Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing.

Inadequate T cell activation has severely limited the success of T cell engager (TCE) therapy, especially in solid tumors. Enhancing T cell activity while maintaining the tumor specificity of TCEs is the key to improving their clinical efficacy. However, currently, there needs to be more effective strategies in clinical practice. Here, we design novel superantigen-fused TCEs that display robust tumor antigen-mediated T cell activation effects. These innovative drugs are not only armed with the powerful T cell activation ability of superantigens but also retain the dependence of TCEs on tumor antigens, realizing the ingenious combination of the advantages of two existing drugs. Superantigen-fused TCEs have been preliminarily proven to have good (>30-fold more potent) and specific (>25-fold more potent) antitumor activity in vitro and in vivo. Surprisingly, they can also induce the activation of T cell chemotaxis signals, which may promote T cell infiltration and further provide an additional guarantee for improving TCE efficacy in solid tumors. Overall, this proof-of-concept provides a potential strategy for improving the clinical efficacy of TCEs.

Yield stress Measurement of municipal sludge: A comprehensive evaluation of testing methods and concentration effects using a rotational rheometer.

Accurate prediction and measurement of yield stress are crucial for optimizing sludge treatment and disposal. However, the differences and applicability of various methods for measuring yield stress are subjects of ongoing debate. Meanwhile, literature on measuring sludge yield stress is limited to low solid concentrations (TS <10%), understanding and studying the yield stress of medium to high solid concentration sludge is crucial due to increasingly stringent standards for sludge treatment and disposal. So, this study employed a rotational rheometer to measure sludge yield stress across a wide range of TS (4-50%) using steady shear, dynamic oscillatory shear, and transient shear. The study derived significant conclusions by comparing and summarizing the applicability and limitations of each testing method: Dynamic oscillatory shear methods, including G'-σ curve method, γ-σ curve method, and G**γc method can measure sludge yield stress ranging from 4% to 40% TS, while other methods are restricted to low or limited solid concentrations; The G' = G″ method, utilizing the intersection of G' and G″ curves, consistently yields the highest value for yield stress when 4%≤ TS ≤ 12%; The rotational rheometer cannot measure sludge yield stress when the solid concentration exceeds 40% TS; The relationship between sludge yield stress and solid concentration is stronger as a power-law for TS ≤ 25%, transitioning to linear for higher concentrations (28%≤ TS <40%). This study systematically explores the applicability and limitations of various measurement methods for characterizing sludge yield stress across a wide range of solid concentrations, providing valuable guidance for scientific measurement and highlighting challenging research issues.

Effects of meteorological factors on influenza transmissibility by virus type/subtype.

BACKGROUND: Quantitative evidence on the impact of meteorological factors on influenza transmissibility across different virus types/subtypes is scarce, and no previous studies have reported the effect of hourly temperature variability (HTV) on influenza transmissibility. Herein, we explored the associations between meteorological factors and influenza transmissibility according to the influenza type and subtype in Guangzhou, a subtropical city in China. METHODS: We collected influenza surveillance and meteorological data of Guangzhou between October 2010 and December 2019. Influenza transmissibility was measured using the instantaneous effective reproductive number (Rt). A gamma regression with a log link combined with a distributed lag non-linear model was used to assess the associations of daily meteorological factors with Rt by influenza types/subtypes. RESULTS: The exposure-response relationship between ambient temperature and Rt was non-linear, with elevated transmissibility at low and high temperatures. Influenza transmissibility increased as HTV increased when HTV < around 4.5 °C. A non-linear association was observed between absolute humidity and Rt, with increased transmissibility at low absolute humidity and at around 19 g/m3. Relative humidity had a U-shaped association with influenza transmissibility. The associations between meteorological factors and influenza transmissibility varied according to the influenza type and subtype: elevated transmissibility was observed at high ambient temperatures for influenza A(H3N2), but not for influenza A(H1N1)pdm09; transmissibility of influenza A(H1N1)pdm09 increased as HTV increased when HTV < around 4.5 °C, but the transmissibility decreased with HTV when HTV < 2.5 °C and 3.0 °C for influenza A(H3N2) and B, respectively; positive association of Rt with absolute humidity was witnessed for influenza A(H3N2) even when absolute humidity was larger than 19 g/m3, which was different from that for influenza A(H1N1)pdm09 and influenza B. CONCLUSIONS: Temperature variability has an impact on influenza transmissibility. Ambient temperature, temperature variability, and humidity influence the transmissibility of different influenza types/subtypes discrepantly. Our findings have important implications for improving preparedness for influenza epidemics, especially under climate change conditions.

