HSP90/LSD1 dual inhibitors against prostate cancer as well as patient-derived colorectal organoids.

The rational installation of pharmacophores targeting HSP90 and LSD1 axes has achieved significant anti-cancer capacity in prostate and colorectal cancer. Among the series of hybrids, inhibitor 6 exhibited remarkable anti-proliferative activity against prostate cancer cell lines PC-3 and DU145, with GI50 values of 0.24 and 0.30 µM, respectively. It demonstrated notable efficacy in combinatorial attack and cell death initiation towards apoptosis. The cell death process was mediated by PARP induction and γH2AX signaling, and was also characterized as caspase-dependent and Bcl-xL/Bax-independent. Notably, no difference in eye size or morphology was observed in the zebrafish treated with compound 6 compared to the reference group (AUY922). The profound treatment response in docetaxel-resistant PC-3 cells highlighted the dual inhibitory ability in improving docetaxel sensitivity. Additionally, at a minimum concentration of 1.25 µM, compound 6 effectively inhibited the growth of patient-derived colorectal cancer (CRC) organoids for up to 10 days in vitro. Together, the designed HSP90/LSD1 inhibitors present a novel route and significant clinical value for anti-cancer drug therapy.

Experimental study of contrast-enhanced ultrasound in the evaluation of random-pattern flap blood supply in the early postoperative stage in rats.

PURPOSE: This study aims to investigate whether contrast-enhanced ultrasound (CEUS) could be used to reveal the status of blood supply of the superficial flap of rat model in the early postoperative stage. METHODS: One viable and one ischemic random-pattern flap were prepared on the left and right back of the same rat respectively with a number of 40. CEUS examinations were applied within 12 h and 7 days postoperatively, and the quantitative measurements of microvascular blood volume (BV) of the base and the end of both flaps were expressed using acoustic intensity as a ratio to that of the healthy skin. RESULTS: Within 12 h post operation, there was a smaller BV value of the ischemic ends than that of both the ischemic bases and viable ends (p < 0.001), while no difference was indicated between ischemic bases and viable bases or between viable bases and viable ends. The same result was provided 7 days post operation. CONCLUSION: Microcirculation of superficial tissues such as random-pattern flaps in this rat model can be assessed quantitatively by CEUS. It could sensitively and accurately reveal the objective status of tissue perfusion in the early postoperative stage.

Apolipoprotein E in patients with undiagnosed pleural effusion: a prospective diagnostic test accuracy study.

INTRODUCTION: Pleural effusion is common in clinical practice, and its differential diagnosis remains challenging for clinicians. This study investigates the diagnostic value of apolipoprotein E (apoE) in patients with undetermined pleural effusion. METHODS: This prospective, double-blind study enrolled 152 patients with undiagnosed pleural effusion. Their pleural fluid apoE levels were measured, and a receiver operating characteristics (ROC) curve was used to evaluate the diagnostic accuracy of apoE. Decision curve analysis (DCA) was used to assess apoE's net benefit. Subgroup analyses were performed to investigate the effect of age on the diagnostic accuracy of apoE. RESULTS: Among the included participants, 23 had heart failure (HF). HF patients had the lowest apoE level among pleural effusion patients. The area under the curve (AUC) of apoE for HF was 0.79 (95% CI: 0.69-0.89). At the threshold of 40 mg/L, the sensitivity and specificity of apoE were 0.96 (95% CI: 0.87-1.00) and 0.33 (95% CI: 0.25-0.42), respectively. The decision curve for apoE was above reference lines. The AUC of apoE decreased in older patients. CONCLUSION: Pleural fluid apoE has moderate diagnostic value for HF and has net benefits in patients with undiagnosed pleural effusion. The diagnostic accuracy of apoE decreases with age.

Molecular interactions of the chaperone CcmS and carboxysome shell protein CcmK1 that mediate ß-carboxysome assembly.

