Stability and chemical bonding in a series of inverse sandwich actinide boride clusters (An2B8) with δ bonding.

An inverse sandwich structure has been computationally predicted for uranium boride and extended to the series of actinide elements (An) from Th to Cm. The electronic structure and chemical bonding of these novel compounds have been analyzed using density functional theory and multireference wave-function based methods. We report the trends in electronic structure and bonding for An2B8, and found that (d-π)π and (d-p)δ are the most important factors in the stability of An2B8. The (f-p)δ bond provides extra stabilization for Pa2B8 and U2B8, owing to the extensive interactions of An-B8-An, resulting in a short distance for the Pa-Pa and U-U bonds.

68Ga-DOTATATE and 68Ga-Pentixafor PET/CT in a Patient with Castleman Disease of the Retroperitoneum.

This is a case of a 42-year-old man with recurrent symptoms of dizziness and a newly found retroperitoneal mass with no 131I-MIBG uptake who was referred for restaging with 68Ga-DOTATATE PET/CT and local 68Ga-pentixafor PET/CT. The examinations both showed intense radioactivity uptake in the retroperitoneal mass and no abnormal uptake in the right adrenal nodule. Two lesions showed distinct properties of radioactivity uptake, which suggested the possibility of different sources. A postoperative pathological test revealed that the morphology and immunohistochemistry of the retroperitoneal mass was found to be consistent with Castleman disease, and the right adrenal gland was normal tissue.

Quasi-static testing of UHPC cupped socket piers-footing connection and its seismic fragility analysis under near-fault ground motions.

Assembly construction is extensively employed in bridge construction due to its ability to accelerate construction and improve quality. To speed the recovery of bridges after major earthquakes, this study proposes an assembled connection for precast piers and footings based on assembly construction. The precast piers are connected to the footings using ultra-high-performance concrete (UHPC) post-cast cupped sockets. Two specimens are tested with a 1:4 scale, namely, the cast-in-place (CIP) specimen and, the UHPC cupped socket pier specimen. Finite element models (FEM) of a continuous girder bridge with cupped socket connections are developed and verified by experimental results. The seismic fragility analysis is conducted to investigate the difference between the cupped socket connection and the CIP connection. The experimental results showed that the plastic hinge was formed on the precast piers and there was little damage to the UHPC sockets. The results of FEA indicate that UHPC cupped socket piers have slightly higher seismic fragility than the seismic fragility of cast-in-place piers. Then, some methods were proposed to reduce the seismic fragility of UHPC cupped socket piers, and their availability was confirmed by comparing them with the seismic fragility of CIP piers. Finally, an example bridge with this connection is introduced to illustrate replacing prefabricated piers after an earthquake.

Clinical value of 68Ga-pentixafor PET/CT in patients with primary aldosteronism and bilateral lesions: preliminary results of a single-centre study.

BACKGROUND: Subtype diagnosis of primary aldosteronism (PA) is used to determine treatment, and the potential utility of 68Ga-pentixafor PET/CT for investigation of PA has long been recognized. The study aimed to evaluate the clinical value of 68Ga-pentixafor PET/CT in the diagnosis and prognosis of patients with bilateral lesions identified by CT. METHODS: In total, 25 patients with PA and bilateral lesions on CT were retrospectively evaluated. All patients underwent 68Ga-Pentixafor PET/CT and adrenal vein sampling. The analysis focused on establishing the relationship between bilateral adrenal lesions SUVmax and the ratio of bilateral adrenal lesions SUVmax (CON) and clinical diagnosis, treatment outcomes, and KCNJ5 gene status. RESULTS: The concordance rate between 68Ga-Pentixafor PET/CT and adrenal venous sampling was 65.2% (15/23). The lateralization results of 68Ga-pentixafor PET/CT supported the clinical decisions of 20 patients with PA, 90% of whom showed effectiveness in treatment. The SUVmax on the dominant side of the surgically treated patients was higher than that of patients treated with drugs. The SUVmax of the KCNJ5 mutant group was higher than that of the KCNJ5 wild group, and 68Ga-Pentixafor uptake was correlated with KCNJ5 gene status. CONCLUSIONS: 68Ga-Pentixafor PET/CT proves beneficial for patients with PA with bilateral lesions on CT. The treatment is generally effective based on the results of PET lateralization. Simultaneously, a certain relationship exists between 68Ga-Pentixafor PET/CT and KCNJ5 gene status, warranting further analysis.