The impact of mixed planting of Poaceae species in the Qinghai-Tibet plateau region on forage yield, soil nutrients, and soil microbial communities.

Establishing cultivated grassland in the Qinghai-Tibet Plateau region is an effective method to address the conflict between vegetation and livestock. However, the high altitude, low temperature, and arid climate in the region result in slow regeneration and susceptibility to degradation of mixed cultivation grassland containing perennial legumes and gramineous plants. Therefore, we aim to through field experiments, explore the feasibility of establishing mixed cultivation grassland of Poaceae species in the region by utilizing two grass species, Poa pratensis L. and Puccinellia tenuiflora. By employing a mixture of P. pratensis and P. tenuiflora to establish cultivated grassland, we observed significant changes in forage yield over time. Specifically, during the 3rd to 6th years of cultivation, the yield in the mixed grassland was higher than in monocultures. It exceeded the yield of monoculture P. tenuiflora by 19.38% to 29.14% and surpassed the monoculture of P. pratensis by 17.18% to 62.98%. Through the analysis of soil physicochemical properties and soil microbial communities in the cultivated grassland, the study suggests that the mixed grassland with Poaceae species can enhance soil enzyme activity and improve soil microbial communities. Consequently, this leads to increased soil nutrient levels, enhanced nitrogen fixation efficiency, and improved organic phosphorus conversion efficiency. Therefore, establishing mixed grasslands with Poaceae species in the Qinghai-Tibet Plateau region is deemed feasible.

Endoscopic ultrasound-guided biliary drainage vs percutaneous transhepatic bile duct drainage in the management of malignant obstructive jaundice.

BACKGROUND: Malignant obstructive jaundice (MOJ) is a condition characterized by varying degrees of bile duct stenosis and obstruction, accompanied by the progressive development of malignant tumors, leading to high morbidity and mortality rates. Currently, the two most commonly employed methods for its management are percutaneous transhepatic bile duct drainage (PTBD) and endoscopic ultrasound-guided biliary drainage (EUS-BD). While both methods have demonstrated favorable outcomes, additional research needs to be performed to determine their relative efficacy. AIM: To compare the therapeutic effectiveness of EUS-BD and PTBD in treating MOJ. METHODS: This retrospective analysis, conducted between September 2015 and April 2023 at The Third Affiliated Hospital of Soochow University (The First People's Hospital of Changzhou), involved 68 patients with MOJ. The patients were divided into two groups on the basis of surgical procedure received: EUS-BD subgroup (n = 33) and PTBD subgroup (n = 35). Variables such as general data, preoperative and postoperative indices, blood routine, liver function indices, myocardial function indices, operative success rate, clinical effectiveness, and complication rate were analyzed and compared between the subgroups. RESULTS: In the EUS-BD subgroup, hospital stay duration, bile drainage volume, effective catheter time, and clinical effectiveness rate were superior to those in the PTBD subgroup, although the differences were not statistically significant (P > 0.05). The puncture time for the EUS-BD subgroup was shorter than that for the PTBD subgroup (P < 0.05). Postoperative blood routine, liver function index, and myocardial function index in the EUS-BD subgroup were significantly lower than those in the PTBD subgroup (P < 0.05). Additionally, the complication rate in the EUS-BD subgroup was lower than in the PTBD subgroup (P < 0.05). CONCLUSION: EUS-BD may reduce the number of punctures, improve liver and myocardial functions, alleviate traumatic stress, and decrease complication rates in MOJ treatment.

