Tfh cell-derived small extracellular vesicles exacerbate the severity of collagen-induced arthritis by enhancing B-cell responses.

Soluble components secreted by Tfh cells are critical for the germinal center responses. In this study, we investigated whether Tfh cells could regulate the B-cell response by releasing small extracellular vesicles (sEVs). Our results showed that Tfh cells promote B-cell differentiation and antibody production through sEVs and that CD40L plays a crucial role in Tfh-sEVs function. In addition, increased Tfh-sEVs were found in mice with collagen-induced arthritis (CIA). Adoptive transfer of Tfh cells significantly exacerbated the severity of CIA; however, the effect of Tfh cells on exacerbating the CIA process was significantly diminished after inhibiting sEVs secretion. Moreover, the levels of plasma Tfh-like-sEVs and CD40L expression on Tfh-like-sEVs in RA patients were significantly higher than those in healthy subjects. In summary, Tfh cell-derived sEVs can enhance the B-cell response, and exacerbate the procession of autoimmune arthritis.

Mycorrhizal associations relate to stable convergence in plant-microbial competition for nitrogen absorption under high nitrogen conditions.

Nitrogen (N) immobilization (Nim, including microbial N assimilation) and plant N uptake (PNU) are the two most important pathways of N retention in soils. The ratio of Nim to PNU (hereafter Nim:PNU ratio) generally reflects the degree of N limitation for plant growth in terrestrial ecosystems. However, the key factors driving the pattern of Nim:PNU ratio across global ecosystems remain unclear. Here, using a global data set of 1018 observations from 184 studies, we examined the relative importance of mycorrhizal associations, climate, plant, and soil properties on the Nim:PNU ratio across terrestrial ecosystems. Our results show that mycorrhizal fungi type (arbuscular mycorrhizal (AM) or ectomycorrhizal (EM) fungi) in combination with soil inorganic N mainly explain the global variation in the Nim:PNU ratio in terrestrial ecosystems. In AM fungi-associated ecosystems, the relationship between Nim and PNU displays a weaker negative correlation (r = -.06, p < .001), whereas there is a stronger positive correlation (r = .25, p < .001) in EM fungi-associated ecosystems. Our meta-analysis thus suggests that the AM-associated plants display a weak interaction with soil microorganisms for N absorption, while EM-associated plants cooperate with soil microorganisms. Furthermore, we find that the Nim:PNU ratio for both AM- and EM-associated ecosystems gradually converge around a stable value (13.8 ± 0.5 for AM- and 12.1 ± 1.2 for EM-associated ecosystems) under high soil inorganic N conditions. Our findings highlight the dependence of plant-microbial interaction for N absorption on both plant mycorrhizal association and soil inorganic N, with the stable convergence of the Nim:PNU ratio under high soil N conditions.

Activation of adenosine A2B receptor alleviates myocardial ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress and restoring autophagy flux.

Myocardial ischemia-reperfusion injury (MIRI) poses a significant threat to patients with coronary heart disease. Adenosine A2A receptors have been known as a protective role in MIRI by regulating autophagy, so we assumed that activation of adenosine A2B receptor (A2BAR) might exert a similar effect during MIRI and underlying mechanism be related to proteostasis maintenance as well. In situ hearts were subjected to 30 min of ischemia and 120 min of reperfusion (IR), while invitro cardiomyocytes from neonatal rats experienced 6 h of oxygen-glucose deprivation followed by 12 h of reoxygenation (OGDR). Initially, we observed that post-ischemia-reperfusion induced autophagy flux blockade and ERS both in vivo and in vitro, evident through the increased expression of p62, LC3II, and BIP, which indicated the deteriorated proteostasis. We used a selective A2BAR agonist, Bay 60-6583, to explore the positive effects of A2BAR on cardiomyocytes and found that A2BAR activation rescued damaged cardiac function and morphological changes in the IR group and improved frail cell viability in the OGDR group. The A2BAR agonist also alleviated the blockage of autophagic flux, coupled with augmented ERS in the IR/OGDR group, which was reassured by using an autophagy inhibitor chloroquine (CQ) and ERS inhibitor (4-PBA) in vitro. Additionally, considering cAMP/PKA as a well-known downstream effector of A2BAR, we utilized H89, a selective PKA inhibitor. We observed that the positive efficacy of Bay 60-6583 was inhibited by H89. Collectively, our findings demonstrate that the A2BAR/cAMP/PKA signaling pathway exerts a protective role in MIRI by mitigating impaired autophagic flux and excessive ERS.