Deep Learning Features and Metabolic Tumor Volume Based on PET/CT to Construct Risk Stratification in Non-small Cell Lung Cancer.

RATIONALE AND OBJECTIVES: To build a risk stratification by incorporating PET/CT-based deep learning features and whole-body metabolic tumor volume (MTVwb), which was to make predictions about overall survival (OS) and progression-free survival (PFS) for those with non-small cell lung cancer (NSCLC) as a complement to the TNM staging. MATERIALS AND METHODS: The study enrolled 590 patients with NSCLC (413 for training and 177 for testing). Features were extracted by employing a convolutional neural network. The combined risk stratification (CRS) was constructed by the selected features and MTVwb, which were contrasted and integrated with TNM staging. In the testing set, those were verified. RESULTS: Multivariate analysis revealed that CRS was an independent predictor of OS and PFS. C-indexes of the CRS demonstrated statistically significant increases in comparison to TNM staging, excepting predicting OS in the testing set (for OS, C-index=0.71 vs. 0.691 in the training set and 0.73 vs. 0.736 in the testing set; for PFS, C-index=0.702 vs. 0.686 in the training set and 0.732 vs. 0.71 in the testing set). The nomogram that combined CRS with TNM staging demonstrated the most superior model performance in the training and testing sets (C-index=0.741 and 0.771). CONCLUSION: The addition of CRS improves TNM staging's predictive power and shows potential as a useful tool to support physicians in making treatment decisions.

Pre-PCI CT-FFR Predicts Target Vessel Failure After Stent Implantation.

OBJECTIVES: To investigate the predictive value of coronary computed tomography angiography-derived fractional flow reserve (CT-FFR) before percutaneous coronary intervention (PCI) to predict target vessel failure (TVF) after stent implantation. METHODS: This retrospective study included 429 patients (429 vessels) who underwent PCI and stent implantation after CCTA within 3 months. All patients underwent coronary stent implantation between January 2012 and December 2019. A dedicated workstation (Syngo Via, Siemens) was used to analyze and measure the CT-FFR value. The cut-off values of pre-PCI CT-FFR for predicting TVF were defined as 0.80 and the value using the log-rank maximization method, respectively. The primary outcome was TVF, defined as a composite of cardiac death, target vessel myocardial infarction, and clinically driven target vessel revascularization (TVR), which was a secondary outcome. RESULTS: During a median 64.0 months follow-up, the cumulative incidence of TVF was 7.9% (34/429). The cutoff value of pre-PCI CT-FFR based on the log-rank maximization method was 0.74, which was the independent predictor for TVF [hazard ratio (HR): 2.61 (95% CI: 1.13, 6.02); P =0.024] and TVR [HR: 3.63 (95%CI: 1.25, 10.51); P =0.018]. Compared with the clinical risk factor model, pre-PCI CT-FFR significantly improved the reclassification ability for TVF [net reclassification improvement (NRI), 0.424, P <0.001; integrative discrimination index (IDI), 0.011, P =0.022]. Adding stent information to the prediction model resulted in an improvement in reclassification for the TVF (C statistics: 0.711, P =0.001; NRI: 0.494, P <0.001; IDI: 0.020, P =0.028). CONCLUSIONS: Pre-PCI CT-FFR ≤0.74 was an independent predictor for TVF or TVR, and integration of clinical, pre-PCI CT-FFR, and stent information models can provide a better risk stratification model in patients with stent implantation.

