cells stimulated by ADCY1, which can discover the cell proliferation that is affected by ADCY1. We investigated cell apoptosis and cell cycles regulated by ADCY1 through the flow cytometry assay. RNA sequencing was used to find the downstream genes affected by ADCY1 which may be associated with drug resistance in lung cancer patients. ADCY1 has higher expression in lung cancer cells than in normal cells. ADCY1 can affect cisplatin resistance in lung cancer cells by regulating cell proliferation, cell apoptosis, and the cell cycle. It may control cell apoptosis by regulating the classical apoptosis biomarkers Bax and Bcl2. Our study showed that ADCY1 may be a new biomarker in the prognosis of lung cancer patients. Much work remains to be carried out to clarify the mechanism in this important emerging field.

The burden of allergic rhinitis is undermanaged in a large proportion of Chinese young adults from Singapore.

Background: Allergic rhinitis (AR) is a nasal disorder characterized by the simultaneous manifestation of at least 2 out of 4 possible symptoms: rhinorrhea, nasal itching, nasal pruritus, and sneezing. Presently, among Chinese young adults from Singapore, we characterised AR phenotypes, established Total Nasal Symptom Score (TNSS) baselines, and examined the management of AR. Methods: Participants completed an investigator-administered International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and underwent a skin prick test (SPT). Individuals exhibiting sensitization during the SPT while having at least 2 rhinitis symptoms were identified as AR cases, then categorized into Allergic Rhinitis in Asthma (ARIA) classifications. Results: There were 9323 subjects analyzed. AR prevalence was estimated at 35.4%. Rhinorrhea was perceived as the most severe (mean Nasal Symptom Score (mNSS) ± SD: 1.42 ± 0.74), while nasal pruritus was the least severe (mNSS ± SD: 1.24 ± 0.68). Among moderate-severe AR (68.1%), most were affected by either troublesome symptoms (27.7%) or sleep disturbances (18.4%). By ARIA classes, 26.6% were mild intermittent, 5.4% were mild persistent, 50.3% were moderate-severe intermittent, and 17.6% were moderate-severe persistent. The mean TNSS (mTNSS) of AR cases was 4.43 (SD = 2.49) and between AR classifications, the mTNSS was significantly different. Notably, a large proportion of AR cases remained undiagnosed (85.2%), untreated (72.5%), or both (65.4%); 19.8% self-medicated for AR. Conclusions: There was a significant difference in TNSS of the AR phenotypes, and among phenotypes with a higher mTNSS, a large proportion remained untreated, undiagnosed, or both. The evidence indicates an existing burden of AR among Chinese young adults in Singapore which is notably undermanaged.

Ac4C modification of lncRNA SIMALR promotes nasopharyngeal carcinoma progression through activating eEF1A2 to facilitate ITGB4/ITGA6 translation.

The dysregulation of long non-coding RNAs (lncRNAs) are involved in regulating tumor progression in multiple manner. However, little is known about whether lncRNA is involved in the translation regulation of proteins. Here, we identified that the suppressor of inflammatory macrophage apoptosis lncRNA (SIMALR) was highly expressed in nasopharyngeal carcinoma (NPC) tissues by analyzing the lncRNA microarray. Clinically, the high expression of SIMALR served as an independent predictor for inferior prognosis in NPC patients. SIMALR functioned as an oncogenic lncRNA that promoted the proliferation and metastasis of NPC cells in vitro and in vivo. Mechanistically, SIMALR served as a critical accelerator of protein synthesis by binding to eEF1A2 (eukaryotic translation elongation factor 1 alpha 2), one of the most crucial regulators in the translation machinery of the eukaryotic cells, and enhancing its endogenous GTPase activity. Furthermore, SIMALR mediated the activation of eEF1A2 phosphorylation to accelerate the translation of ITGB4/ITGA6, ultimately promoting the malignant phenotype of NPC cells. In addition, N-acetyltransferase 10 (NAT10) enhanced the stability of SIMALR and caused its overexpression in NPC through the N4-acetylcytidine (ac4C) modification. In sum, our results illustrate SIMALR functions as an accelerator for protein translation and highlight the oncogenic role of NAT10-SIMALR-eEF1A2-ITGB4/6 axis in NPC.