An enhanced model for environmental dry eye: Exploring pathological features and underlying factors.

This study aimed to develop an enhanced environmental dry eye (EDE) model that accurately reproduces the etiology of prolonged visual fatigue and investigates the underlying pathological features. A total of 40 adult SPF-grade Wistar rats were randomly assigned to control (n = 20) and model (n = 20) groups. Rats in the control group were maintained under normal conditions, while rats in the model group were exposed to a controlled frontal airflow of 2-4 m/s from a fan for 7.5 h daily while placed on a suspended cylindrical wire mesh frame. Various assessments were performed at different time points during the 14-day experiment, including blink frequency, tear secretion (phenol red thread test), tear film breakup time (BUT), fluorescein staining (FL), corneal epithelial status (light microscopy), ultrastructure of corneal epithelial cells (electron microscopy), and expression levels of inflammatory cytokines (IL-1ß, TNF-α) in tears (enzyme-linked immunosorbent assay). Additionally, mRNA and protein expression levels of MMP-9, IL1ß, IL6, TNF-α, IFN-γ, and caspase-3 in corneal tissues were quantified (real-time quantitative PCR and Western blotting). Compared to the control group, the model group rats exhibited significant decreases in blink frequency (P < 0.001), tear secretion (Schirmer I test) values (P < 0.001), and tear film breakup time levels (P < 0.001). There was also a significant increase in fluorescein staining scores (P < 0.001) in the model group. Histological examination revealed distinct differences of the corneal epithelium between groups. The corneal epithelium of the model group appeared thicker, with disorganized cell arrangement in the superficial and basal layers, partial defects or detachment of superficial epithelial cells, and a rough, uneven surface. Scanning electron microscopy observations showed a rough corneal epithelial surface with numerous cracks and scattered vesicular-like structures in the model group. Furthermore, the model group rats exhibited a significant increase in expression of IL-1ß and TNF-α in tears (P < 0.001), and upregulated expression levels of MMP-9, TNF-α, IL-1ß, caspase-3, IL-6, and IFN-γ at both the mRNA and protein levels in corneal tissues (P < 0.001). In conclusion, the modified "wire-meshing cylindrical board" model effectively overcomes the limitations of the traditional "jogging board " dry eye model and successfully simulates the etiology of prolonged visual fatigue. This innovative EDE model demonstrates a high degree of relevance to dry eye conditions resulting from prolonged visual tasks, with a high success rate of model induction. Moreover, it proves to be a simple, practical, and easily replicable model, making it highly suitable for further studies on prolonged visual fatigue and facilitating its widespread adoption in research and clinical applications.

Sex differences in mortality and liver-related events in non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND & AIMS: Many systematic reviews explore the association of non-alcoholic fatty liver disease (NAFLD) with mortality, but none of them explores sex-based differences in detail. We aimed to assess whether NAFLD is associated with cause-specific mortality, all-cause mortality, and cancer incidence in both men and women. METHODS: The PubMed, Embase, and Medline databases were searched from inception through April 2023 for eligible studies. We separately pooled relative risks (RRs) for men and women using a random effects model. Subsequently, the RRs and 95% CIs (confidence intervals) in each study were used to calculate the women-to-men ratio of RRs (RRR). Furthermore, subgroup analyses were performed to explore the robustness of outcomes. The random-effects model was employed to conduct sensitivity analyses to determine the impact of specific studies on the overall findings. RESULTS: The meta-analysis included nine cohort studies comprising 557 614 patients with NAFLD were chosen. Women were 44% more likely than men to get cancer among those with NAFLD (RRR: 1.44; 95% CI: 1.02-2.04; p = .039). However, no sex-related differences were observed between NAFLD and all-cause mortality (RRR: 1.06; 95% CI: 0.56-2.01; p = .861), liver-related mortality (RRR: 1.06; 95% CI: 0.02-69.82; p = .977), cardiovascular mortality (RRR: 1; 95% CI: 0.65-1.53; p = .987) and liver cancer (RRR: 0.76; 95% CI: 0.43-1.36; p = .36). CONCLUSIONS: There may be sex variations between NAFLD and the risk of cancer, with the connection being stronger in females than in males.