Determination of the binding affinities of OPEs to integrin αvß3 and elucidation of the underlying mechanisms via a competitive binding assay, pharmacophore modeling, molecular docking and QSAR modeling.

Organophosphate esters (OPEs) can cause adverse biological effects through binding to integrin αvß3. However, few studies have focused on the binding activity and mechanism of OPEs to integrin αvß3. Herein, a comprehensive investigation of the mechanisms by which OPEs bind to integrin αvß3 and determination of the binding affinity were conducted by in vitro and in silico approaches: competitive binding assay as well as pharmacophore, molecular docking and QSAR modeling. The results showed that all 18 OPEs exhibited binding activities to integrin αvß3; moreover, hydrogen bonds were identified as crucial intermolecular interactions. In addition, essential factors, including the -P = O structure of OPEs, key amino acid residues and suitable cavity volume of integrin αvß3, were identified to contribute to the formation of hydrogen bonds. Moreover, aryl-OPEs exhibited a lower binding activity with integrin αvß3 than halogenated- and alkyl-OPEs. Ultimately, the QSAR model constructed in this study was effectively used to predict the binding affinity of OPEs to integrin αvß3, and the results suggest that some OPEs might pose potential risks in aquatic environments. The results of this study comprehensively elucidated the binding mechanism of OPEs to integrin αvß3, and supported the environmental risk management of these emerging pollutants.

Spatial distribution characteristics and degradation mechanism of microorganisms in n-hexadecane contaminated vadose zone.

The damage caused by petroleum hydrocarbon pollution to soil and groundwater environment is becoming increasingly significant. The vadose zone is the only way for petroleum hydrocarbon pollutants to leak from surface into groundwater. The spatial distribution characteristics of indigenous microorganisms in vadose zone, considering presence of capillary zones, have rarely been reported. To explore the spatial distribution characteristics of indigenous microorganisms in vadose zone contaminated by petroleum hydrocarbons, a one-dimensional column migration experiment was conducted using n-hexadecane as characteristic pollutant. Soil samples were collected periodically from different heights during experiment. Corresponding environmental factors were monitored online. The microbial community structure and spatial distribution characteristics of the cumulative relative abundance were systematically analyzed using 16S rRNA sequencing. In addition, the microbial degradation mechanism of n-hexadecane was analyzed using metabolomics. The results showed that presence of capillary zone had a strong retarding effect on n-hexadecane infiltration. Leaked pollutants were mainly concentrated in areas with strong capillary action. Infiltration and displacement of NAPL-phase pollutants were major driving force for change in moisture content (θ) and electric conductivity (EC) in vadose zone. The degradation by microorganisms results in a downward trend in potential of hydrogen (pH) and oxidation-reduction potential (ORP). Five petroleum hydrocarbon-degrading bacterial phyla and 11 degradable straight-chain alkane bacterial genera were detected. Microbial degradation was strong in the area near edge of capillary zone and locations of pollutant accumulation. Mainly Sphingomonas and Nocardioides bacteria were involved in microbial degradation of n-hexadecane. Single-end oxidation involved microbial degradation of n-hexadecane (C16H34). The oxygen consumed, hexadecanoic acid (C16H32O2) produced during this process, and release of hydrogen ions (H+) were the driving factors for reduction of ORP and pH. The vadose zone in this study considered presence of capillary zone, which was more in line with actual contaminated site conditions compared with previous studies. This study systematically elucidated vertical distribution characteristics of petroleum hydrocarbon pollutants and spatiotemporal variation characteristics of indigenous microorganisms in vadose zone considered presence of capillary zone. In addition, the n-hexadecane degradation mechanism was elucidated using metabolomics. This study provides theoretical support for development of natural attenuation remediation measures for petroleum-hydrocarbon-contaminated soil and groundwater.