The carboxysome is a natural proteinaceous organelle for carbon fixation in cyanobacteria and chemoautotrophs. It comprises hundreds of protein homologs that self-assemble to form a polyhedral shell structure to sequester cargo enzymes, ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) and carbonic anhydrases. How these protein components assemble to construct a functional carboxysome is a central question in not only understanding carboxysome structure and function but also synthetic engineering of carboxysomes for biotechnological applications. Here, we determined the structure of the chaperone protein CcmS, which has recently been identified to be involved in ß-carboxysome assembly, and its interactions with ß-carboxysome proteins. The crystal structure at 1.99 Å resolution reveals CcmS from Nostoc sp. PCC 7120 forms a homodimer, and each CcmS monomer consists of five α-helices and four ß-sheets. Biochemical assays indicate that CcmS specifically interacts with the C-terminal extension of the carboxysome shell protein CcmK1, but not the shell protein homolog CcmK2 or the carboxysome scaffolding protein CcmM. Moreover, we solved the structure of a stable complex of CcmS and the C-terminus of CcmK1 at 1.67 Å resolution and unveiled how the CcmS dimer interacts with the C-terminus of CcmK1. These findings allowed us to propose a model to illustrate CcmS-mediated ß-carboxysome assembly by interacting with CcmK1 at the outer shell surface. Collectively, our study provides detailed insights into the accessory factors that drive and regulate carboxysome assembly, thereby improving our knowledge of carboxysome structure, function, and bioengineering.

Deep Cross-View Reconstruction GAN Based on Correlated Subspace for Multi-View Transformation.

In scenarios where identifying face information in the visible spectrum (VIS) is challenging due to poor lighting conditions, the use of near-infrared (NIR) and thermal (TH) cameras can provide viable alternatives. However, the unique data distribution of images captured by these cameras compared to VIS images presents challenges in matching face identities. To address these challenges, we propose a novel image transformation framework. The framework includes feature extraction from the input image, followed by a transformation network that generates target domain images with perceptual fidelity. Additionally, a reconstruction network preserves original information by reconstructing the original domain image from the extracted features. By considering the correlation between features from both domains, our framework utilizes paired data obtained from the same individual. We apply this framework to two well-established image-to-image transformation models, pix2pix and CycleGAN, known as CRC-pix2pix and CRC-CycleGAN respectively. The versatility of our approach allows extension to other models based on pix2pix or CycleGAN architectures. Our models generate high-quality images while preserving the identity information of the original face. Performance evaluation on TFW and BUAA NIR-VIS datasets demonstrates the superiority of our models in terms of generated image face matching and evaluation metrics such as SSIM, MSE, PSNR, and LPIPS. Moreover, we introduce the CQUPT-VIS-TH dataset, which enriches the paired dataset with thermal-visual face data capturing various angles and expressions.

[Mechanisms of oxidative stress in myocardial ischemia-reperfusion injury and protective effects of traditional Chinese medicines].

Myocardial ischemia is a disease characterized by high morbidity and mortality rates, restoring blood supply to the ischemic area through reperfusion is an effective intervention method. However, numerous studies have shown that reperfusion may cause severe myocardial damage, resulting in myocardial systolic and diastolic dysfunction and seriously affecting myocardial function. This phenomenon is called myocardial ischemia reperfusion injury(MIRI). The physiological and pathological mechanisms of MIRI include oxidative stress, calcium overload, autophagy, pyrolysis, endoplasmic reticulum stress, apoptosis, etc. Oxidative stress plays an important role in MIRI-related cell death and is considered to be the main mechanism of MIRI. The occurrence of oxidative stress is mainly due to the excessive production of reactive oxygen species(ROS), which disrupts the balance of the redox system of the body or tissue. A large number of highly reactive ROS exceed the antioxidant defense capacity of cardiomyocytes, causing modifications in biological macromolecules such as DNA and proteins and resulting in severe reactions like DNA damage, protein dysfunction, cell damage or death, and local inflammation. Oxidative stress mediates apoptosis, autophagy, and inflammatory injury through various pathways, resulting in irreversible cardiomyocyte injury and myocardial dysfunction, which brings significant challenges for clinical treatment and prognosis. In recent years, remarkable progress has been made in understanding oxidative stress in ischemia reperfusion(I/R) injury of different organs and tissue. However, the injury mechanism caused by oxidative stress in restoring blood supply to the ischemic area and the protective effect of TCM remain largely unexplored. This article reviewed the role of oxidative stress in MIRI, the main production pathways of ROS, and the protective effects of TCM on oxidative stress injury during ischemic myocardial reperfusion, so as to provide a reference for future research and clinical treatment in this field.

