Simultaneous Quantitation of Persulfides, Biothiols, and Hydrogen Sulfide through Sulfur Exchange Reaction with Trityl Spin Probes.

Reactive sulfur species (RSS) including persulfides (RSSHs), biothiols, and hydrogen sulfide (H2S) are key regulators in various physiological processes. To better understand the symbiotic relationship and interconversion of these RSS, it is highly desirable but challenging to develop analytical techniques that are capable of detecting and quantifying them. Herein, we report the rational design and synthesis of novel trityl-radical-based electron paramagnetic resonance (EPR) probes dubbed CT02-TNB and OX-TNB. CT02-TNB underwent fast sulfur exchange reactions with two reactive RSSHs (PS1 and PS2) which were released from their corresponding donors PSD1 and PSD2 to afford the specific conjugates. The resulting conjugates exhibit characteristic EPR spectra, thus enabling discriminative detection and quantitation of the two RSSHs. Moreover, CT02-TNB showed good response toward other RSS including glutathione (GSH), cysteine (Cys), H2S, and sulfite as well. Importantly, based on the updated EPR spectral simulation program, simultaneous quantitation of multiple RSS (e.g., PS1/GSH/Cys or PS1/GSH/H2S) by CT02-TNB was also achieved. Finally, the levels of released PS1 from PSD1 and endogenous GSH in isolated mouse livers were measured by the hydrophilic OX-TNB. This work represents the first study achieving discriminative and quantitative detection of different persulfides and other RSS by a spectroscopic method.

LASP1 in the nucleus accumbens modulates methamphetamine-induced conditioned place preference in mice.

Methamphetamine (METH) is a highly addictive and widely abused drug that causes complex adaptive changes in the brain's reward system, such as the nucleus accumbens (NAc). LASP1 (LIM and SH 3 domain protein 1) as an actin-binding protein, regulates synaptic plasticity. However, the role and mechanism by which NAc LASP1 contributes to METH addiction remains unclear. In this study, adult male C57BL/6J mice underwent repeated METH exposure or METH-induced conditioned place preference (CPP). Western blotting and immunohistochemistry were used to determine LASP1 expression in the NAc. Furthermore, LASP1 knockdown or overexpression using adeno-associated virus (AAV) administration via stereotactic injection into the NAc was used to observe the corresponding effects on CPP. We found that repeated METH exposure and METH-induced CPP upregulated LASP1 expression in the NAc. LASP1 silencing in the NAc reversed METH-induced CPP and reduced PSD95, NR2A, and NR2B expression, whereas LASP1 overexpression in the NAc enhanced CPP acquisition, accompanied by increased PSD95, NR2A, and NR2B expression. Our findings demonstrate an important role of NAc LASP1 in modulating METH induced drug-seeking behavior and the underlying mechanism may be related to regulate the expression of synapse-associated proteins in the NAc. These results reveal a novel molecular regulator of the actions of METH on the NAc and provide a new strategy for treating METH addiction.

Photo-ferroelectric perovskite interfaces for boosting VOC in efficient perovskite solar cells.

Interface engineering is the core of device optimization, and this is particularly true for perovskite photovoltaics (PVs). The steady improvement in their performance has been largely driven by careful manipulation of interface chemistry to reduce unwanted recombination. Despite that, PVs devices still suffer from unavoidable open circuit voltage (VOC) losses. Here, we propose a different approach by creating a photo-ferroelectric perovskite interface. By engineering an ultrathin ferroelectric two-dimensional perovskite (2D) which sandwiches a perovskite bulk, we exploit the electric field generated by external polarization in the 2D layer to enhance charge separation and minimize interfacial recombination. As a result, we observe a net gain in the device VOC reaching 1.21 V, the highest value reported to date for highly efficient perovskite PVs, leading to a champion efficiency of 24%. Modeling depicts a coherent matching of the crystal and electronic structure at the interface, robust to defect states and molecular reorientation. The interface physics is finely tuned by the photoferroelectric field, representing a new tool for advanced perovskite device design.

Constraining the Excessive Aggregation of Non-Fullerene Acceptor Molecules Enables Organic Solar Modules with the Efficiency >16.