Nocardioides bizhenqiangii sp. nov. and Nocardioides renjunii sp. nov., isolated from soil and faeces of Tibetan antelope (Pantholops hodgsonii) on the Qinghai-Tibet Plateau.

Two novel strain pairs (HM61T/HM23 and S-34T/S-58) were isolated from soil and the faeces of Tibetan antelope (Pantholops hodgsonii) collected at the Qinghai-Tibet Plateau of PR China. All four new isolates were aerobic, non-motile, Gram-stain-positive, catalase-positive, oxidase-negative, and short rod-shaped bacteria. The results of phylogenetic analysis based on the full-length 16S rRNA genes and 283 core genomic genes indicated that the four strains were separated into two independent branches belonging to the genus Nocardioides. Strains HM61T and HM23 were most closely related to Nocardioides pelophilus THG T63T (98.58 and 98.65 % 16S rRNA gene sequence similarity). Strains S-34T and S-58 were most closely related to Nocardioides okcheonensis MMS20-HV4-12T (98.89 and 98.89 % 16S rRNA gene sequence similarity). The G+C contents of the genomic DNA of strains HM61T and S-34T were 70.6 and 72.5 mol%, respectively. Strains HM61T, S-34T and the type strains of closely related species in the analysis had average nucleotide identity values of 75.4-90.5 % as well as digital DNA-DNA hybridization values between 20.1 and 40.8 %, which clearly indicated that the four isolates represent two novel species within the genus Nocardioides. The chemotaxonomic characteristics of strains HM61T and S-34T were consistent with the genus Nocardioides. The major fatty acids of all four strains were iso-C16 : 0, C17 : 1 ω8c or C18 : 1 ω9c. For strains HM61T and S-34T, MK-8(H4) was the predominant respiratory quinone, ll-2,6-diaminopimelic acid was the diagnostic diamino acid in the cell-wall peptidoglycan, and the polar lipids profiles were composed of diphosphatidylglycerol and phosphatidylglycerol. Based on phylogenetic, phenotypic, and chemotaxonomic data, we propose that strains HM61T and S-34T represent two novel species of the genus Nocardioides, respectively, with the names Nocardioides bizhenqiangii sp. nov. and Nocardioides renjunii sp. nov. The type strains are HM61T (=GDMCC 4.343T=JCM 36399T) and S-34T (=CGMCC 4.7664T=JCM 33792T).

Regulation mechanism and bioactivity characteristic of surfactin homologues with C14 and C15 fatty acid chains.

BACKGROUND: Surfactin, a green lipopeptide bio-surfactant, exhibits excellent surface, hemolytic, antibacterial, and emulsifying activities. However, a lack of clear understanding of the synthesis regulation mechanism of surfactin homologue components has hindered the customized production of surfactin products with different biological activities. RESULTS: In this study, exogenous valine and 2-methylbutyric acid supplementation significantly facilitated the production of C14-C15 surfactin proportions (up to 75% or more), with a positive correlation between the homologue proportion and fortified concentration. Subsequently, the branched-chain amino acid degradation pathway and the glutamate synthesis pathway are identified as critical pathways in regulating C14-C15 surfactin synthesis by transcriptome analysis. Overexpression of genes bkdAB and glnA resulted in a 1.4-fold and 1.3-fold increase in C14 surfactin, respectively. Finally, the C14-rich surfactin was observed to significantly enhance emulsification activity, achieving an EI24 exceeding 60% against hexadecane, while simultaneously reducing hemolytic activity. Conversely, the C15-rich surfactin demonstrated an increase in both hemolytic and antibacterial activities. CONCLUSION: This study presents the first evidence of a potential connection between surfactin homologue synthesis and the conversion of glutamate and glutamine, providing a theoretical basis for targeting the synthesis regulation and structure-activity relationships of surfactin and other lipopeptide compounds.