Coronary Microvascular Dysfunction is Associated with Augmented Lysosomal Signaling in Hypercholesterolemic Mice.

Accumulating evidence indicates that coronary microvascular dysfunction (CMD) caused by hypercholesterolemia can lead to myocardial ischemia, with or without obstructive atherosclerotic coronary artery disease (CAD). However, the molecular pathways associated with compromised coronary microvascular function prior to the development of myocardial ischemic injury remain poorly defined. In this study, we investigated the effects of hypercholesterolemia on the function and integrity of the coronary microcirculation in mice and the underlying mechanisms. Mice were fed with a hypercholesterolemic Paigen's diet (PD) for 8 weeks. Echocardiography data showed that PD caused CMD, characterized by significant reductions in coronary blood flow and coronary flow reserve (CFR), but did not affect cardiac remodeling or dysfunction. Immunofluorescence studies revealed that PD-induced CMD was associated with activation of coronary arterioles inflammation and increased myocardial inflammatory cell infiltration. These pathological changes occurred in parallel with the upregulation of lysosomal signaling pathways in endothelial cells (ECs). Treating hypercholesterolemic mice with the cholesterol-lowering drug ezetimibe significantly ameliorated PD-induced adverse effects, including hypercholesterolemia, steatohepatitis, reduced CFR, coronary EC inflammation, and myocardial inflammatory cell infiltration. In cultured mouse cardiac endothelial cells (MCECs), 7-ketocholesterol (7K) increased mitochondrial reactive oxygen species (ROS) and inflammatory responses. Meanwhile, 7K induced the activation of TFEB and lysosomal signaling in MCECs, whereas the lysosome inhibitor bafilomycin A1 blocked 7K-induced TFEB activation and exacerbated 7K-induced inflammation and cell death. Interestingly, ezetimibe synergistically enhanced 7K-induced TFEB activation and attenuated 7K-induced mitochondrial ROS and inflammatory responses in MCECs. These results suggest that CMD can develop and precede detectable cardiac functional or structural changes in the setting of hypercholesterolemia, and that upregulation of TFEB-mediated lysosomal signaling in ECs plays a protective role against CMD.

A rapid and accurate method for evaluating the degradation of pan-Akt in cells by PROTACs using NanoLuc luciferase.

Proteolysis targeting chimera (PROTAC) is a protein degradation technique that has been increasingly used in the development of new drugs in recent years. Akt is a classical serine/threonine kinase, and its role outside of the kinase has gradually gained attention in recent years, making it one of the proteins targeted by PROTACs. Currently, there are many methods used for the evaluation of intracellular protein degradation, but each has its own advantages or disadvantages. This study aimed to investigate the feasibility of evaluating the degradation of pan-Akt proteins in cells by PROTACs (MS21 and MS170) using the NanoLuc luciferase method. After conducting a thorough comparison between this method and the classical western blot assay in various cells, as well as testing the stability of the experiments between multiple batches, we found that NanoLuc luciferase is a highly accurate, stable, low-cost and easy-to-operate method for the evaluation of intracellular pan-Akt degradation by PROTACs with a short cycle time and high cellular expandability. Given the numerous advantages of this method, it is hypothesized that it could be extended to evaluate the degradation of more target proteins of PROTACs. In summary, the NanoLuc luciferase is a suitable method for early protein degradation screening of PROTAC compounds.

Real-world effectiveness of GLP-1 receptor agonist-based treatment strategies on "time in range" in patients with type 2 diabetes.