Translating high-performance organic solar cell (OSC) materials from spin-coating to scalable processing is imperative for advancing organic photovoltaics. For bridging the gap between laboratory research and industrialization, it is essential to understand the structural formation dynamics within the photoactive layer during printing processes. In this study, two typical printing-compatible solvents in the doctor-blading process are employed to explore the intricate mechanisms governing the thin-film formation in the state-of-the-art photovoltaic system PM6:L8-BO. Our findings highlight the synergistic influence of both the donor polymer PM6 and the solvent with a high boiling point on the structural dynamics of L8-BO within the photoactive layer, significantly influencing its morphological properties. The optimized processing strategy effectively suppresses the excessive aggregation of L8-BO during the slow drying process in doctor-blading, enhancing thin-film crystallization with preferential molecular orientation. These improvements facilitate more efficient charge transport, suppress thin-film defects and charge recombination, and finally enhance the upscaling potential. Consequently, the optimized PM6:L8-BO OSCs demonstrate power conversion efficiencies of 18.42% in small-area devices (0.064 cm2) and 16.02% in modules (11.70 cm2), respectively. Overall, this research provides valuable insights into the interplay among thin-film formation kinetics, structure dynamics, and device performance in scalable processing.

Vertically oriented low-dimensional perovskites for high-efficiency wide band gap perovskite solar cells.

Controlling crystal growth alignment in low-dimensional perovskites (LDPs) for solar cells has been a persistent challenge, especially for low-n LDPs (n < 3, n is the number of octahedral sheets) with wide band gaps (>1.7 eV) impeding charge flow. Here we overcome such transport limits by inducing vertical crystal growth through the addition of chlorine to the precursor solution. In contrast to 3D halide perovskites (APbX3), we find that Cl substitutes I in the equatorial position of the unit cell, inducing a vertical strain in the perovskite octahedra, and is critical for initiating vertical growth. Atomistic modelling demonstrates the thermodynamic stability and miscibility of Cl/I structures indicating the preferential arrangement for Cl-incorporation at I-sites. Vertical alignment persists at the solar cell level, giving rise to a record 9.4% power conversion efficiency with a 1.4 V open circuit voltage, the highest reported for a 2 eV wide band gap device. This study demonstrates an atomic-level understanding of crystal tunability in low-n LDPs and unlocks new device possibilities for smart solar facades and indoor energy generation.

Progress on SOX9 and its enhancers in mammalian sex determination.

The sex determination in mammals refers to the development of an initial bipotential organ, termed the bipotential gonad/genital ridge, into either a testis or an ovary at the early stages of embryonic development, under the precise regulation of transcription factors. SOX9 (SRY-box transcription factor 9) is a multifunctional transcription factor in mammalian development and plays a critical role in sex determination and subsequent male reproductive organs development. Recent studies have shown that several enhancers upstream of SOX9 also play an important role in the process of sex determination. In this review, we summarize the progress on the role of SOX9 and its gonadal enhancers in sex determination. This review will facilitate to understand the regulatory mechanism of sex determination of SOX9 and provides a theoretical basis for the further development of animal sex manipulation technologies.

3-Methylthiophene: A Sustainable Solvent for High-Performance Organic Solar Cells.

The use of harmful halogenated or aromatic solvents such as chloroform (CF), chlorobenzene (CB), and o-xylene (o-XY) is one of the greatest barriers to the industrial-scale manufacturing of high-performance organic solar cells (OSCs). Therefore, it is necessary to eliminate the effects of these solvents to ensure practical feasibility of OSCs. We found that the anthracene-terminated polymer donor and small-molecule acceptor BO-4Cl had good solubility in 3-methylthiophene (3-MeT). There were no toxicity labels in the SDS and exposure control limits for 3-MeT. An overall power conversion efficiency of 16.87% was achieved by using 3-MeT as the solvent for solar cell fabrication, which was higher than that of the cells made from CF (16.18%) and o-XY (15.69%). The best OSC based on PM6:D18:L8-BO and fabricated with 3-MeT exhibited a high PCE of 18.13%, which is one of the highest values for cells fabricated from halogen-free solvents. These results indicate that 3-MeT is an eco-friendly and low-toxicity solvent for the sustainable fabrication of the OSC active layer.

ESFPNet: Efficient Stage-Wise Feature Pyramid on Mix Transformer for Deep Learning-Based Cancer Analysis in Endoscopic Video.