Preparation of cellulose acetate based flexible separator and its application in zinc-air batteries.

Flexible solid-state zinc-air batteries as a wearable energy storage device with great potential, and their separators, which control ion permeability, inhibit zinc dendrite generation, and regulate catalytic active sites, have been developed as gel electrolyte separators with high retention of electrolyte uptake. However, the gel electrolyte separator still has problems such as poor affinity with the electrolyte and poor ionic conductivity, which limits its further application. In order to further improve the electrolyte absorption, ionic conductivity and mechanical strength of cellulose acetate(CA)/polyvinyl alcohol (PVA) nanofibers, TiO2was added to CA/PVA to increase the porosity, and glutaraldehyde (GA) was used to modify the CA/PVA/TiO2separator by acetal reaction with CA and PVA to make the molecules closely linked. The results shows that the optimal mass fractions of TiO2and GA were 2% and 5%, respectively. At this time, the porosity and absorption rate of the separator increased from 48% to 68.2% and 142.4% to 285.3%, respectively. The discharge capacity reached 179 mA cm-3, and the cycle stability rate was 89% after 7 stable constant current charge/discharge cycles.

Association of daily sitting time and coffee consumption with the risk of all-cause and cardiovascular disease mortality among US adults.

BACKGROUND: Sedentary behavior has been demonstrated to be a modifiable factor for several chronic diseases, while coffee consumption is believed to be beneficial for health. However, the joint associations of daily sitting time and coffee consumption with mortality remains poorly understood. This study aimed to evaluate the independent and joint associations of daily sitting time and coffee intakes with mortality from all-cause and cardiovascular disease (CVD) among US adults. METHODS: An analysis of a prospective cohort from the 2007-2018 National Health and Nutrition Examination Survey of US adults (n = 10,639). Data on mortality were compiled from interview and physical examination data until December 31, 2019. Daily sitting time was self-reported. Coffee beverages were from the 24-hour diet recall interview. The main outcomes of the study were all-cause and cardiovascular disease mortality. The adjusted hazard ratios [HRs] and 95% confidence intervals [CI] were imputed by Cox proportional hazards regression. RESULTS: Among 10,639 participants in the study cohort, there were 945 deaths, 284 of whom died of CVD during the follow-up period of up to 13 years. Multivariable models showed that sitting more than 8 h/d was associated with higher risks of all-cause (HR, 1.46; 95% CI, 1.17-1.81) and CVD (HR, 1.79; 95% CI, 1.21-2.66) mortality, compared with those sitting for less than 4 h/d. People with the highest quartile of coffee consumption were observed for the reduced risks of both all-cause (HR, 0.67; 95% CI, 0.54-0.84) and CVD (HR, 0.46; 95% CI, 0.30-0.69) mortality compared with non-coffee consumers. Notably, joint analyses firstly showed that non-coffee drinkers who sat six hours or more per day were 1.58 (95% CI, 1.25-1.99) times more likely to die of all causes than coffee drinkers sitting for less than six hours per day, indicating that the association of sedentary with increased mortality was only observed among adults with no coffee consumption but not among those who had coffee intake. CONCLUSIONS: This study identified that sedentary behavior for more than 6 h/d accompanied with non-coffee consumption, were strongly associated with the increased risk of mortality from all-cause and CVD.

The Therapeutic Effect of Buyang Huanwu Decoction on Mild Cognitive Impairment (MCI) in Patients with Diabetes.