A synthetic moving-envelope metasurface antenna for independent control of arbitrary harmonic orders.

Flexible frequency controls are crucial in many photonic and electronic applications, ranging from communications systems, spectroscopy, and metrology to quantum information processing. However, the state-of-the-art solutions based on nonlinear bulk media, electro-optic effect, and nonlinear metasurfaces incur very limited spectral controllability, and merely a couple of harmonic orders can be independently manipulated. Here, we theoretically propose and experimentally demonstrate synthetic moving-envelope metasurface antennas capable of simultaneously generating arbitrary harmonic orders and independently manipulating their wave properties in a software-defined manner. As proof-of-principle examples, we demonstrate unidirectional frequency transition, frequency comb generation, arbitrary harmonic orders independent control, and their applications in frequency-division multiplexing communications. All these complicated functionalities are achieved by the 1-bit spatiotemporally ON-OFF switching of meta-atoms of the waveguide-integrated metasurface antenna. Our proposed synthetic metasurface antenna solution greatly expands the frontiers of wave engineering and information manipulation, showing promising potential in wireless communications, spectroscopy, metrology, and quantum science.

Unveiling the shield: Troglitazone's impact on epilepsy-induced nerve injury through ferroptosis inhibition.

BACKGROUND: Epilepsy is a widespread central nervous system disorder with an estimated 50 million people affected globally. It is characterized by a bimodal incidence peak among infants and the elderly and is influenced by a variety of risk factors, including a significant genetic component. Despite the use of anti-epileptic drugs (AEDs), drug-refractory epilepsy develops in about one-third of patients, highlighting the need for alternative therapeutic approaches. AIMS: The primary aim of this study was to evaluate the neuroprotective effects of troglitazone (TGZ) in epilepsy and to explore the potential mechanisms underlying its action. METHODS: We employed both in vitro and in vivo models to assess TGZ's effects. The in vitro model involved glutamate-induced toxicity in HT22 mouse hippocampal neurons, while the in vivo model used kainic acid (KA) to induce epilepsy in mice. A range of methods, including Hoechst/PI staining, CCK-8 assay, flow cytometry, RT-PCR analysis, Nissl staining, scanning electron microscopy, and RNA sequencing, were utilized to assess various parameters such as cellular damage, viability, lipid-ROS levels, mitochondrial membrane potential, mRNA expression, seizure grade, and mitochondrial morphology. RESULTS: Our results indicate that TGZ, at doses of 5 or 20 mg/kg/day, significantly reduces KA-induced seizures and neuronal damage in mice by inhibiting the process of ferroptosis. Furthermore, TGZ was found to prevent changes in mitochondrial morphology. In the glutamate-induced HT22 cell damage model, 2.5 µM TGZ effectively suppressed neuronal ferroptosis, as shown by a reduction in lipid-ROS accumulation, a decrease in mitochondrial membrane potential, and an increase in PTGS2 expression. The anti-ferroptotic effect of TGZ was confirmed in an erastin-induced HT22 cell damage model as well. Additionally, TGZ reversed the upregulation of Plaur expression in HT22 cells treated with glutamate or erastin. The downregulation of Plaur expression was found to alleviate seizures and reduce neuronal damage in the mouse hippocampus. CONCLUSION: This study demonstrates that troglitazone has significant therapeutic potential in the treatment of epilepsy by reducing epileptic seizures and the associated brain damage through the inhibition of neuronal ferroptosis. The downregulation of Plaur expression plays a crucial role in TGZ's anti-ferroptotic effect, offering a promising avenue for the development of new epilepsy treatments.

HR-MRI-based nomogram network calculator to predict stroke recurrence in high-risk non-disabling ischemic cerebrovascular events patients.