Pleural carbohydrate antigen 50 and malignant pleural effusion: a prospective, double-blind diagnostic accuracy test.

Background: Serum carbohydrate antigen 50 (CA50) is an auxiliary diagnostic marker for various solid tumors, but it remains unclear whether CA50 in pleural fluid can assist in the diagnosis of malignant pleural effusion (MPE). This study aimed to evaluate the diagnostic accuracy of pleural fluid CA50 for MPE in pleural effusion patients with undetermined causes. Methods: This study prospectively recruited pleural effusion patients with undetermined causes who visited the Affiliated Hospital of Inner Mongolia Medical University between September 2018 and July 2021. We measured pleural fluid CA50 level with an electrochemiluminescence assay. We analyzed the diagnostic accuracy of CA50 and carcinoembryonic antigen (CEA) for MPE with the receiver operating characteristic (ROC) curve. The net benefits of CA50 and CEA were analyzed using the decision curve analysis (DCA). Results: We enrolled 66 MPEs and 87 benign pleural effusions (BPEs). MPE patients had significantly higher CA50 and CEA than BPE patients. The area under the ROC curve (AUC) of CA50 was 0.72 (95% CI: 0.63-0.80). CA50 had a sensitivity of 0.30 (95% CI: 0.19-0.41) and a specificity of 1.00 (95% CI: 1.00-1.00) at the threshold of 15 IU/mL. The decision curve of CA50 was above the reference line at the calculated risk probability of between 0.30 and 1.00. Venn diagram indicated that some patients with low CEA (<50 or <150 ng/mL) and/or negative cytology can be identified by positive CA50 (>15 IU/mL). Conclusions: Pleural fluid CA50 has moderate accuracy and net benefit for detecting MPE. CA50 >15 IU/mL can be used to diagnose MPE. The combination of CA50 and CEA improves the diagnostic sensitivity for MPE.

A neural network-based algorithm for the reconstruction and filtering of single particle trajectory in magnetic particle tracking.

Magnetic particle tracking (MPT) is a recently developed non-invasive measurement technique that has gained popularity for studying dense particulate or granular flows. This method involves tracking the trajectory of a magnetically labeled particle, the field of which is modeled as a dipole. The nature of this method allows it to be used in opaque environments, which can be highly beneficial for the measurement of dense particle dynamics. However, since the magnetic field of the particle used is weak, the signal-to-noise ratio is usually low. The noise from the measuring devices contaminates the reconstruction of the magnetic tracer's trajectory. A filter is then needed to reduce the noise in the final trajectory results. In this work, we present a neural network-based framework for MPT trajectory reconstruction and filtering, which yields accurate results and operates at very high speed. The reconstruction derived from this framework is compared to the state-of-the-art extended Kalman filter-based reconstruction.