OBJECTIVE: This study aims to comprehensively verify the efficacy of Buyang Huanwu Decoction in improving cognitive function in patients with diabetes. METHODS: Patients clinically diagnosed with mild cognitive impairment (MCI) assigned to either the placebo group or the Buyang Huanwu Decoction group. After strict screening and exclusions, a total of 156 participants completed the clinical trial, with 76 in the placebo group and 80 in the Buyang Huanwu Decoction group. RESULTS: After treatment, Buyang Huanwu Decoction group showed higher Mini-Mental State Examination and Montreal Cognitive Assessment scores compared to placebo (p < 0.05). Memory and Executive Screening, Boston Naming Test, and Animal Fluency Test scores were also higher in the treatment group (p < 0.05). No significant differences were found in DST and CDT scores (p > 0.05). Trail Making Test scores were lower in the treatment group (p < 0.05). No significant difference was observed between the two groups in terms of complications (p > 0.05). CONCLUSION: Patients receiving Buyang Huanwu Decoction treatment demonstrated improvement in cognitive function, showing positive effects and providing preliminary evidence for the role of Buyang Huanwu Decoction in improving cognitive function in patients with diabetes. This suggests its potential for clinical application and further promotion.

Research on Bearing Surface Scratch Detection Based on Improved YOLOV5.

Bearings are crucial components of machinery and equipment, and it is essential to inspect them thoroughly to ensure a high pass rate. Currently, bearing scratch detection is primarily carried out manually, which cannot meet industrial demands. This study presents research on the detection of bearing surface scratches. An improved YOLOV5 network, named YOLOV5-CDG, is proposed for detecting bearing surface defects using scratch images as targets. The YOLOV5-CDG model is based on the YOLOV5 network model with the addition of a Coordinate Attention (CA) mechanism module, fusion of Deformable Convolutional Networks (DCNs), and a combination with the GhostNet lightweight network. To achieve bearing surface scratch detection, a machine vision-based bearing surface scratch sensor system is established, and a self-made bearing surface scratch dataset is produced as the basis. The scratch detection final Average Precision (AP) value is 97%, which is 3.4% higher than that of YOLOV5. Additionally, the model has an accuracy of 99.46% for detecting defective and qualified products. The average detection time per image is 263.4 ms on the CPU device and 12.2 ms on the GPU device, demonstrating excellent performance in terms of both speed and accuracy. Furthermore, this study analyzes and compares the detection results of various models, demonstrating that the proposed method satisfies the requirements for detecting scratches on bearing surfaces in industrial settings.

Enhanced dewaterability of food waste digestate by biochar/potassium ferrate treatments: Performance and mechanisms.

The combined process of biochar (BC) and potassium ferrate (PF) offers a fascinating technique for efficient dewatering of digestate. However, the effects of BC/PF treatment on the dewaterability and mechanisms of FWD are still unknown. This study aimed to reveal the impact mechanisms of BC/PF treatment on digestate dewatering performance. Experimental results indicated that BC/PF treatment significantly enhanced the dewaterability of digestate, with the minimum specific resistance to filtration of (1.05 ± 0.02) × 1015 m·kg-1 and water content of 57.52 ± 0.51% being obtained at the concentrations of 0.018 g·g-1 total solid (TS) BC300 and 0.20 g·g-1 TS PF, which were 8.60% and 13.59% lower than PF treatment, respectively. BC/PF treatment proficiently reduced the fractal dimension, bound water content, apparent viscosity, and gel-like network structure strength of digestate, as well as increased the floc size and zeta potential of digestate. BC/PF treatment promoted the conversion of extracellular polymeric substances (EPS) fractions from inner EPS to soluble EPS, increased the fluorescence intensity of the dissolved compounds, and enhanced the hydrophobicity of proteins. Mechanisms investigations showed that BC/PF enhanced dewatering through non-reactive oxygen species pathways, i.e., via strong oxidative intermediate irons species Fe(V)/Fe(IV). BC/PF treatment enhanced the solubilization of nutrients, the inactivation of fecal coliforms, and the mitigation of heavy metal toxicity. The results suggested that BC/PF treatment is an effective digestate dewatering technology which can provide technological supports to the closed-loop treatment of FWD.

