Nucleic-acid-base photofunctional cocrystal for information security and antimicrobial applications.

Cocrystal engineering is an efficient and simple strategy to construct functional materials, especially for the exploitation of novel and multifunctional materials. Herein, we report two kinds of nucleic-acid-base cocrystal systems that imitate the strong hydrogen bond interactions constructed in the form of complementary base pairing. The two cocrystals studied exhibit different colors of phosphorescence from their monomeric counterparts and show the feature of rare high-temperature phosphorescence. Mechanistic studies reveal that the strong hydrogen bond network stabilizes the triplet state and suppresses non-radiative transitions, resulting in phosphorescence even at 425 K. Moreover, the isolation effects of the hydrogen bond network regulate the interactions between the phosphor groups, realizing the manipulation from aggregation to single-molecule phosphorescence. Benefiting from the long-lived triplet state with a high quantum yield, the generation of reactive oxygen species by energy transfer is also available to utilize for some applications such as in photodynamic therapy and broad-spectrum microbicidal effects. In vitro experiments show that the cocrystals efficiently kill bacteria on a tooth surface and significantly help prevent dental caries. This work not only provides deep insight into the relationship of the structure-properties of cocrystal systems, but also facilitates the design of multifunctional cocrystal materials and enriches their potential applications.

MircoRNA-25-3p in skin precursor cell-induced Schwann cell-derived extracellular vesicles promotes axon regeneration by targeting Tgif1.

Nerve injury often leads to severe dysfunction because of the lack of axon regeneration in adult mammal. Intriguingly a series of extracellular vesicles (EVs) have the obvious ability to accelerate the nerve repair. However, the detailed molecular mechanisms to describe that EVs switch neuron from a transmitter to a regenerative state have not been elucidated. This study elucidated the microRNA (miRNA) expression profiles of two types of EVs that promote nerve regeneration. The functions of these miRNAs were screened in vitro. Among the 12 overlapping miRNAs, miR-25-3p was selected for further analysis as it markedly promoted axon regeneration both in vivo and in vitro. Furthermore, knockdown experiments confirmed that PTEN and Klf4, which are the major inhibitors of axon regeneration, were the direct targets of miR-25-3p in dorsal root ganglion (DRG) neurons. The utilization of luciferase reporter assays and functional tests provided evidence that miR-25-3p enhances axon regeneration by targeting Tgif1. Additionally, miR-25-3p upregulated the phosphorylation of Erk. Furthermore, Rapamycin modulated the expression of miR-25-3p in DRG neurons. Finally, the pro-axon regeneration effects of EVs were confirmed by overexpressing miR-25-3p and Tgif1 knockdown in the optic nerve crush model. Thus, the enrichment of miR-25-3p in EVs suggests that it regulates axon regeneration, proving a potential cell-free treatment strategy for nerve injury.

DTTZ suppresses ferroptosis and reverses mitochondrial dysfunction in normal tissues affected by chemotherapy.

Conventional antineoplastic therapies cause severe normal tissue damage and existing cytoprotectants with acute toxicities or potential tumor protection limit their clinical application. We evaluated the selective cytoprotection of 2,2-dimethylthiazolidine hydrochloride in this study, which could protect normal tissue toxicity without interfering antineoplastic therapies. By using diverse cell lines and A549 xenograft model, we discovered a synthetic aminothiol 2,2-dimethylthiazolidine hydrochloride selectively diminished normal cellular ferroptosis via SystemXc-/Glutathione Peroxidase 4 pathway upon antineoplastic therapies without interfering the anticancer efficacy. We revealed the malignant and non-malignant tissues presenting different energy metabolism patterns. And cisplatin induces disparate replicative stress, contributing to the distinguishable cytoprotection of 2,2-dimethylthiazolidine in normal and tumor cells. The compound pre-application could mitigate cisplatin-induced normal cellular mitochondrial oxidative phosphorylation (OXPHOS) dysfunction. Pharmacologic ablation of mitochondria reversed 2,2-dimethylthiazolidine chemoprotection against cisplatin in the normal cell line. Combined, these results provide a potential therapeutic adjuvant to selectively diminish normal tissue damages retaining antineoplastic efficacy.

Establishment of FDHSi003-A, a human induced pluripotent stem cell (hiPSC) line with a mutation of RNF216 c.1948G > T.

