Rochebest3667

The unique permselectivity of cellular membranes is of crucial importance to maintain intracellular homeostasis while adapting to microenvironmental changes. Although liposomes and polymersomes have been widely engineered to mimic microstructures and functions of cells, it still remains a considerable challenge to synergize the stability and permeability of artificial cells and to imitate local milieu fluctuations. Herein, we report concurrent crosslinking and permeabilizing of pH-responsive polymersomes containing Schiff base moieties within bilayer membranes via enzyme-catalyzed acid production. Notably, this synergistic crosslinking and permeabilizing strategy allows tuning of the mesh sizes of the crosslinked bilayers with subnanometer precision, showing discriminative permeability toward maltooligosaccharides with molecular sizes of ~1.4-2.6 nm. The permselectivity of bilayer membranes enables intravesicular pH oscillation, fueled by a single input of glucose. This intravesicular pH oscillation can further drive the dissipative self-assembly of pH-sensitive dipeptides. Moreover, the permeabilization of polymersomes can be regulated by intracellular pH gradient as well, enabling the controlled release of encapsulated payloads.Topoisomerase IIIα is a type 1A topoisomerase that forms a complex with RMI1 and RMI2 called TRR in human cells. TRR plays an essential role in resolving DNA replication and recombination intermediates, often alongside the helicase BLM. While the TRR catalytic cycle is known to involve a protein-mediated single-stranded (ss)DNA gate, the detailed mechanism is not fully understood. Here, we probe the catalytic steps of TRR using optical tweezers and fluorescence microscopy. We demonstrate that TRR forms an open gate in ssDNA of 8.5 ± 3.8 nm, and directly visualize binding of a second ssDNA or double-stranded (ds)DNA molecule to the open TRR-ssDNA gate, followed by catenation in each case. Strikingly, dsDNA binding increases the gate size (by ~16%), while BLM alters the mechanical flexibility of the gate. These findings reveal an unexpected plasticity of the TRR-ssDNA gate size and suggest that TRR-mediated transfer of dsDNA may be more relevant in vivo than previously believed.The aim of the study was to compare the supra-alveolar gingival dimension (GD) and the clinical pocket probing depth (PD) by combining data from an intraoral scanner (IOS) and cone-beam computed tomography (CBCT) and identify the clinical features affecting the clinical PD. 1,071 sites from 11 patients were selected for whom CBCT, IOS images, and periodontal charts were recorded at the same visit. CBCT and IOS data were superimposed. GD was measured on cross-sectional images of the probed sites. The level of agreement and correlation between GD and PD were assessed for the entire population and within groups (treated vs untreated, bleeding on probing [BOP] vs no BOP, and PDs of 0-3 mm vs 4-5 mm vs ≥ 6 mm). The mean [± SD] difference between GD and PD was 0.82 [± 0.69] mm, and they were positively correlated (r = 0.790, p  less then  0.001). The correlations between GD and PD were stronger for untreated sites, sites with BOP, and sites with a larger PD. Within the limitations of this study, the similarity between GD and PD may suggest a possible tendency of overestimation when recording PD.Osteosarcoma accounts for a frequently occurring cancer of the primary skeletal system. In osteosarcoma cells, a hypoxic microenvironment is commonly observed that drives tumor growth, progression, and heterogeneity. Hypoxia and tumor-infiltrating immune cells might be closely related to the prognosis of osteosarcoma. In this study, we aimed to determine the biomarkers and therapeutic targets related to hypoxia and immunity through bioinformatics methods to improve the clinical prognosis of patients. We downloaded the gene expression data of osteosarcoma samples and normal samples in the UCSC Xena database and GTEx database, respectively, and downloaded the validation dataset (GSE21257) in the GEO database. Subsequently, we performed GO enrichment analysis and KEGG pathway enrichment analysis on the data of the extracted osteosarcoma hypoxia-related genes. Through univariate COX regression analysis, lasso regression analysis, multivariate COX regression analysis, etc., we established a predictive model for the prognosis of osteosarcoma. Five genes, including ST3GAL4, TRIM8, STC2, TRPS1, and FAM207A, were found by screening. In particular, we analyzed the immune cell composition of each gene based on the five genes through the CIBERSORT algorithm and verified each gene at the cell and tissue level. Our findings are valuable for the clinical diagnosis and treatment of this disease.Risk stratification in multiple myeloma is important for prognostication, patient selection for clinical trials, and comparison of treatment approaches. We developed and validated a staging system that incorporates additional FISH abnormalities not included in the R-ISS and reflects the additive effects of co-occurring high-risk disease features. We first evaluated the prognostic value of predefined cytogenetic and laboratory abnormalities in 2556 Mayo Clinic patients diagnosed between February 2004 and June 2019. We then used data from 1327 patients to develop a risk stratification model and validated this in 502 patients enrolled in the MMRF CoMMpass study. On multivariate analysis, high-risk IgH translocations [risk ratio (RR) 1.7], 1q gain/amplification (RR 1.4), chromosome17 abnormalities (RR 1.6), ISS III (RR 1.7), and elevated LDH (RR 1.3) were independently associated with decreased overall survival (OS). Among 1327 evaluable patients, OS was 11.0 (95% CI 9.2-12.6), 7.0 (95% CI 6.3-9.2), and 4.5 (95% CI 3.7-5.2) years in patients with 0 (stage I), 1 (stage II), and ≥2 (stage III) high-risk factors, respectively. In the MMRF cohort, median OS was 7.8 (95% CI NR-NR), 6.0 (95% CI 5.7-NR), and 4.3 (95% CI 2.7-NR) years in the 3 groups, respectively (P  less then  0.001). This 