Thermodynamic Entropy-Based Fatigue Life Assessment Method for Nickel-Based Superalloy GH4169 at Elevated Temperature Considering Cyclic Viscoplasticity.

This paper develops a thermodynamic entropy-based life prediction model to estimate the low-cycle fatigue (LCF) life of the nickel-based superalloy GH4169 at elevated temperature (650 °C). The gauge section of the specimen was chosen as the thermodynamic system for modeling entropy generation within the framework of the Chaboche viscoplasticity constitutive theory. Furthermore, an explicitly numerical integration algorithm was compiled to calculate the cyclic stress-strain responses and thermodynamic entropy generation for establishing the framework for fatigue life assessment. A thermodynamic entropy-based life prediction model is proposed with a damage parameter based on entropy generation considering the influence of loading ratio. Fatigue lives for GH4169 at 650 °C under various loading conditions were estimated utilizing the proposed model, and the results showed good consistency with the experimental results. Finally, compared to the existing classical models, such as Manson-Coffin, Ostergren, Walker strain, and SWT, the thermodynamic entropy-based life prediction model provided significantly better life prediction results.

Climate warming interacts with other global change drivers to influence plant phenology: A meta-analysis of experimental studies.

Shifts in plant phenology influence ecosystem structures and functions, yet how multiple global change drivers interact to affect phenology remains elusive. We conducted a meta-analysis of 242 published articles to assess interactions between warming (W) and other global change drivers including nitrogen addition (N), increased precipitation (IP), decreased precipitation (DP) and elevated CO2 (eCO2 ) on multiple phenophases in experimental studies. We show that leaf out and first flowering were most strongly affected by warming, while warming and decreased precipitation were the most pronounced drivers for leaf colouring. Moreover, interactions between warming and other global change drivers were common and both synergistic and antagonistic interactions were observed: interactions W + IP and W + eCO2 were frequently synergistic, whereas interactions W + N and W + DP were mostly antagonistic. These findings demonstrate that global change drivers often affect plant phenology interactively. Incorporating the multitude of interactions into models is crucial for accurately predicting plant responses to global changes.

GhPYL9-5D and GhPYR1-3 A positively regulate Arabidopsis and cotton responses to ABA, drought, high salinity and osmotic stress.

BACKGROUND: Abscisic acid (ABA) receptor pyrabactin resistance 1/PYR1-like/regulatory components of ABA receptor proteins (PYR/PYL/RCARs) have been demonstrated to play pivotal roles in ABA signaling and in response to diverse environmental stimuli including drought, salinity and osmotic stress in Arabidopsis. However, whether and how GhPYL9-5D and GhPYR1-3A, the homologues of Arabidopsis PYL9 and PYR1 in cotton, function in responding to ABA and abiotic stresses are still unclear. RESULTS: GhPYL9-5D and GhPYR1-3A were targeted to the cytoplasm and nucleus. Overexpression of GhPYL9-5D and GhPYR1-3A in Arabidopsis wild type and sextuple mutant pyr1pyl1pyl2pyl4pyl5pyl8 plants resulted in ABA hypersensitivity in terms of seed germination, root growth and stomatal closure, as well as seedling tolerance to water deficit, salt and osmotic stress. Moreover, the VIGS (Virus-induced gene silencing) cotton plants, in which GhPYL9-5D or GhPYR1-3A were knocked down, showed clearly reduced tolerance to polyethylene glycol 6000 (PEG)-induced drought, salinity and osmotic stresses compared with the controls. Additionally, transcriptomic data revealed that GhPYL9-5D was highly expressed in the root, and GhPYR1-3A was strongly expressed in the fiber and stem. GhPYL9-5D, GhPYR1-3A and their homologs in cotton were highly expressed after treatment with PEG or NaCl, and the two genes were co-expressed with redox signaling components, transcription factors and auxin signal components. These results suggest that GhPYL9-5D and GhPYR1-3A may serve important roles through interplaying with hormone and other signaling components in cotton adaptation to salt or osmotic stress. CONCLUSIONS: GhPYL9-5D and GhPYR1-3A positively regulate ABA-mediated seed germination, primary root growth and stomatal closure, as well as tolerance to drought, salt and osmotic stresses likely through affecting the expression of multiple downstream stress-associated genes in Arabidopsis and cotton.