Background: Diabetes affects millions of people worldwide annually, and several methods, including medications, are used for its management; glucagon-like peptide-1 receptor agonists (GLP-1RAs) are one such class of medications. The efficacy and safety of GLP-1RAs in treating type 2 diabetes mellitus (T2DM) have been assessed and have been shown to significantly improve time in range (TIR) in several clinical trials. However, presently, there is a lack of real-world evidence on the efficacy of GLP-1RAs in improving TIR. To address this, we investigated the effect of GLP-1RA-based treatment strategies on TIR among patients with T2DM in real-world clinical practice. Methods: This multicenter, retrospective, real-world study included patients with T2DM who had previously used a continuous glucose monitoring (CGM) system and received treatment with GLP-1RAs or oral antidiabetic drugs (OADs). Patients who received OADs served as controls and were matched in a 1:1 ratio to their GLP-1RA counterparts by propensity score matching. The primary endpoint was the TIR after 3-6 months of treatment. Results: According to propensity score matching, 202 patients were equally divided between the GLP-1RA and OAD groups. After 3-6 months of treatment, the TIR values for the GLP-1RA and OAD groups were 76.0% and 65.7%, respectively (p < 0.001). The GLP-1RA group displayed significantly lower time above range (TAR) and mean glucose values than the OAD group (p < 0.001). Subgroup analysis revealed that, compared with the administration of liraglutide, the administration of semaglutide and polyethylene glycol loxenatide (PEG-Loxe) significantly improved TIR over 3-6 months of treatment (p < 0.05). Conclusion: These real-world findings indicate that GLP-1RA-based treatment strategies could be superior to oral treatment strategies for improving TIR among patients with T2DM and that once-weekly GLP-1RA may be more effective than a once-daily GLP-1RA. Clinical trial registration: http://www.chinadrugtrials.org.cn/index.html, identifier number ChiCTR2300073697.

The value of gallium-68 prostate-specific membrane antigen PET/CT and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT in the detection of thyroid cancer lesions: a prospective head-to-head comparison.

OBJECTIVE: Thyroid cancer is increasing in incidence. Prostate-specific membrane antigen (PSMA) targeted radionuclide imaging and treatment demonstrated remarkable value in prostate cancer patients. Studies have shown that PSMA is also expressed in thyroid cancer. Our purpose is to evaluate the clinical usefulness of [68Ga]Ga-PSMA-11 PET/CT for the diagnosis of thyroid cancer. METHODS: We enrolled 23 DTC and 17 RAIR-DTC patients prospectively. All patients underwent [68Ga]Ga-PSMA-11 PET/CT and 2-[18F]FDG PET/CT. PSMA expression was determined by immunohistochemistry on histological samples of lymphatic metastasis of 12 patients. We compared the detection rates and semi-quantitative parameters between [68Ga]Ga-PSMA-11PET/CT and 2-[18F]FDG PET/CT. RESULTS: A total of 72 lesions were detected. Detection rates of DTC and RAIR-DTC by [68Ga]Ga-PSMA-11 PET/CT were lower than those by 2-[18F]FDG PET/CT (60.00% vs. 90.00%, P = .004; 59.38% vs. 96.88%). Compared with DTC, RAIR-DTC had higher semi-quantitative parameters of 2-[18F]FDG PET/CT. There was no significant difference in semi-quantitative parameters of [68Ga]Ga-PSMA-11 PET/CT between DTC and RAIR-DTC. Immunohistochemistry showed a significantly higher PSMA expression for RAIR-DTC than for DTC. However, there was no significant correlation between PSMA expression and SUVmax on 68Ga-PSMA [68Ga]Ga-PSMA-11 PET/CT. CONCLUSIONS: [68Ga]Ga-PSMA-11 PET/CT can detect thyroid cancer metastases but its detection rate was lower than that of 2-[18F]FDG PET/CT. There was a difference in PSMA expression levels between DTC and RAIR-DTC, but the difference was not reflected on [68Ga]Ga-PSMA-11 PET/CT. ADVANCES IN KNOWLEDGE: [68Ga]Ga-PSMA-11 PET/CT has potential value in the diagnosis of thyroid cancer. [68Ga]Ga-PSMA-11 PET/CT could screen out patients who may benefit from PSMA-targeted radionuclide therapy.