Gordon Holmes Syndrome (GDHS) is a hereditary neurodegenerative disease mainly associated with mutations of RNF216. We established a human induced pluripotent stem cell (hiPSC) line, FDHSi003-A, derived from PBMC of a patient baring a mutation of RNF216 c.1948G > T, who shows typical symptoms of GDHS. The generated FDHSi003-A expresses pluripotency markers, displays a normal karyotype, and has the potency to differentiate into all three germ layers. Thus, FDHSi003-A is an ideal model to investigate the mechanism of RNF216 in GDHS.

The cyclimids: Degron-inspired cereblon binders for targeted protein degradation.

Cereblon (CRBN) is an E3 ligase substrate adapter widely exploited for targeted protein degradation (TPD) strategies. However, achieving efficient and selective target degradation is a preeminent challenge with ligands that engage CRBN. Here, we report that the cyclimids, ligands derived from the C-terminal cyclic imide degrons of CRBN, exhibit distinct modes of interaction with CRBN and offer a facile approach for developing potent and selective bifunctional degraders. Quantitative TR-FRET-based characterization of 60 cyclimid degraders in binary and ternary complexes across different substrates revealed that ternary complex binding affinities correlated strongly with cellular degradation efficiency. Our studies establish the unique properties of the cyclimids as versatile warheads in TPD and a systematic biochemical approach for quantifying ternary complex formation to predict their cellular degradation activity, which together will accelerate the development of ligands that engage CRBN.

Role of automated functional imaging and myocardial work in assessment of cardiac function in children with obstructive sleep apnea.

BACKGROUND: Early identification of abnormal left ventricular function in children with obstructive sleep apnea (OSA) is difficult using conventional echocardiographic indices and commonly used clinical markers of myocardial damage. We sought to investigate the value of automatic function imaging and myocardial work parameters in predicting early cardiac impairment in children having OSA with preserved left heart function and thereby identifying an optimal index for assessment. PATIENTS AND METHODS: Fifty-two children who presented with symptoms of nocturnal sleep snoring and open-mouth breathing and 34 healthy controls were enrolled in this study. Clinical characteristics and conventional echocardiographic data were collected, and image analysis was performed using two-dimensional speckle-tracking echocardiography to obtain left ventricular global longitudinal strain (GLS), post-systolic index, peak strain dispersion, global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency. RESULTS: Children with OSA had significantly lower GLS, GWI, and GCW than those without (P < 0.05). Additionally, GWI (ß = -32.87, 95% CI: -53.47 to -12.27), and GCW (ß = -35.09, 95% CI: -55.35 to -14.84) were found to correlate with the disease severity in the multiple linear regression mode, with worsening values observed as the severity of the disease increased. ROC curve analysis revealed that GCW was the best predictor of myocardial dysfunction, with an AUC of 0.809 (P < 0.001), and the best cutoff point for diagnosing myocardial damage in children with OSA was 1965.5 mmHg%, with a sensitivity of 92.5% and a specificity of 58.7%. CONCLUSIONS: GLS, GWI, and GCW were identified as predictors of myocardial dysfunction in children with OSA, with GCW being the best predictor.

Clot ratio, new clot burden score with deep learning, correlates with the risk stratification of patients with acute pulmonary embolism.

Background: Risk stratification for patients with acute pulmonary embolism (APE) is significantly important for treatment and prognosis evaluation. We aimed to develop a novel clot burden score on computed tomography pulmonary angiography (CTPA) based on deep learning (DL) algorithm for risk stratification of APE. Methods: The study retrospectively enrolled patients newly diagnosed with APE in China-Japan Friendship Hospital consecutively. We collected baseline data and CTPA parameters, and calculated four different clot burden scores, including Qanadli score, Mastora score, clot volume and clot ratio. The former two were calculated by two radiologists separately, while clot volume and clot ratio were based on the DL algorithm. The area under the curve (AUC) of four clot burden scores were analyzed. Results: Seventy patients were enrolled, including 17 in high-/intermediate-high risk and 53 in low-/intermediate-low risk. Clot burden was related to the risk stratification of APE. Among four clot burden scores, clot ratio had the highest AUC (0.719, 95% CI: 0.569-0.868) to predict patients with higher risk. In the patients with hemodynamically stable APE, only clot ratio presented statistical difference (P=0.046). Conclusions: Clot ratio is a new imaging marker of clot burden which correlates with the risk stratification of patients with APE. Higher clot ratio may indicate higher risk and acute right ventricular dysfunction in patients with hemodynamically stable status.

circCPA4 induces malignant behaviors of prostate cancer via miR-491-5p/SHOC2 feedback loop.