Background and objective: To investigate the use of high-resolution magnetic resonance imaging (HR-MRI) to identify the characteristics of culprit plaques in intracranial arteries, and to evaluate the predictive value of the characteristics of culprit plaques combined with the modified Essen score for the recurrence risk of high-risk non-disabling ischemic cerebrovascular events (HR-NICE) patients. Methods: A retrospective analysis was conducted on 180 patients with HR-NICE at the First Affiliated Hospital of Xinxiang Medical University, including 128 patients with no recurrence (non-recurrence group) and 52 patients with recurrence (recurrence group). A total of 65 patients with HR-NICE were collected from the Sixth Affiliated Hospital of Shanghai Jiaotong University as a validation group, and their modified Essen scores, high-resolution magnetic resonance vessel wall images, and clinical data were collected. The culprit plaques were analyzed using VesselExplorer2 software. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for recurrence, and a nomogram was constructed using R software to evaluate the discrimination of the model. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) was used to evaluate the model performance. Calibration curves and Decision Curve Analysis (DCA) were used to evaluate the model efficacy. Results: Intra-plaque hemorrhage (OR = 3.592, 95% CI = 1.474-9.104, p = 0.006), homocysteine (OR = 1.098, 95% CI = 1.025-1.179, p = 0.007), and normalized wall index (OR = 1.114, 95% CI = 1.027-1.222, p = 0.015) were significantly higher in the recurrent stroke group than in the non-recurrent stroke group, and were independent risk factors for recurrent stroke. The performance of the nomogram model (AUC = 0.830, 95% CI: 0.769-0.891; PR-AUC = 0.628) was better than that of the modified Essen scoring model (AUC = 0.660, 95% CI: 0.583-0.738) and the independent risk factor combination model (AUC = 0.827, 95% CI: 0.765-0.889). The nomogram model still had good model performance in the validation group (AUC = 0.785, 95% CI: 0.671-0.899), with a well-fitting calibration curve and a DCA curve indicating good net benefit efficacy for patients. Conclusion: High-resolution vessel wall imaging combined with a modified Essen score can effectively assess the recurrence risk of HR-NICE patients, and the nomogram model can provide a reference for identifying high-risk populations with good clinical application prospects.

Effectiveness and safety of brucea javanica oil assisted TACE versus TACE in the treatment of liver cancer: a systematic review and meta-analysis of randomized controlled trials.

Background: The effectiveness and safety of using Brucea javanica oil (BJO) in combination with Transarterial Chemoembolization (TACE) for liver cancer treatment are subjects of debate. This study aims to assess the comparative effectiveness and safety of BJO-assisted TACE versus TACE alone and quantifies the differences between these two treatment methods. Methods: A systematic search was conducted in multiple databases including PubMed, Cochrane, CNKI, and Wanfang, until 1 July 2023. Meta-analysis was conducted, and the results were presented as mean difference (MD), risk ratio (RR), and 95% confidence intervals (CI). Results: The search yielded 11 RCTs, with a combined sample size of 1054 patients. Meta-analysis revealed that BJO-assisted TACE exhibited superior outcomes compared to standalone TACE. Specific data revealed that BJO-assisted TACE improves clinical benefit rate by 22% [RR = 1.22, 95% CI (1.15, 1.30)], increases the number of people with improved quality of life by 32%, resulting in an average score improvement of 9.53 points [RR = 1.32, 95% CI (1.22, 1.43); MD = 9.53, 95% CI (6.95, 12.10)]. Furthermore, AFP improvement rate improved significantly by approximately 134% [RR = 2.34, 95% CI (1.58, 3.46)], accompanied by notable improvements in liver function indicators, with an average reduction of 27.19 U/L in AST [MD = -27.19, 95% CI (-40.36, -14.02)], 20.77 U/L in ALT [MD = -20.77, 95% CI (-39.46, -2.08)], 12.17 µmol/L in TBIL [MD = -12.17, 95% CI (-19.38, -4.97)], and a decrease of 43.72 pg/mL in VEGF [MD = -43.72, 95% CI (-63.29, -24.15)]. Most importantly, there was a 29% reduction in the occurrence of adverse reactions [RR = 0.71, 95% CI (0.60, 0.84)]. Conclusion: These findings indicate that BJO-assisted TACE may be considered as a potentially beneficial treatment option for liver cancer patients when compared to standalone TACE. It appears to contribute to improved treatment outcomes, enhanced quality of life, and potentially reduced adverse reactions, suggesting it warrants further investigation as a promising approach for liver cancer treatment. Systematic Review Registration: identifier CRD42023428948.