Inhibition of Poly(ADP-ribose) Polymerase Sensitizes [177Lu]Lu-DOTAGA.(SA.FAPi)2-Mediated Radiotherapy in Triple-Negative Breast Cancer.

Fibroblast activation protein (FAP) is highly expressed in many tumor types and constitutes a promising target for tumor-specific delivery of therapeutic radionuclides. [177Lu]Lu-DOTAGA.(SA.FAPi)2 is a novel radiopharmaceutical based on a novel bidentate inhibitor of FAP that is excreted more slowly than its monomeric counterparts. Still, the efficacy of radiotherapy is mitigated by cascades of DNA damage repair signaling in tumor cells including those via Poly(ADP-ribose) polymerase (PARP). We hereby aimed to evaluate the efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2 in combination with a PARP inhibitor, Olaparib, in the 4T1 murine triple negative breast cancer (TNBC) model. The therapeutic efficacy was visualized using 18F-FDG and [68Ga]Ga-FAPI-04 positron emission imaging/computer tomography (PET/CT). Our results demonstrated that Olaparib suppressed BALB/3T3 fibroblasts in vitro and sensitized the efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2 in mice bearing 4T1 tumors via enhancement of DNA damage. Treatment-associated toxicity was tolerable with only mild leukopenia. Therefore, the combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and Olaparib is a feasible treatment against TNBC.

Preparation of PFPE-Based Polymeric Nanoparticles via Polymerization-Induced Self-Assembly as Contrast Agents for 19F MRI.

Fluorine-19 magnetic resonance imaging (19F MRI) probes have received considerable research interest as imaging contrast agents (CAs), but they remain neglected and underutilized due to the limited fluorine content or poor performance of fluorinated tracers. Here, we present polymeric nanoparticles (NPs) as 19F MRI CAs with a simple synthesis method and promising imaging performance. First, hydrophilic random copolymers were synthesized from oligo(ethylene glycol) methyl ether acrylate and perfluoropolyether methacrylate by reversible addition-fragmentation chain transfer (RAFT) polymerization. The optimal fluorine content, polymer concentration, and cytotoxicity as 19F MRI CAs were investigated in detail. Then, the optimal copolymer was selected as the macromolecular chain transfer agent, and the chain extension was performed with 2-(perfluorooctyl ethyl methacrylate). Subsequently, the NPs with different morphologies, such as ellipsoidal, spherical nanoparticles and vesicles, were prepared in situ by the RAFT-mediated polymerization-induced self-assembly method. In addition, the 19F MRI signal and cytotoxicity studies further confirmed that these polymeric NPs are nontoxic and have great potential as promising 19F MRI CAs for biological applications.

Photo-Responsive Self-Assembled Polymeric Nanoparticle Probes for 19F MRI Theranostics.

19F magnetic resonance imaging (MRI)-assisted drug delivery provides the possibility to monitor and track drug transportation details in situ. A series of photo-responsive amphiphilic block copolymers consisting of hydrophilic poly(ethylene glycol) and 19F-containing hydrophobic segments, poly(2,2,2-trifluoroethyl acrylate) (PTFEA), with different chain lengths were synthesized by reversible addition-fragmentation chain-transfer polymerization. In particular, the photo-sensitive functional group of o-nitrobenzyl oxygen was introduced to control the photolysis behavior of the copolymers under ultraviolet irradiation. With the extension of the hydrophobic chain length, the drug loading capacity and photoresponsivity were both enhanced, while the chain mobility of PTFEA was suppressed, and the 19F MRI signal was attenuated. When the polymerization degree of PTFEA was about 10, the nanoparticles exhibit detectable 19F MRI signals and sufficient drug loading capacity (loading efficiency = 10%, cumulative release = 49%). These results offer a promising "smart" theranostic platform for 19F MRI.