OBJECTIVE: circCPA4 has been defined to be an oncogenic gene. This study examined whether circCPA4 regulates Prostate Cancer (PC) development and revealed its molecular mechanism. METHODS: PC tissues and PC cell lines were collected, in which circCPA4/miR-491-5p/SHOC2 levels were evaluated by RT-qPCR and immunoblot. Colony formation assay and EdU assay assessed cell proliferation, flow cytometry measured apoptosis, and Transwell assessed invasion and migration. Ki-67, cleaved caspase-3, E-cadherin, and N-cadherin were evaluated by immunoblot. Based on the luciferase reporter assay and RIP assay the authors investigated the targeting relationship between circCPA4/miR-491-5p/SHOC2. The effect of circCPA4 on tumor growth was evaluated by xenotransplantation in nude mice. RESULTS: circCPA4 and SHOC2 levels were abundant while miR-491-5p expression was low in PC. Loss of circCPA4 decreased the proliferation and EdU-positive rate of PC cells, enhanced apoptosis, and inhibited invasion, migration, and EMT. Upregulation of circCPA4 forced the malignant behaviors of PC cells, and this promotion could be abolished when miR-491-5p was overexpressed or SHOC2 was silenced. CircCAP4 competitively decoyed miR-491-5p mediating SHOC2 expression. circCAP4 suppression inhibited PC tumor growth. CONCLUSION: circCAP4 acts as a novel oncogenic factor in PC, accelerating the malignant behavior of PC cells via miR-491-5p/SHOC2 interaction. This novel ceRNA axis may be a potential target for PC drug development and targeted therapy in the future.

Catalytic removal of gaseous pollutant NO using CO: Catalyst structure and reaction mechanism.

Carbon monoxide (CO) has recently been considered an ideal reducing agent to replace NH3 in selective catalytic reduction of NOx (NH3-SCR). This shift is particularly relevant in diesel engines, coal-fired industry, the iron and steel industry, of which generate substantial amounts of CO due to incomplete combustion. Developing high-performance catalysts remain a critical challenge for commercializing this technology. The active sites on catalyst surface play a crucial role in the various microscopic reaction steps of this reaction. This work provides a comprehensive overview and insights into the reaction mechanism of active sites on transition metal- and noble metal-based catalysts, including the types of intermediates and active sites, as well as the conversion mechanism of active molecules or atoms. In addition, the effects of factors such as O2, SO2, and alkali metals, on NO reduction by CO were discussed, and the prospects for catalyst design are proposed. It is hoped to provide theoretical guidance for the rational design of efficient CO selective catalytic denitration materials based on the structure-activity relations.

circCPA4 induces malignant behaviors of prostate cancer via miR-491-5p/ SHOC2 feedback loop

ABSTRACT Objective: circCPA4 has been defined to be an oncogenic gene. This study examined whether circCPA4 regulates Prostate Cancer (PC) development and revealed its molecular mechanism. Methods: PC tissues and PC cell lines were collected, in which circCPA4/miR-491-5p/SHOC2 levels were evaluated by RT-qPCR and immunoblot. Colony formation assay and EdU assay assessed cell proliferation, flow cytometry measured apoptosis, and Transwell assessed invasion and migration. Ki-67, cleaved caspase-3, E-cadherin, and N-cadherin were evaluated by immunoblot. Based on the luciferase reporter assay and RIP assay the authors investigated the targeting relationship between circCPA4/miR-491-5p/SHOC2. The effect of circCPA4 on tumor growth was evaluated by xenotransplantation in nude mice. Results: circCPA4 and SHOC2 levels were abundant while miR-491-5p expression was low in PC. Loss of circCPA4 decreased the proliferation and EdU-positive rate of PC cells, enhanced apoptosis, and inhibited invasion, migration, and EMT. Upregulation of circCPA4 forced the malignant behaviors of PC cells, and this promotion could be abolished when miR-491-5p was overexpressed or SHOC2 was silenced. CircCAP4 competitively decoyed miR-491-5p mediating SHOC2 expression. circCAP4 suppression inhibited PC tumor growth. Conclusion: circCAP4 acts as a novel oncogenic factor in PC, accelerating the malignant behavior of PC cells via miR-491-5p/SHOC2 interaction. This novel ceRNA axis may be a potential target for PC drug development and targeted therapy in the future.