For patients at risk of developing either lung cancer or colorectal cancer, the identification of suspect lesions in endoscopic video is an important procedure. The physician performs an endoscopic exam by navigating an endoscope through the organ of interest, be it the lungs or intestinal tract, and performs a visual inspection of the endoscopic video stream to identify lesions. Unfortunately, this entails a tedious, error-prone search over a lengthy video sequence. We propose a deep learning architecture that enables the real-time detection and segmentation of lesion regions from endoscopic video, with our experiments focused on autofluorescence bronchoscopy (AFB) for the lungs and colonoscopy for the intestinal tract. Our architecture, dubbed ESFPNet, draws on a pretrained Mix Transformer (MiT) encoder and a decoder structure that incorporates a new Efficient Stage-Wise Feature Pyramid (ESFP) to promote accurate lesion segmentation. In comparison to existing deep learning models, the ESFPNet model gave superior lesion segmentation performance for an AFB dataset. It also produced superior segmentation results for three widely used public colonoscopy databases and nearly the best results for two other public colonoscopy databases. In addition, the lightweight ESFPNet architecture requires fewer model parameters and less computation than other competing models, enabling the real-time analysis of input video frames. Overall, these studies point to the combined superior analysis performance and architectural efficiency of the ESFPNet for endoscopic video analysis. Lastly, additional experiments with the public colonoscopy databases demonstrate the learning ability and generalizability of ESFPNet, implying that the model could be effective for region segmentation in other domains.

Exploration of novel human neutrophil elastase inhibitors from natural compounds: Virtual screening, in vitro, molecular dynamics simulation and in vivo study.

BACKGROUND: Human neutrophil elastase (HNE) is an important contributor to lung diseases such as acute lung injury (ALI) or acute respiratory distress syndrome. Therefore, this study aimed to identify natural HNE inhibitors with anti-inflammatory activity through machine learning algorithms, in vitro assays, molecular dynamic simulation, and an in vivo ALI assay. METHODS: Based on the optimized Discovery Studio two-dimensional molecular descriptors, combined with different molecular fingerprints, six machine learning models were established using the Naïve Bayesian (NB) method to identify HNE inhibitors. Subsequently, the optimal model was utilized to screen 6925 drug-like compounds obtained from the Traditional Chinese Medicine Systems Pharmacy Database and Analysis Platform (TCMSP), followed by ADMET analysis. Finally, 10 compounds with reported anti-inflammatory activity were selected to determine their inhibitory activities against HNE in vitro, and the compounds with the best activity were selected for a 100 ns molecular dynamics simulation and its anti-inflammatory effect was evaluated using Poly (I:C)-induced ALI model. RESULTS: The evaluation of the in vitro HNE inhibition efficiency of the 10 selected compounds showed that the flavonoid tricetin had the strongest inhibitory effect on HNE. The molecular dynamics simulation indicated that the binding of tricetin to HNE was relatively stable throughout the simulation. Importantly, in vivo experiments indicated that tricetin treatment substantially improved the Poly (I:C)-induced ALI. CONCLUSION: The proposed NB model was proved valuable for exploring novel HNE inhibitors, and natural tricetin was screened out as a novel HNE inhibitor, which was confirmed by in vitro and in vivo assays for its inhibitory activities.

Attitude and willingness of biodiversity conservation in Chinese university students: Associated factors and the mediation of social support.

In this cross-sectional study of 1475 Chinese university students, we explored associated factors of attitude and willingness of biodiversity conservation, analyzed the hypothesized mediation by social support in the association between attitude and willingness of biodiversity conservation. Multivariate logistic regression model revealed that major and social support were prominently related to both attitude and willingness of biodiversity conservation. Besides, path model identified a statistically significant mediation by social support, sex, race, and family residence presented noticeable effect modification on the mediation of social support. These major findings suggest that intervention measures which aiming at enhancing social support could be considered for elevating attitude and willingness of biodiversity conservation among Chinese university students.

Metabolomics reveals dysregulated all-trans retinoic acid and polyunsaturated fatty acid metabolism contribute to PXR-induced hepatic steatosis in mice.

Activation of pregnane X receptor (PXR) by xenobiotics has been associated with metabolic diseases. This study aimed to reveal the impact of PXR activation on hepatic metabolome and explore novel mechanisms underlying PXR-mediated lipid metabolism disorder in the liver. Wild-type and PXR-deficient male C57BL/6 mice were used as in vivo models, and hepatic steatosis was induced by pregnenolone-16α-carbonitrile, a typical rodent PXR agonist. Metabolomic analysis of liver tissues showed that PXR activation led to significant changes in metabolites involved in multiple metabolic pathways previously reported, including lipid metabolism, energy homeostasis, and amino acid metabolism. Moreover, the level of hepatic all-trans retinoic acid (ATRA), the main active metabolite of vitamin A, was significantly increased by PXR activation, and genes involved in ATRA metabolism exhibited differential expression following PXR activation or deficiency. Consistent with previous research, the expression of downstream target genes of peroxisome proliferator-activated receptor α (PPARα) was decreased. Analysis of fatty acids by Gas Chromatography-Mass Spectrometer further revealed changes in polyunsaturated fatty acid metabolism upon PXR activation, suggesting inhibition of PPARα activity. Taken together, our findings reveal a novel metabolomic signature of hepatic steatosis induced by PXR activation in mice.

Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder.

Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.

Degradation of perineuronal nets in the medial prefrontal cortex promotes extinction and reduces reinstatement of methamphetamine-induced conditioned place preference in female mice.

The high rate of relapse to compulsive methamphetamine (MA)-taking and seeking behaviors after abstinence constitutes a major obstacle to the treatment of MA addiction. Perineuronal nets (PNNs), essential components of the extracellular matrix, play a critical role in synaptic function, learning, and memory. Abnormalities in PNNs have been closely linked to a series of neurological diseases, such as addiction. However, the exact role of PNNs in MA-induced related behaviors remains elusive. Here, we established a MA-induced conditioned place preference (CPP) paradigm in female mice and found that the number and average optical density of PNNs increased significantly in the medial prefrontal cortex (mPFC) of mice during the acquisition, extinction, and reinstatement stages of CPP. Notably, the removal of PNNs in the mPFC via chondroitinase ABC (ChABC) before extinction training not only facilitated the extinction of MA-induced CPP and attenuated the relapse of extinguished MA preference but also significantly reduced the activation of c-Fos in the mPFC. Similarly, the ablation of PNNs in the mPFC before reinstatement markedly lessened the reinstatement of MA-induced CPP, which was accompanied by the decreased expression of c-Fos in the mPFC. Collectively, our results provide more evidence for the implication of degradation of PNNs in facilitating extinction and preventing relapse of MA-induced CPP, which indicate that targeting PNNs may be an effective therapeutic option for MA-induced CPP memories.

Cajaninstilbene acid ameliorates depression-like behaviors in mice by suppressing TLR4/NF-κB mediated neuroinflammation and promoting autophagy.

Depression is a life-threatening neurodegenerative disease lacking a complete cure. Cajaninstilbene acid (CSA), a potent stilbene compound, has demonstrated neuroprotective effects, however, studies on its antidepressant mechanisms are still scarce. This study examined the effects of CSA on lipopolysaccharide (LPS)-induced and chronic unpredictable mild stress (CUMS)-induced depression in mice, investigating its mechanisms related to inflammation and autophagy. Mice were treated with CSA (7.5, 15, and 30 mg/kg) daily for 3 weeks before intraperitoneal LPS injection (0.8 mg/kg). Another cohort underwent the same doses of CSA (7.5-30 mg/kg) daily for 6 weeks in accompany with CUMS stimulation. Behavioral assessments were conducted, and cortical samples were collected for molecular analysis. Findings indicate that CSA ameliorated depressive behaviors induced by both LPS and CUMS. Notably, CSA (15 mg/kg) reversed despair behavior in mice more persistently than amitriptyline, indicating that optimal doses of CSA may effectively decelerate the procession of mood despair and yield a good compliance. CSA countered CUMS-induced activation of TLR4/NF-κB pathway and the reduction in autophagy levels. Furthermore, CSA attenuated the CUMS-induced decline in neuroplasticity. Collectively, these findings suggest that CSA mitigates depression-like behaviors in mice by inhibiting TLR4/NF-κB-mediated neuroinflammation and enhancing autophagy. This research provides further insights into CSA's mechanisms of action in ameliorating depressive behaviors, offering a scientific foundation for developing CSA-based antidepressants.

Microglial activation in the medial prefrontal cortex after remote fear recall participates in the regulation of auditory fear extinction.