5-factor, 3-tier system is easy to implement in practice and improves upon the current R-ISS.The effects of photo-oxidative degradation of polyacids at various concentrations and with different durations of ultraviolet (UV) irradiation on the photo-reduction of ceria nanoparticles were investigated. The effect of UV-treated ceria on the performance of chemical mechanical polishing (CMP) for the dielectric layer was also evaluated. When the polyacids were exposed to UV light, they underwent photo-oxidation with consumption of the dissolved oxygen in slurry. UV-treated ceria particles formed oxygen vacancies by absorbing photon energy, resulting in increased Ce3+ ions concentration on the surface, and when the oxygen level of the solution was lowered by the photo-oxidation of polymers, the formation of Ce3+ ions was promoted from 14.2 to 36.5%. Furthermore, chain scissions of polymers occurred during the oxidation process, and polyacids with lower molecular weights were found to be effective in ceria particle dispersion in terms of the decrease in the mean diameter and size distribution maintaining under 0.1 of polydispersity index. With increasing polyacid concentration and UV irradiation time, the Ce3+ concentration and the dispersity of ceria both increased due to the photo-oxidative degradation of the polymer; this enhanced the CMP performance in terms of 87% improved material removal rate and 48% lowered wafer surface roughness.Nonalcoholic fatty liver disease (NAFLD) is an important health concern worldwide and progresses into nonalcoholic steatohepatitis (NASH). Although prevalence and severity of NAFLD/NASH are higher in men than premenopausal women, it remains unclear how sex affects NAFLD/NASH pathophysiology. Formyl peptide receptor 2 (FPR2) modulates inflammatory responses in several organs; however, its role in the liver is unknown. Here we show that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH. NASH-like liver injury was induced in both sexes during choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) feeding, but compared with females, male mice had more severe hepatic damage. Fpr2 was more highly expressed in hepatocytes and healthy livers from females than males, and FPR2 deletion exacerbated liver damage in CDAHFD-fed female mice. Estradiol induced Fpr2 expression, which protected hepatocytes and the liver from damage. In conclusion, our results demonstrate that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH, suggesting a novel therapeutic target for NAFLD/NASH.Spreading centre jumps are a common feature of oceanic back-arc basins. Jumps are conventionally suggested to be triggered by plate velocity changes, pre-existing weaknesses, or punctuated events such as the opening of slab windows. Here, we present 3D numerical models of back-arc spreading centre jumps evolving naturally in a homogeneous subduction system surrounded by continents without a trigger event. Spreading centres jump towards their subduction zone if the distance from trench to spreading centre becomes too long. In particular, jumps to a new spreading centre occur when the resistance on the boundary transform faults enabling relative motion of back-arc and neighbouring plates is larger than the resistance to break the overriding plate closer to trench. Time and distance of spreading centres jumps are, thus, controlled by the ratio between the transform fault and overriding plate strengths. Despite being less complex than natural systems, our models explain why narrow subducting plates (e.g. Calabrian slab), have more frequent and closely-spaced spreading jumps than wider subduction zones (e.g. Scotia). It also explains why wide back-arc basins undergo no spreading centre jumps in their life cycle.Substrate inhibition of enzymes can be a major obstacle to the production of valuable chemicals in engineered microorganisms. Here, we show substrate inhibition of lycopene cyclase as the main limitation in carotenoid biosynthesis in Yarrowia lipolytica. To overcome this bottleneck, we exploit two independent approaches. Structure-guided protein engineering yields a variant, Y27R, characterized by complete loss of substrate inhibition without reduction of enzymatic activity. Alternatively, establishing a geranylgeranyl pyrophosphate synthase-mediated flux flow restrictor also prevents the onset of substrate inhibition by diverting metabolic flux away from the inhibitory metabolite while maintaining sufficient flux towards product formation. Both approaches result in high levels of near-exclusive β-carotene production. TVB-3166 Ultimately, we construct strains capable of producing 39.5 g/L β-carotene at a productivity of 0.165 g/L/h in bioreactor fermentations (a 1441-fold improvement over the initial strain). Our findings provide effective approaches for removing substrate inhibition in engineering pathways for efficient synthesis of natural products.Emotional stress is considered a severe pathogenetic factor of psychiatric disorders. However, the circuit mechanisms remain largely unclear. Using a three-chamber vicarious social defeat stress (3C-VSDS) model in mice, we here show that chronic emotional stress (CES) induces anxiety-like behavior and transient social interaction changes. Dopaminergic neurons of ventral tegmental area (VTA) are required to control this behavioral deficit. VTA dopaminergic neuron hyperactivity induced by CES is involved in the anxiety-like behavior in the innate anxiogenic environment. Chemogenetic activation of VTA dopaminergic neurons directly triggers anxiety-like behavior, while chemogenetic inhibition of these neurons promotes resilience to the CES-induced anxiety-like behavior. Moreover, VTA dopaminergic neurons receiving nucleus accumbens (NAc) projections are activated in CES mice. Bidirectional modulation of the NAc-VTA circuit mimics or reverses the CES-induced anxiety-like behavior. In conclusion, we propose that a NAc-VTA circuit critically establishes and regulates the CES-induced anxiety-like behavior.