Comparison of cardiovascular metrics on computed tomography pulmonary angiography of the updated and old diagnostic criteria for pulmonary hypertension in patients with chronic thromboembolic pulmonary hypertension.

Background: In the 2022 European Society of Cardiology (ESC) and the European Respiratory Society (ERS) guidelines, the diagnostic criteria for pulmonary hypertension (PH) included a reduced mean pulmonary artery pressure (mPAP) of 20 mmHg (mPAP >20 mmHg). This study aimed to reassess cardiovascular metrics on computed tomography pulmonary angiography (CTPA) for chronic thromboembolic pulmonary hypertension (CTEPH) to optimize the timely diagnosis of patients with suspected PH. Methods: Patients with suspected CTEPH who underwent CTPA and right heart catheterization (RHC) between January 2019 and December 2022 in China-Japan Friendship Hospital were retrospectively included. They were grouped into CTEPH and non-PH groups according to the new and old criteria (2022 and 2015 ESC/ERS guidelines) for the diagnosis of PH. Cardiovascular metrics including the main pulmonary artery diameter (MPAd), Cobb angle, and right ventricular free wall thickness (RVWT), among others, were measured. The correlation of these metrics with hemodynamic data was analyzed with Spearman rank correlation analysis, while the differences in cardiovascular metrics between the updated (mPAP >20 mmHg) and old PH criteria (mPAP ≥25 mmHg) were compared with independent samples t-test or the Mann-Whitney test. Receiver operator characteristic (ROC) curve analysis was performed for the prediction model. Results: The study enrolled 180 patients (males n=86; age 55.5±12.0 years old). According to the old guidelines, 119 patients were placed into the PH group (mPAP ≥25 mmHg) , while according to the new guidelines, 130 patients were placed into the PH group (mPAP >20 mmHg). Cardiovascular metrics on CTPA between the updated and old guidelines were comparable (P>0.05). Compared to other metrics, an MPAd of 30.4 mm exhibited the highest area under the curve (AUC: 0.934±0.021), with a sensitivity of 0.88 and specificity of 0.90. MPAd [odds ratio (OR) =1.271], transverse diameter of the right ventricle (RVtd; OR =1.176), Cobb angle (OR =1.108), and RVWT (OR =3.655) were independent factors for diagnosing CTEPH (P<0.05). Cobb angle, right and left ventricular transverse diameter ratio, and right and left ventricular area ratio moderately correlated with mPAP (r=0.586, r=0.583, r=0.629) and pulmonary vascular resistance (PVR) (r=0.613, r=0.593, r=0.642). Conclusions: Cardiovascular metrics on CTPA were comparable between the new and old guidelines for CTEPH diagnosis. Cardiovascular metrics on CTPA can noninvasively assess the hemodynamics of patients with CTEPH.

Single-Atom Ru Alloyed with Ni Nanoparticles Boosts CO2 Methanation.

Designing catalysts to proceed with catalytic reactions along the desired reaction pathways, e.g., CO2 methanation, has received much attention but remains a huge challenge. This work reports one Ru1 Ni single-atom alloy (SAA) catalyst (Ru1 Ni/SiO2 ) prepared via a galvanic replacement reaction between RuCl3 and Ni nanoparticles (NPs) derived from the reduction of Ni phyllosilicate (Ni-ph). Ru1 Ni/SiO2 achieved much improved selectivity toward hydrogenation of CO2 to CH4 and catalytic activity (Turnover frequency (TOF) value: 40.00 × 10-3  s-1 ), much higher than those of Ni/SiO2 (TOF value: 4.40 × 10-3  s-1 ) and most reported Ni-based catalysts (TOF value: 1.03 × 10-3 -11.00 × 10-3  s-1 ). Experimental studies verify that Ru single atoms are anchored onto the Ni NPs surface via the Ru1 -Ni coordination accompanied by electron transfer from Ru1 to Ni. Both in situ experiments and theoretical calculations confirm that the interface sites of Ru1 Ni-SAA are the intrinsic active sites, which promote the direct dissociation of CO2 and lower the energy barrier for the hydrogenation of CO* intermediate, thereby directing and enhancing the CO2 hydrogenation to CH4 .

Rapid and Widespread Distribution of Intranasal Small Extracellular Vesicles Derived from Mesenchymal Stem Cells throughout the Brain Potentially via the Perivascular Pathway.