Neisseria lisongii sp. nov. and Neisseria yangbaofengii sp. nov., isolated from the respiratory tracts of marmots.

Four Gram-stain-negative, oxidase-positive, non-motile, cocci-shaped bacteria strains (ZJ106T, ZJ104, ZJ785T and ZJ930) were isolated from marmot respiratory tracts. Phylogenetic analyses based on 16S rRNA genes, 53 ribosomal protein sequences and 441 core genes supported that all four strains belonged to the genus Neisseria with close relatives Neisseria weixii 10022T and Neisseria iguanae ATCC 51483T. Average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values were below the species-level thresholds (95-96 % for ANI, and 70 % for dDDH). The major fatty acids of all four strains were C16 : 1 ω7c /C16 : 1 ω6c, C16 : 0 and C18 : 1 ω9c. Major polar lipids were composed of diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. MK-8 was the major menaquinone. Based on Virulence Factor Database analysis, the four strains were found to contain NspA and PorB H-factor binding proteins that promote evasion of host immunity. Strains ZJ106T and ZJ104 contained structures similar to the capsule synthesis manipulator of Neisseria meningitidis. Based on phenotypic and phylogenetic evidence, we propose that strains ZJ106T and ZJ785T represent two novel species of the genus Neisseria, respectively, with the names Neisseria lisongii sp. nov. and Neisseria yangbaofengii sp. nov. The type strains are ZJ106T (=GDMCC 1.3111T=JCM 35323T) and ZJ785T (=GDMCC 1.1998T=KCTC 82336T).

Relationship between key continuous glucose monitoring-derived metrics and specific cognitive domains in patients with type 2 diabetes mellitus.

BACKGROUND: Continuous glucose monitoring (CGM)-derived time in range (TIR) is closely associated with micro- and macrovascular complications in type 2 diabetes mellitus (T2DM). This study was performed to investigate the relationship between key CGM-derived metrics and specific cognitive domains in patients with T2DM. METHODS: Outpatients with T2DM who were otherwise healthy were recruited for this study. A battery of neuropsychological tests was performed to evaluate cognitive function, including memory, executive functioning, visuospatial ability, attention, and language. Participants wore a blinded flash continuous glucose monitoring (FGM) system for 72 h. The key FGM-derived metrics were calculated, including TIR, time below range (TBR), time above range (TAR), glucose coefficient of variation (CV), and mean amplitude of glycemic excursions (MAGE). Furthermore, the glycemia risk index (GRI) was also calculated by the GRI formula. Binary logistic regression was used to assess risk factors for TBR, and we further analysed the associations between neuropsychological test results and key FGM-derived metrics with multiple linear regressions. RESULTS: A total of 96 outpatients with T2DM were recruited for this study, with 45.8% experiencing hypoglycemia (TBR< 3.9 mmol/L). Spearman analysis results revealed that a higher TBR< 3.9 mmol/L was correlated with worse performance on the Trail Making Test A (TMTA), Clock Drawing Test (CDT), and cued recall scores (P < 0.05). Logistic regression analysis results indicated that the TMTA (OR = 1.010, P = 0.036) and CDT (OR = 0.429, P = 0.016) scores were significant factors influencing the occurrence of TBR< 3.9 mmol/L. Multiple linear regressions further demonstrated that TBR< 3.9 mmol/L (ß = -0.214, P = 0.033), TAR> 13.9 mmol/L (ß = -0.216, P = 0.030) and TAR10.1-13.9 mmol/L (ß = 0.206, P = 0.042) were significantly correlated with cued recall scores after adjusting for confounding factors. However, TIR, GRI, CV and MAGE showed no significant correlation with the results of neuropsychological tests (P > 0.05). CONCLUSIONS: A higher TBR< 3.9 mmol/L and TAR> 13.9 mmol/L were associated with worse cognitive functions (memory, visuospatial ability, and executive functioning). Conversely, a higher TAR of 10.1-13.9 mmol/L was associated with better memory performance in memory tasks.