Arbitrarily rotating polarization direction and manipulating phases in linear and nonlinear ways using programmable metasurface.

Independent controls of various properties of electromagnetic (EM) waves are crucially required in a wide range of applications. Programmable metasurface is a promising candidate to provide an advanced platform for manipulating EM waves. Here, we propose an approach that can arbitrarily control the polarization direction and phases of reflected waves in linear and nonlinear ways using a stacked programmable metasurface. Further, we extend the space-time-coding theory to incorporate the dimension of polarization, which provides an extra degree of freedom for manipulating EM waves. As proof-of-principle application examples, we consider polarization rotation, phase manipulation, and beam steering at linear and nonlinear frequencies. For validation, we design, fabricate, and measure a metasurface sample. The experimental results show good agreement with theoretical predictions and simulations. The proposed approach has a wide range of applications in various areas, such as imaging, data storage, and wireless communication.

DCAF7 Acts as A Scaffold to Recruit USP10 for G3BP1 Deubiquitylation and Facilitates Chemoresistance and Metastasis in Nasopharyngeal Carcinoma.

Despite docetaxel combined with cisplatin and 5-fluorouracil (TPF) being the established treatment for advanced nasopharyngeal carcinoma (NPC), there are patients who do not respond positively to this form of therapy. However, the mechanisms underlying this lack of benefit remain unclear. DCAF7 is identified as a chemoresistance gene attenuating the response to TPF therapy in NPC patients. DCAF7 promotes the cisplatin resistance and metastasis of NPC cells in vitro and in vivo. Mechanistically, DCAF7 serves as a scaffold protein that facilitates the interaction between USP10 and G3BP1, leading to the elimination of K48-linked ubiquitin moieties from Lys76 of G3BP1. This process helps prevent the degradation of G3BP1 via the ubiquitin‒proteasome pathway and promotes the formation of stress granule (SG)-like structures. Moreover, knockdown of G3BP1 successfully reversed the formation of SG-like structures and the oncogenic effects of DCAF7. Significantly, NPC patients with increased levels of DCAF7 showed a high risk of metastasis, and elevated DCAF7 levels are linked to an unfavorable prognosis. The study reveals DCAF7 as a crucial gene for cisplatin resistance and offers further understanding of how chemoresistance develops in NPC. The DCAF7-USP10-G3BP1 axis contains potential targets and biomarkers for NPC treatment.

Novel overlapping constructed wetlands with water drops reoxygenation and lightweight fillers for decentralized wastewater treatment.

Constructed wetlands (CWs), crucial for the rural decentralized wastewater treatment, have encountered limitations in nutrient removal efficiency and require extensive land area. This study has constructed a novel overlapping horizontal subsurface flow CWs (OLCWs). Remarkably, OLCWs with mixed lightweight fillers (M-OLCWs) exhibited a significant enhancement in total nitrogen (TN) removal efficiency (88-91 %) in different hydraulic loading rates compared to single filler OLCWs (48-62 %). This significant enhancement can be attributed to the lightweight fillers, which have higher abundances and diversity of nitrogen related microorganisms. The treatment dynamics revealed that the second stage exhibited an excellent TN removal efficiency (73-75 %) attributed to sufficient dissolved oxygen concentration by water drops reoxygenation. The research reveals that M-OLCWs, by utilizing water drops reoxygenation and lightweight fillers, not only enhance pollutant treatment efficiency but also reduce required land area, thereby offering a sustainable solution for rural decentralized wastewater treatment.

Plasma metabolomics of immune-related adverse events for patients with lung cancer treated with PD-1/PD-L1 inhibitors.