Intranasal administration is a promising strategy to enhance the delivery of the sEVsomes-based drug delivery system to the central nervous system (CNS). This study aimed to explore central distributive characteristics of mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) and underlying pathways. Here, we observed that intranasal MSC-sEVs were rapidly distributed to various brain regions, especially in the subcortex distant from the olfactory bulb, and were absorbed by multiple cells residing in these regions. We captured earlier transportation of intranasal MSC-sEVs into the perivascular space and found an increase in cerebrospinal fluid influx after intranasal administration, particularly in subcortical structures of anterior brain regions where intranasal sEVs were distributed more significantly. These results suggest that the perivascular pathway may underlie the rapid and widespread central delivery kinetics of intranasal MSC-sEVs and support the potential of the intranasal route to deliver MSC-sEVs to the brain for CNS therapy.

Fluorescent Visualization of Chemical Profiles across the Air-Water Interface.

Chemical transfer across the air-water interface is one of the most important geochemical processes of global significance. Quantifying such a process has remained extremely challenging due to the lack of suitable technologies to measure chemical diffusion across the air-water microlayer. Herein, we present a fluorescence optical system capable of visualizing the formation of the air-water microlayer with a spatial resolution of 10 µm and quantifying air-water diffusion fluxes using pyrene as a target chemical. We show for the first time that the air-water microlayer is composed of the surface microlayer in water (∼290 ± 40 µm) and a diffusion layer in air (∼350 ± 40 µm) with 1 µg L-1 of pyrene. The diffusion flux of pyrene across the air-water interface is derived from its high-resolution concentration profile without any pre-emptive assumption, which is 2 orders of magnitude lower than those from the conventional method. This system can be expanded to visualize diffusion dynamics of other fluorescent chemicals across the air-water interface and provides a powerful tool for furthering our understanding of air-water mass transfer of organic chemicals related to their global cycling.

A machine learning model for diagnosing acute pulmonary embolism and comparison with Wells score, revised Geneva score, and Years algorithm.

BACKGROUND: Acute pulmonary embolism (APE) is a fatal cardiovascular disease, yet missed diagnosis and misdiagnosis often occur due to non-specific symptoms and signs. A simple, objective technique will help clinicians make a quick and precise diagnosis. In population studies, machine learning (ML) plays a critical role in characterizing cardiovascular risks, predicting outcomes, and identifying biomarkers. This work sought to develop an ML model for helping APE diagnosis and compare it against current clinical probability assessment models. METHODS: This is a single-center retrospective study. Patients with suspected APE were continuously enrolled and randomly divided into two groups including training and testing sets. A total of 8 ML models, including random forest (RF), Naïve Bayes, decision tree, K-nearest neighbors, logistic regression, multi-layer perceptron, support vector machine, and gradient boosting decision tree were developed based on the training set to diagnose APE. Thereafter, the model with the best diagnostic performance was selected and evaluated against the current clinical assessment strategies, including the Wells score, revised Geneva score, and Years algorithm. Eventually, the ML model was internally validated to assess the diagnostic performance using receiver operating characteristic (ROC) analysis. RESULTS: The ML models were constructed using eight clinical features, including D-dimer, cardiac troponin T (cTNT), arterial oxygen saturation, heart rate, chest pain, lower limb pain, hemoptysis, and chronic heart failure. Among eight ML models, the RF model achieved the best performance with the highest area under the curve (AUC) (AUC = 0.774). Compared to the current clinical assessment strategies, the RF model outperformed the Wells score (P = 0.030) and was not inferior to any other clinical probability assessment strategy. The AUC of the RF model for diagnosing APE onset in internal validation set was 0.726. CONCLUSIONS: Based on RF algorithm, a novel prediction model was finally constructed for APE diagnosis. When compared to the current clinical assessment strategies, the RF model achieved better diagnostic efficacy and accuracy. Therefore, the ML algorithm can be a useful tool in assisting with the diagnosis of APE.

Development and validation of a lung graph-based machine learning model to predict acute pulmonary thromboembolism on chest noncontrast computed tomography.