Diagnostic Accuracy of Transthoracic Echocardiography for Acute Type A Aortic Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Transthoracic echocardiography (TTE) is currently recognized as the potential first-line imaging test for patients with suspected acute type A aortic syndrome (AAAS). Direct TTE sign for detecting AAAS is positive if there is an intimal flap separating two aortic lumens or aortic wall thickening seen in the ascending aorta. Indirect TTE sign indicates high-risk features of AAAS, such as aortic root dilatation, pericardial effusion, and aortic regurgitation. Our aim is to summarize the existing clinical evidence regarding the diagnostic accuracy of TTE and to evaluate its potential role in the management of patients with suspected AAAS. METHODS: We included prospective or retrospective diagnostic cohort studies, written in any language, that specifically focused on using TTE to diagnose AAAS from databases such as PubMed, EMBASE, MEDLINE, and the Cochrane Library. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio [1], and hierarchical summary receiver-operating characteristic (HSROC) curve were calculated for TTE in diagnosing AAAS. We applied Quality Assessment of Diagnostic Accuracy (QUADAS-2) tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) quality assessment criteria. RESULTS: Ten studies (2886 patients) were included in the meta-analysis. The pooled sensitivity and specificity of direct TTE signs were 58% (95% CI, 38-76%) and 94% (95% CI, 89-97%). For any TTE signs, the pooled sensitivity and specificity were 91% (95% CI, 85-94%) and 74% (95% CI, 61-84%). The diagnostic accuracy of direct TTE signs was significantly higher than that of any TTE signs, as measured by the area under the HSROC curve [0.95 (95% CI, 0.92-0.96) vs. 0.87 (95% CI, 0.84-0.90)] in four studies. CONCLUSIONS: Our study suggests that TTE could serve as the initial imaging test for patients with suspected AAAS. Given its high specificity, the presence of direct TTE signs may indicate AAAS, whereas the absence of any TTE signs, combined with low clinical suspicion, could suggest a lower likelihood of AAAS.

Diet Outcome in Patients With Hypopharyngeal Defects Repaired With Different Reconstruction Flaps: A Comparative Study.

OBJECTIVES: To assess potential risk factors influencing diet outcomes after reconstruction of subtotal hypopharyngeal defects using free patch- or tube-shaped anterolateral thigh (ALT) fasciocutaneous flaps. STUDY DESIGN: Retrospective cohort study. SETTING: First-level referral hospital. METHODS: Between January 2011 and December 2020, we studied hypopharyngeal cancer patients who underwent the reconstruction of hypopharyngeal defects using free patch- or tube-shaped ALT fasciocutaneous flaps. The choice between patch- or tube-shaped ALT flaps depended on the defect's nature, favoring patch-shaped for subtotal defects and tube-shaped for circumferential defects. A restricted diet was characterized by a history of enterostomy or endoscopic esophageal dilation treatment postreconstruction. We analyzed patients with restricted diets at 1- and 3-year follow-up visits. RESULTS: Ninety-eight patients were enrolled; 39 patch-shaped flaps, and 59 tube-shaped flaps. No significances were noted in demographics, postoperative radiotherapy (RT) or chemotherapy, rates of free flap reoperation/salvage, or complications. However, a significant difference emerged in diet outcomes at the 1-year follow-up (P = .005). The rate of a restricted diet was 6.08 times higher in patients with tube-shaped flaps compared to patch-shaped flaps (95% confidence interval [CI]: 1.95-18.94). Stratifying based on postoperative RT revealed a 5.47 times higher rate of a restricted diet in tube-shaped flap recipients compared to patch-shaped flap recipients (95% CI: 1.44-20.48). No significances were observed in 5-year survival rates. CONCLUSION: Concerning postoperative RT, patch-shaped flaps exhibited a lower incidence of a restricted diet compared to tube-shaped flaps. Preservation of the posterior mucosa may play a crucial role in preventing RT-induced esophageal stricture.

Trx4, a novel thioredoxin protein, is important for Toxoplasma gondii fitness.