Excessive or inappropriate fear responses can lead to anxiety-related disorders, such as post-traumatic stress disorder (PTSD). Studies have shown that microglial activation occurs after fear conditioning and that microglial inhibition impacts fear memory. However, the role of microglia in fear memory recall remains unclear. In this study, we investigated the activated profiles of microglia after the recall of remote-cued fear memory and the role of activated microglia in the extinction of remote-cued fear in adult male C57BL/6 mice. The results revealed that the expression of the microglia marker Iba1 increased in the medial prefrontal cortex (mPFC) at 10 min and 1 h following remote-cued fear recall, which was accompanied by amoeboid morphology. Inhibiting microglial activation through PLX3397 treatment before remote fear recall did not affect recall, reconsolidation, or regular extinction but facilitated recall-extinction and mitigated spontaneous recovery. Moreover, our results demonstrated reduced co-expression of Iba1 and postsynaptic density protein 95 (PSD95) in the mPFC, along with decreases in the p-PI3K/PI3K ratio, p-Akt/Akt ratio, and KLF4 expression after PLX3397 treatment. Our results suggest that microglial activation after remote fear recall impedes fear extinction through the pruning of synapses in the mPFC, accompanied by alterations in the expression of the PI3K/AKT/KLF4 pathway. This finding can help elucidate the mechanism involved in remote fear extinction, contributing to the theoretical foundation for the intervention and treatment of PTSD.

Synthesis and Evaluation of a Novel c-Met-Targeting Cyclic Peptide as a Potential Diagnostic Agent for Colorectal Cancer.

The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase linked to the proliferation, survival, invasion, and metastasis of several types of cancers, including colorectal cancer (CRC), particularly when aberrantly activated. Our study strategically designs peptides derived from interactions between c-Met and the antibody Onartuzumab. By utilizing a cyclic strategy, we achieved significantly enhanced peptide stability and affinity. Our in vitro assessments confirmed that the cyclic peptide HYNIC-cycOn exhibited a higher affinity (KD = 83.5 nM) and greater specificity compared with its linear counterpart. Through in vivo experiments, [99mTc]Tc-HYNIC-cycOn displayed exceptional tumor-targeting capabilities and minimal absorption in nontumor cells, as confirmed by single-photon emission computed tomography. Notably, the ratios of tumor to muscle and tumor to intestine, 1 h postinjection, were 4.78 ± 0.86 and 3.24 ± 0.47, respectively. Comparable ratios were observed in orthotopic CRC models, recording 4.94 ± 0.32 and 3.88 ± 0.41, respectively. In summary, [99mTc]Tc-HYNIC-cycOn shows substantial promise as a candidate for clinical applications. We show that [99mTc]Tc-HYNIC-cycOn can effectively target and visualize c-Met-expressing tumors in vivo, providing a promising approach for enhancing diagnostic accuracy when detecting c-Met in CRC.

In Situ Generation and High Bioresistance of Trityl-based Semiquinone Methide Radicals Under Anaerobic Conditions in Cellular Systems.

Bioreduction of spin labels and polarizing agents (generally stable radicals) has been an obstacle limiting the in-cell applications of pulsed electron paramagnetic resonance (EPR) spectroscopy and dynamic nuclear polarization (DNP). In this work, we have demonstrated that two semiquinone methide radicals (OXQM⋅ and CTQM⋅) can be easily produced from the trityl-based quinone methides (OXQM and CTQM) via reduction by various reducing agents including biothiols and ascorbate under anaerobic conditions. Both radicals have relatively low pKa's and exhibit EPR single line signals at physiological pH. Moreover, the bioreduction of OXQM in three cell lysates enables quantitative generation of OXQM⋅ which was most likely mediated by flavoenzymes. Importantly, the resulting OXQM⋅ exhibited extremely high stability in the E.coli lysate under anaerobic conditions with 76- and 14.3-fold slower decay kinetics as compared to the trityl OX063 and a gem-diethyl pyrrolidine nitroxide, respectively. Intracellular delivery of OXQM into HeLa cells was also achieved by covalent conjugation with a cell-permeable peptide as evidenced by the stable intracellular EPR signal from the OXQM⋅ moiety. Owing to extremely high resistance of OXQM⋅ towards bioreduction, OXQM and its derivatives show great application potential in in-cell EPR and in-cell DNP studies for various cells which can endure short-term anoxic treatments.

Comprehensive Urinary Proteome Profiling Analysis Identifies Diagnosis and Relapse Surveillance Biomarkers for Bladder Cancer.