Background: Computed tomography pulmonary angiography (CTPA) is a first-line noninvasive method to diagnose acute pulmonary thromboembolism (APE); however, whether chest noncontrast CT (NC-CT) could aid in the diagnosis of APE remains unknown. The aim of this study was to build and evaluate a holistic lung graph-based machine learning (HLG-ML) using NC-CT for the diagnosis of APE and to compare its performance with that of radiologists and the YEARS algorithm. Methods: This study enrolled 178 cases (77 males; age 63.9±16.7 years) who underwent NC-CT and CTPA in the same day from January 2019 to December 2020. Of these patients, 133 (75% of cases; 58 males; age 65.4±15.6 years) were placed into a training group and 45 (25% of cases; 19 males; age 59.6±19.2 years) into a testing group. The other 43 cases (18 males; age 62.8±20.0 years) were used to externally validate the model between January 2021 and March 2022. A HLG was developed with a pulmonary radiomics descriptor derived from NC-CT images. The approach extracted local radiomics features and encoded these local features into a radiomics descriptor as a characterization of global radiomics feature distribution. Subsequently, 8 ML models were trained and compared based on the radiomics descriptor. In the validation group, area under the curves (AUCs) of the HLG-ML model in the diagnosis of APE were compared with those of the 3 radiologists and the YEARS algorithm. Results: Among the 8 ML models, gradient boosting decision tree demonstrated the best classification performance (AUC =0.772) on the training set. In the testing set, the AUC of gradient boosting decision trees was 0.857 [95% confidence intervals (CIs): 0.699-0.951]. In the validation set, the performance of gradient boosting decision tree (AUC =0.810; 95% CI: 0.669-0.952; Youden index =0.621) outperformed 3 radiologists (AUC =0.508, 95% CI: 0.335-0.681, Youden index =0.016; AUC =0.504, 95% CI: 0.354-0.654, Youden index =0.008; AUC =0.527, 95% CI: 0.363-0.691, Youden index =0.050) and the YEARS algorithm (AUC =0.618; 95% CI: 0.469-0.767; Youden index =0.237). Conclusions: Compared to all 3 radiologists and the YEARS algorithm, the proposed HLG-based gradient boosting decision tree model achieved a superior performance in the diagnosis of APE on the NC-CT and may thus serve as a valuable tool for physicians in the diagnosis of APE.

A potent and broad-spectrum neutralizing nanobody for SARS-CoV-2 viruses, including all major Omicron strains.

SARS-CoV-2 viruses are highly transmissible and immune evasive. It is critical to develop broad-spectrum prophylactic and therapeutic antibodies for potential future pandemics. Here, we used the phage display method to discover nanobodies (Nbs) for neutralizing SARS-CoV-2 viruses especially Omicron strains. The leading nanobody (Nb), namely, Nb4, with excellent physicochemical properties, can neutralize Delta and Omicron subtypes, including BA.1, BA.1.1 (BA.1 + R346K), BA.2, BA.5, BQ.1, and XBB.1. The crystal structure of Nb4 in complex with the receptor-binding domain (RBD) of BA.1 Spike protein reveals that Nb4 interacts with an epitope on the RBD overlapping with the receptor-binding motif, and thus competes with angiotensin-converting enzyme 2 (ACE2) binding. Nb4 is expected to be effective for neutralizing most recent Omicron variants, since the epitopes are evolutionarily conserved among them. Indeed, trivalent Nb4 interacts with the XBB1.5 Spike protein with low nM affinity and competes for ACE2 binding. Prophylactic and therapeutic experiments in mice indicated that Nb4 could reduce the Omicron virus loads in the lung. In particular, in prophylactic experiments, intranasal administration of multivalent Nb4 completely protected mice from Omicron infection. Taken together, these results demonstrated that Nb4 could serve as a potent and broad-spectrum prophylactic and therapeutic Nb for COVID-19.

Cardiovascular metrics on CT pulmonary angiography in patients with pulmonary hypertension - re-evaluation under the updated guidelines of pulmonary hypertension.