BACKGROUND: To successfully replicate within the host cell, Toxoplasma gondii employs several mechanisms to overcome the host cell defenses and mitigate the harmful effects of the free radicals resulting from its own metabolic processes using effectors such as thioredoxin proteins. In this study, we characterize the location and functions of a newly identified thioredoxin in T. gondii, which was named Trx4. METHODS: We characterized the functional role of Trx4 in T. gondii Type I RH and Type II Pru strains by gene knockout and studied its subcellular localization by endogenous protein HA tagging using CRISPR-Cas9 gene editing. The enzyme-catalyzed proximity labeling technique, the TurboID system, was employed to identify the proteins in proximity to Trx4. RESULTS: Trx4 was identified as a dense granule protein of T. gondii predominantly expressed in the parasitophorous vacuole (PV) and was partially co-localized with GRA1 and GRA5. Functional analysis showed that deletion of trx4 markedly influenced the parasite lytic cycle, resulting in impaired host cell invasion capacity in both RH and Pru strains. Mutation of Trx domains in Trx4 in RH strain revealed that two Trx domains were important for the parasite invasion. By utilizing the TurboID system to biotinylate proteins in proximity to Trx4, we identified a substantial number of proteins, some of which are novel, and others are previously characterized, predominantly distributed in the dense granules. In addition, we uncovered three novel proteins co-localized with Trx4. Intriguingly, deletion of trx4 did not affect the localization of these three proteins. Finally, a virulence assay demonstrated that knockout of trx4 resulted in a significant attenuation of virulence and a significant reduction in brain cyst loads in mice. CONCLUSIONS: Trx4 plays an important role in T. gondii invasion and virulence in Type I RH strain and Type II Pru strain. Combining the TurboID system with CRISPR-Cas9 technique revealed many PV-localized proximity proteins associated with Trx4. These findings suggest a versatile role of Trx4 in mediating the processes that occur in this distinctive intracellular membrane-bound vacuolar compartment.

Diagnostic accuracy and cellular origin of pleural fluid CXCR3 ligands for tuberculous pleural effusion.

BACKGROUND: Pleural biomarkers represent potential diagnostic tools for tuberculous pleural effusion (TPE) due to their advantages of low cost, short turnaround time, and less invasiveness. This study evaluated the diagnostic accuracy of two CXCR3 ligands, C-X-C motif chemokine ligand 9 (CXCL9) and CXCL11, for TPE. In addition, we investigated the cellular origins and biological roles of CXCL9 and CXCL11 in the development of TPE. METHODS: This double-blind study prospectively enrolled patients with undiagnosed pleural effusion from two centers (Hohhot and Changshu) in China. Pleural fluid on admission was obtained and levels of CXCL9 and CXCL11 were measured by an enzyme-linked immunosorbent assay (ELISA). The receiver operating characteristic (ROC) curve and the decision curve analysis (DCA) were used to evaluate their diagnostic accuracy and net benefit, respectively. THP-1 cell-derived macrophages were treated with Bacillus Calmette-Guérin (BCG), and quantitative real-time PCR (qRT-PCR) and ELISA were used to determine the mRNA and protein levels of CXCL9 and CXCL11. The chemoattractant activities of CXCL9 and CXCL11 for T helper (Th) cells were analyzed by a transwell assay. RESULTS: One hundred and fifty-three (20 TPEs and 133 non-TPEs) patients were enrolled in the Hohhot Center, and 58 (13 TPEs and 45 non-TPEs) were enrolled in the Changshu Center. In both centers, we observed increased CXCL9 and CXCL11 in TPE patients. The areas under the ROC curves (AUCs) of pleural CXCL9 and CXCL11 in the Hohhot Center were 0.70 (95 % CI: 0.55-0.85) and 0.68 (95 % CI: 0.52-0.84), respectively. In the Changshu Center, the AUCs of CXCL9 and CXCL11 were 0.96 (95 % CI: 0.92-1.00) and 0.97 (95 % CI: 0.94-1.00), respectively. The AUCs of CXCL9 and CXCL11 decreased with the advancement of age. The decision curves of CXCL9 and CXCL11 showed net benefits in both centers. CXCL9 and CXCL11 were upregulated in BCG-treated macrophages. Pleural fluid from TPE and conditioned medium from BCG-treated macrophages were chemotactic for Th cells. Anti-CXCL9 or CXCL11 neutralizing antibodies could partly block the chemotactic activity. CONCLUSIONS: Pleural CXCL9 and CXCL11 are potential diagnostic markers for TPE, but their diagnostic accuracy is compromised in elderly patients. CXCL9 and CXCL11 can promote the migration of peripheral Th cells, thus representing a therapeutic target for the treatment of TPE.