Bladder cancer (BCa) is the predominant malignancy of the urinary system. Herein, a comprehensive urine proteomic feature was initially established for the noninvasive diagnosis and recurrence monitoring of bladder cancer. 279 cases (63 primary BCa, 87 nontumor controls (NT), 73 relapsed BCa (BCR), and 56 nonrelapsed BCa (BCNR)) were collected to screen urinary protein biomarkers. 4761 and 3668 proteins were qualified and quantified by DDA and sequential window acquisition of all theoretical mass spectra (SWATH-MS) analysis in two discovery sets, respectively. Upregulated proteins were validated by multiple reaction monitoring (MRM) in two independent combined sets. Using the multi-support vector machine-recursive feature elimination (mSVM-RFE) algorithm, a model comprising 13 proteins exhibited good performance between BCa and NT with an AUC of 0.821 (95% CI: 0.675-0.967), 90.9% sensitivity (95% CI: 72.7-100%), and 73.3% specificity (95% CI: 53.3-93.3%) in the diagnosis test set. Meanwhile, an 11-marker classifier significantly distinguished BCR from BCNR with 75.0% sensitivity (95% CI: 50.0-100%), 81.8% specificity (95% CI: 54.5-100%), and an AUC of 0.784 (95% CI: 0.609-0.959) in the test cohort for relapse surveillance. Notably, six proteins (SPR, AK1, CD2AP, ADGRF1, GMPS, and C8A) of 24 markers were newly reported. This paper reveals novel urinary protein biomarkers for BCa and offers new theoretical insights into the pathogenesis of bladder cancer (data identifier PXD044896).

Gut microbial alterations in arginine metabolism determine bone mechanical adaptation.

Although mechanical loading is essential for maintaining bone health and combating osteoporosis, its practical application is limited to a large extent by the high variability in bone mechanoresponsiveness. Here, we found that gut microbial depletion promoted a significant reduction in skeletal adaptation to mechanical loading. Among experimental mice, we observed differences between those with high and low responses to exercise with respect to the gut microbial composition, in which the differential abundance of Lachnospiraceae contributed to the differences in bone mechanoresponsiveness. Microbial production of L-citrulline and its conversion into L-arginine were identified as key regulators of bone mechanoadaptation, and administration of these metabolites enhanced bone mechanoresponsiveness in normal, aged, and ovariectomized mice. Mechanistically, L-arginine-mediated enhancement of bone mechanoadaptation was primarily attributable to the activation of a nitric-oxide-calcium positive feedback loop in osteocytes. This study identifies a promising anti-osteoporotic strategy for maximizing mechanical loading-induced skeletal benefits via the microbiota-metabolite axis.

Prognostic Impact of Left Atrial Appendage Patency After Device Closure.

BACKGROUND: The prognostic impact of left atrial appendage (LAA) patency, including those with and without visible peri-device leak (PDL), post-LAA closure in patients with atrial fibrillation, remains elusive. METHODS: Patients with atrial fibrillation implanted with the WATCHMAN 2.5 device were prospectively enrolled. The device surveillance by cardiac computed tomography angiography was performed at 3 months post-procedure. Adverse events, including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular death, all-cause death, and the combined major adverse events (MAEs), were compared between patients with complete closure and LAA patency. RESULTS: Among 519 patients with cardiac computed tomography angiography surveillance at 3 months post-LAA closure, 271 (52.2%) showed complete closure, and LAA patency was detected in 248 (47.8%) patients, including 196 (37.8%) with visible PDL and 52 (10.0%) without visible PDL. During a median of 1193 (787-1543) days follow-up, the presence of LAA patency was associated with increased risks of stroke/TIA (adjusted hazard ratio for baseline differences, 3.22 [95% CI, 1.17-8.83]; P=0.023) and MAEs (adjusted hazard ratio, 1.12 [95% CI, 1.06-1.17]; P=0.003). Specifically, LAA patency with visible PDL was associated with increased risks of stroke/TIA (hazard ratio, 3.66 [95% CI, 1.29-10.42]; P=0.015) and MAEs (hazard ratio, 3.71 [95% CI, 1.71-8.07]; P=0.001), although LAA patency without visible PDL showed higher risks of MAEs (hazard ratio, 3.59 [95% CI, 1.28-10.09]; P=0.015). Incidences of stroke/TIA (2.8% versus 3.0% versus 6.7% versus 22.2%; P=0.010), cardiovascular death (0.9% versus 0% versus 1.7% versus 11.1%; P=0.005), and MAEs (4.6% versus 9.0% versus 11.7% versus 22.2%; P=0.017) increased with larger PDL (0, >0 to ≤3, >3 to ≤5, or >5 mm). Older age and discontinuing antiplatelet therapy at 6 months were independent predictors of stroke/TIA and MAEs in patients with LAA patency. CONCLUSIONS: LAA patency detected by cardiac computed tomography angiography at 3 months post-LAA closure is associated with unfavorable prognosis in patients with atrial fibrillation implanted with WATCHMAN 2.5 device. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03788941.