PURPOSE: To re-assess cardiovascular metrics on computed tomography pulmonary angiography (CTPA) in predicting pulmonary hypertension (PH) under the 2022 ESC/ERS guidelines. MATERIALS AND METHODS: This observational study retrospectively included 272 patients (female 143, mean age = 54.9 ± 12.5 years old) with suspected PH. 218 patients were grouped to evaluate cardiovascular metrics on CTPA and develop a binary logistic regression model. The other 54 patients were grouped into the validation group to assess the performance of the prediction model under the updated criteria. Based on mean pulmonary artery pressure (mPAP), patients were divided into three groups: group A consisted of patients with mPAP ≤ 20 mmHg, group B included patients with 20 mmHg < mPAP < 25 mmHg, and group C comprised patients with mPAP ≥ 25 mmHg. Cardiovascular metrics among the three groups were compared, and receiver operating characteristic curves (ROCs) were used to evaluate the performance of cardiovascular metrics in predicting mPAP > 20 mmHg. RESULTS: The main pulmonary arterial diameter (MPAd), MPAd/ascending aorta diameter ratio (MPAd/AAd ratio), and right ventricular free wall thickness (RVFWT) showed significant differences among the three groups (p < 0.05). The area under curve (AUC) of MPAd was larger than MPAd/AAd ratio and RVFWT. A MPAd cutoff value of 30.0 mm has a sensitivity of 83.1% and a specificity of 90.4%. The AUC of the binary logistic regression model (Z = - 12.98187 + 0.31053 MPAd + 1.04863 RVFWT) was 0.938 ± 0.018. In the validation group, the AUC, sensitivity, specificity, and accuracy of the prediction model were 0.878, 92.7%, 76.9%, and 88.9%, respectively. CONCLUSION: Under the updated criteria, MPAd with a threshold value of 30.0 mm has better sensitivity and specificity in predicting PH. The binary logistic regression model may improve the diagnostic accuracy. CRITICAL RELEVANCE STATEMENT: Under the updated criteria, the main pulmonary arterial diameter with a threshold value of 30.0 mm has better sensitivity and specificity in predicting pulmonary hypertension. The binary logistic regression model may improve diagnostic accuracy. KEY POINTS: • According to 2022 ESC/ERS guidelines, a MPAd cutoff value of 30.0 mm has better sensitivity and specificity in predicting mPAP > 20 mmHg • A binary logistic regression model (Z = - 12.98187 + 0.31053 MPAd + 1.04863 RVFWT) was developed and had a sensitivity, specificity, and accuracy of 92.7%, 76.9%, and 88.9% in predicting mPAP > 20 mmHg. • A binary logistic regression prediction model outperforms MPAd in predicting mPAP > 20 mmHg.

2, 2-dimethylthiazolidine hydrochloride protects against experimental contrast-induced acute kidney injury via inhibition of tubular ferroptosis.

Contrast-induced acute kidney injury (CI-AKI) has become the third leading cause of AKI acquired in hospital, lacking of effective interventions. In the study, we identified the renal beneficial role of 2, 2-dimethylthiazolidine hydrochloride (DMTD), a safer compound which is readily hydrolyzed to cysteamine, in the rodent model of CI-AKI. Our data showed that administration of DMTD attenuated the impaired renal function and tubular injury induced by the contrast agent. Levels of MDA, 4-hydroxynonenal, ferrous iron and morphological signs showed that contrast agent induced ferroptosis, which could be inhibited in the DMTD group. In vitro, DMTD suppressed ferroptosis induced by ioversol in the cultured tubular cells. Treatment of DMTD upregulated glutathione (GSH) and glutathione peroxidase 4 (GPX4). Moreover, we found that DMTD promoted the ubiquitin-mediated proteasomal degradation of Keap1, and thus increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2). Mechanistically, increase of the ubiquitylation degradation of Keap1 mediates the upregulated effect of DMTD on Nrf2. Consequently, activated Nrf2/Slc7a11 results in the increase of GSH and GPX4, and therefore leads to the inhibition of ferroptosis. Herein, we imply DMTD as a potential therapeutic agent for the treatment of CI-AKI.

Structure and function of extreme TLS DNA polymerase TTEDbh from Thermoanaerobacter tengcongensis.

Translesion synthesis (TLS) is a kind of DNA repair that maintains the stability of the genome and ensures the normal growth of life in cells under emergencies. Y-family DNA polymerases, as a kind of error-prone DNA polymerase, mainly perform TLS. Previous studies have suggested that the occurrence of tumors is associated with the overexpression of human DNA polymerase of the Y family. And the combination of Y-family DNA polymerase inhibitors is promising for cancer therapy. Here we report the functional and structural characterization of a member of the Y-family DNA polymerases, TTEDbh. We determine TTEDbh is an extreme TLS polymerase that can cross oxidative damage sites, and further identify the amino acids and novel structures that are critical for DNA binding, synthesis, fidelity, and oxidative damage bypass. Moreover, previously unnoticed structural elements with important functions have been discovered and analyzed. These studies provide a more experimental basis for further elucidating the molecular mechanisms of DNA polymerase in the Y family. It could also shed light on the design of drugs to target tumors.