A novel approach for sludge deep-dewatering via flowing-out enhancement but not relying on cell lysis and bound water release.

Effective deep-dewatering is crucial for wastewater sludge management. Currently, the dominant methods focus on promoting cell lysis to release intracellular water, but these techniques often lead to secondary pollution and require stringent conditions, limiting their practical use. This study explores an innovative method using a commercially available complex quaternary ammonium salt surfactant, known as G-agent. This agent remarkably reduces the sludge water content from 98.6 % to 56.8 % with a low dosage (50 mg/g DS) and under neutral pH conditions. This approach surpasses Fenton oxidation in terms of dewatering efficiency and avoids the necessity for cell lysis and bound water release, thereby reducing the risk of secondary pollution in the filtrate, including heavy metals, nitrogen, phosphorus, and other contaminants. The G-agent plays a significant role in destabilizing flocs and enhancing flocculation during the conditioning and initial dewatering stages, effectively reducing the solid-liquid interfacial affinity of the sludge. In the compression filtration stage, the agent's solidification effect is crucial in forming a robust skeleton that improves pore connectivity within the filter cake, leading to increased water permeability, drainage performance and water flow-out efficiency. This facilitates deep dewatering of sludge without cell lysis. The study reveals that the G-agent primarily improves water flow-out efficiency rather than water flowability, indicating that cell lysis and bound water release are not indispensable prerequisites for sludge deep-dewatering. Furthermore, it presents an encouraging prospect for overcoming the limitations associated with conventional sludge deep-dewatering processes.

De novo GABRA1 variants in childhood epilepsies and the molecular subregional effects.

Background: The GABRA1 gene, encoding the GABRAR subunit α1, plays vital roles in inhibitory neurons. Previously, the GABRA1 gene has been identified to be associated with developmental and epileptic encephalopathy (DEE) and idiopathic generalized epilepsy (IGE). This study aims to explore the phenotypic spectrum of GABRA1 and molecular subregional effect analysis. Methods: Trios-based whole-exome sequencing was performed in patients with epilepsy. Previously reported GABRA1 mutations were systematically reviewed to analyze the molecular subregional effects. Results: De novo GABRA1 mutations were identified in six unrelated patients with heterogeneous epilepsy, including three missense mutations (p.His83Asn, p.Val207Phe, and p.Arg214Cys) and one frameshift mutation (p.Thr453Hisfs*47). The two missense mutations, p.His83Asn and p.Val207Phe, were predicted to decrease the protein stability but no hydrogen bond alteration, with which the two patients also presented with mild genetic epilepsy with febrile seizures plus and achieved seizure-free status by monotherapy. The missense variant p.Arg214Cys was predicted to decrease protein stability and destroy hydrogen bonds with surrounding residues, which was recurrently identified in three cases with severe DEE. The frameshift variant p.Thr453Hisfs*47 was located in the last fifth residue of the C-terminus and caused an extension of 47 amino acids, with which the patients presented with moderated epilepsy with generalized tonic-clonic seizures alone (GTCA) but achieved seizure-free status by four drugs. The four variants were not presented in gnomAD and were evaluated as "pathogenic/likely pathogenic" according to ACMG criteria. Analysis of all reported cases indicated that patients with mutations in the N-terminal extracellular region presented a significantly higher percentage of FS and DEE, and the patients with variants in the transmembrane region presented earlier seizure onset ages. Significance: This study suggested that GABRA1 variants were potentially associated with a spectrum of epilepsies, including EFS+, DEE, and GTCA. Phenotypic severity may be associated with the damaging effect of variants. The molecular subregional effects help in understanding the underlying mechanism of phenotypic variation.