CircHIPK3 targets DRP1 to mediate hydrogen peroxide-induced necroptosis of vascular smooth muscle cells and atherosclerotic vulnerable plaque formation.

INTRODUCTION: Necroptosis triggered by H2O2 is hypothesized to be a critical factor in the rupture of atherosclerotic plaques, which may precipitate acute cardiovascular events. Nevertheless, the specific regulatory molecules of this development remain unclear. We aims to elucidate a mechanism from the perspective of circular RNA. OBJECTIVES: There are few studies on circRNA in VSMCs necroptosis. The objective of our research is to shed light on the intricate roles that circHIPK3 plays in the process of necroptosis in VSMCs and the development of atherosclerotic plaques that are prone to rupture. Our study elucidates the specific molecular mechanisms by which circHIPK3 regulates necroptosis and atherosclerotic vulnerable plaque formation through targeted proteins. Identifying this mechanism at the cellular level offers a molecular framework for understanding plaque progression and stability regulation, as well as a potential biomarker for the prognosis of susceptible atherosclerotic plaques. METHODS: We collected clinical vascular tissue for HE staining and Masson staining to determine the presence and stability of plaques. Then, NCBI database was used to screen out circRNA with elevated expression level in plaque tissue, and the up-regulated circRNA, circHIPK3, was verified by qRT-PCR and FISH. Further, we synthesized circHIPK3's small interference sequence and overexpressed plasmid in vitro, and verified its regulation effect on necroptosis of VSMCs under physiological and pathological conditions by WB, qRT-PCR and PI staining. Through RNA pull down, mass spectrometry and RNA immunoprecipitation, DRP1 was identified as circHIPK3 binding protein and was positively regulated by circHIPK3. Meanwhile, on the basis of silencing of DRP1, the regulation of circHIPK3 on necroptosis is verified to be mediated by DRP1. Finally, we validated the regulation of circHIPK3 on vulnerable plaque formation in ApoE-/- mice. RESULTS: We investigated that circHIPK3 was highly expressed in vulnerable plaques, and the increase in expression level promoted H2O2 induced necroptosis of VSMCs. CircHIPK3 targeted the protein DRP1, leading to an elevation in mitochondrial division rate, resulting in increased reactive oxygen species and impaired mitochondrial function, ultimately leading to necroptosis of VSMCs and vulnerable plaque formation. CONCLUSION: CircHIPK3 interact with DRP1 involve in H2O2 induced Mitochondrial damage and necroptosis of VSMCs, and Silencing circHIPK3 in vivo can reduce atherosclerotic vulnerable plaque formation. Our research findings may have applications in providing diagnostic biomarkers for vulnerable plaques.

[Ginsenoside Re regulates mitochondrial biogenesis through Nrf2/HO-1/PGC-1α pathway to reduce hypoxia/reoxygenation injury in H9c2 cells].