BACKGROUND: Metabolomics has the characteristics of terminal effects and reflects the physiological state of biological diseases more directly. Several current biomarkers of multiple omics were revealed to be associated with immune-related adverse events (irAEs) occurrence. However, there is a lack of reliable metabolic biomarkers to predict irAEs. This study aims to explore the potential metabolic biomarkers to predict risk of irAEs and to investigate the association of plasma metabolites level with survival in patients with lung cancer receiving PD-1/PD-L1 inhibitor treatment. METHODS: The study collected 170 plasmas of 85 patients with lung cancer who received immune checkpoint inhibitors (ICIs) treatment. 58 plasma samples of 29 patients with irAEs were collected before ICIs treatment and at the onset of irAEs. 112 plasma samples of 56 patients who did not develop irAEs were collected before ICIs treatment and plasma matched by treatment cycles to onset of irAEs patients. Untargeted metabolomics analysis was used to identify the differential metabolites before initiating ICIs treatment and during the process that development of irAEs. Kaplan-Meier curves analysis was used to detect the associations of plasma metabolites level with survival of patients with lung cancer. RESULTS: A total of 24 differential metabolites were identified to predict the occurrence of irAEs. Baseline acylcarnitines and steroids levels are significantly higher in patients with irAEs, and the model of eight acylcarnitine and six steroid metabolites baseline level predicts irAEs occurrence with area under the curve of 0.91. Patients with lower concentration of baseline decenoylcarnitine(AcCa(10:1) 2, decenoylcarnitine(AcCa(10:1) 3 and hexanoylcarnitine(AcCa(6:0) in plasma would have better overall survival (OS). Moreover, 52 differential metabolites were identified related to irAEs during ICIs treatment, dehydroepiandrosterone sulfate, corticoserone, cortisol, thyroxine and sphinganine 1-phaosphate were significantly decreased in irAEs group while oxoglutaric acid and taurocholic acid were significantly increased in irAEs group. CONCLUSIONS: High levels of acylcarnitines and steroid hormone metabolites might be risk factor to development of irAEs, and levels of decenoylcarnitine (AcCa(10:1) 2, decenoylcarnitine (AcCa(10:1) 3 and hexanoylcarnitine (AcCa(6:0) could be used to predict OS for patients with lung cancer received ICIs treatment.

Origins of High Air Sensitivity and Treatment Strategies in O3-Type NaMn1/3 Fe1/3Ni1/3O2.

Sodium-ion layered oxides are one of the most highly regarded sodium-ion cathode materials and are expected to be used in electric vehicles and large-scale grid-level energy storage systems. However, highly air-sensitive issues limit sodium-ion layered oxide cathode materials to maximize cost advantages. Industrial and scientific researchers have been developing cost-effective air sensitivity treatment strategies with little success because the impurity formation mechanism is still unclear. Using density functional theory calculations and ab initio molecular dynamics simulations, this work shows that the poor air stability of O3-type NaMn1/3Fe1/3Ni1/3O2 (NMFNO) may be as follows: (1) low percentage of nonreactive (003) surface; (2) strong surface adsorption capacity and high surface reactivity; and (3) instability of the surface sodium ions. Our physical images point out that the high reactivity of the NMFNO surface originates from the increase in electron loss and unpaired electrons (magnetic moments) of the surface oxygen active site as well as the enhanced metal coactivation effect due to the large radius of the sodium ion. We also found that the hydrolysis reaction requires a higher reactivity of the surface oxygen active site, while the carbon hybridization mode transformation in carbonate formation depends mainly on metal activation and does not even require the involvement of surface oxygen active sites. Based on the calculation results and our proposed physical images, we discuss the feasibility of these treatment strategies (including surface morphology modulation, cation/anion substitution, and surface configuration design) for air-sensitive issues.

Halogen Bond Unlocks Ultra-High Birefringence.

Anisotropy is crucial for birefringence (Δn) in optical materials, but optimizing it remains a formidable challenge (Δn >0.3). Supramolecular frameworks incorporating π-conjugated components are promising for achieving enhanced birefringence because of their structural diversity and inherent anisotropy. Herein, we first synthesized (C6H6NO2)+Cl- (NAC) and then constructed a halogen-bonded supramolecular framework I+(C6H4NO2)- (INA) by halogen aliovalent substitution of Cl- with I+. The organic moieties are protonated and deprotonated nicotinic acid (NA), respectively. The antiparallel arrangement of birefringent-active units in NAC and INA leads to significant differences in the bonding characteristics between the interlayer and intralayer domains. Moreover, the [O⋅⋅⋅I+⋅⋅⋅N] halogen bond in 1D [I+(C6H4NO2)-] chain exhibits stronger interactions and stricter directionality, resulting in a more pronounced in-plane anisotropy between the intrachain and interchain directions. Consequently, INA exhibits exceptional birefringent performance, with a value of 0.778 at 550 nm, twice that of NAC (0.363 at 550 nm). This value significantly exceeds those of commercial birefringent crystals, such as CaCO3 (0.172 at 546 nm), and is the highest reported value among ultraviolet birefringent crystals. This work presents a novel design strategy that employs halogen bonds as connection sites and modes for birefringent-active units, opening new avenues for developing high-performance birefringent crystals.

Enhancing UHPC Tensile Performance Using Polystyrene Beads: Significant Improvements and Mechanisms.

This study investigates utilizing spherical polystyrene (PS) beads as artificial flaws to improve ultrahigh-performance concrete (UHPC) tensile performance using a uniaxial tensile test and explains the corresponding mechanisms by analyzing the internal material structure of UHPC specimens with X-ray CT scanning. With a hooked steel fiber volume fraction of 2%, three PS bead dosages were employed to study tensile behavior changes in dog-bone UHPC specimens. A 33.4% increase in ultimate tensile strength and 174.8% increase in ultimate tensile strain were recorded after adding PS beads with a volume fraction of 2%. To explain this improvement, X-ray CT scanning was utilized to investigate the post-test internal material structures of the dog-bone specimens. AVIZO software was used to analyze the CT information. The CT results revealed that PS beads could not only serve as the artificial flaws to increase the cracking behavior of the matrix of UHPC but also significantly optimize the fiber orientation. The PS beads could serve as stirrers during the mixing process to distribute fiber more uniformly. The test results indicate a relationship between fiber orientation and UHPC tensile strength.

PJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma.

Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.

Transvaginal versus transabdominal specimen extraction in minimally invasive surgery: a systematic review and meta-analysis.

AIM: Natural orifice specimen extraction (NOSE) is an alternative to conventional transabdominal retrieval. We aimed to compare outcomes following transvaginal specimen extraction (TVSE) and transabdominal specimen extraction (TASE) in minimally invasive abdominal surgery. METHODS: An electronic database search of PubMed, Embase and CENTRAL was performed from inception until March 2023. Comparative studies evaluating TVSE versus TASE in adult female patients were included. Studies involving transanal NOSE, endoluminal surgery, or TVSE with concomitant hysterectomy were excluded. Weighted mean differences (WMD) and odds ratio were estimated for continuous and dichotomous outcomes respectively. Primary outcomes were postoperative day 1 (POD1) pain and length of stay (LOS). Secondary outcomes were operative time, rescue analgesia, morbidity, and cosmesis. A review of sexual, oncological, and technical outcomes was performed. RESULTS: Thirteen studies (2 randomised trials, 11 retrospective cohort studies), involving 1094 patients (TASE 583, TVSE 511), were included in the analysis. Seven studies involved colorectal disease and six assessed gynaecological conditions. TVSE resulted in significantly decreased POD1 pain (WMD 1.08, 95% CI: 0.49, 1.68) and shorter LOS (WMD 1.18 days, 95% CI: 0.14, 2.22), compared to TASE. Operative time was similar between both groups, with fewer patients requiring postoperative rescue analgesia with TVSE. Overall morbidity rates, as well as both wound-related and non-wound related complication rates were better with TVSE, while anastomotic morbidity rates were comparable. Cosmetic scores were higher with TVSE. TVSE did not result in worse sexual or oncological outcomes. CONCLUSION: TVSE may be feasible and beneficial compared to TASE when performed by proficient laparoscopic operators, using appropriate selection criteria. Continued evaluation with prospective studies is warranted.

T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin.

T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA × CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490's clinical potential.