This article explored the mechanism by which ginsenoside Re reduces hypoxia/reoxygenation(H/R) injury in H9c2 cells by regulating mitochondrial biogenesis through nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)/peroxisome prolife-rator-activated receptor gamma coactivator-1α(PGC-1α) pathway. In this study, H9c2 cells were cultured in hypoxia for 4 hours and then reoxygenated for 2 hours to construct a cardiomyocyte H/R injury model. After ginsenoside Re pre-administration intervention, cell activity, superoxide dismutase(SOD) activity, malondialdehyde(MDA) content, intracellular reactive oxygen species(Cyto-ROS), and intramitochondrial reactive oxygen species(Mito-ROS) levels were detected to evaluate the protective effect of ginsenoside Re on H/R injury of H9c2 cells by resisting oxidative stress. Secondly, fluorescent probes were used to detect changes in mitochondrial membrane potential(ΔΨ_m) and mitochondrial membrane permeability open pore(mPTP), and immunofluorescence was used to detect the expression level of TOM20 to study the protective effect of ginsenoside Re on mitochondria. Western blot was further used to detect the protein expression levels of caspase-3, cleaved caspase-3, Cyto C, Nrf2, HO-1, and PGC-1α to explore the specific mechanism by which ginsenoside Re protected mitochondria against oxidative stress and reduced H/R injury. Compared with the model group, ginse-noside Re effectively reduced the H/R injury oxidative stress response of H9c2 cells, increased SOD activity, reduced MDA content, and decreased Cyto-ROS and Mito-ROS levels in cells. Ginsenoside Re showed a good protective effect on mitochondria by increasing ΔΨ_m, reducing mPTP, and increasing TOM20 expression. Further studies showed that ginsenoside Re promoted the expression of Nrf2, HO-1, and PGC-1α proteins, and reduced the activation of the apoptosis-related regulatory factor caspase-3 to cleaved caspase-3 and the expression of Cyto C protein. In summary, ginsenoside Re can significantly reduce I/R injury in H9c2 cells. The specific mechanism is related to the promotion of mitochondrial biogenesis through the Nrf2/HO-1/PGC-1α pathway, thereby increasing the number of mitochondria, improving mitochondrial function, enhancing the ability of cells to resist oxidative stress, and alleviating cell apoptosis.

[Tetrahydropalmatine inhibiting mitophagy through ULK1/FUNDC1 pathway to alleviate hypoxia/reoxygenation injury in H9c2 cells].

This study explored the specific mechanism by which tetrahydropalmatine(THP) inhibited mitophagy through the UNC-51-like kinase 1(ULK1)/FUN14 domain containing 1(FUNDC1) pathway to reduce hypoxia/reoxygenation(H/R) injury in H9c2 cells. This study used H9c2 cells as the research object to construct a cardiomyocyte H/R injury model. First, a cell viability detection kit was used to detect cell viability, and a micro-method was used to detect lactate dehydrogenase(LDH) leakage to evaluate the protective effect of THP on H/R injury of H9c2 cells. In order to evaluate the protective effect of THP on mitochondria, the chemical fluorescence method was used to detect intracellular reactive oxygen species, intramitochondrial reactive oxygen species, mitochondrial membrane potential, and autophagosomes, and the luciferin method was used to detect intracellular adenosine 5'-triphosphate(ATP) content. Western blot was further used to detect the ratio of microtubule-associated protein 1 light chain 3(LC3) membrane type(LC3-Ⅱ) and slurry type(LC3-Ⅰ) and activated cleaved caspase-3 expression level. In addition, ULK1 expression level and its phosphorylation degree at Ser555 site, as well as the FUNDC1 expression level and its phosphorylation degree of Ser17 site were detected to explore its specific mechanism. The results showed that THP effectively reduced mitochondrial damage in H9c2 cells after H/R. THP protected mitochondria by reducing the level of reactive oxygen species in cells and mitochondria, increasing mitochondrial membrane potential, thereby increasing cellular ATP production, enhancing cellular activity, reducing cellular LDH leakage, and finally alleviating H/R damage in H9c2 cells. Further studies have found that THP could reduce the production of autophagosomes, reduce the LC3-Ⅱ/LC3-Ⅰ ratio, and lower the expression of the apoptosis-related protein, namely cleaved caspase-3, indicating that THP could reduce apoptosis by inhibiting autophagy. In-depth studies have found that THP could inhibit the activation of the ULK1/FUNDC1 pathway of mitophagy and the occurrence of mitophagy by reducing the phosphorylation degree of ULK1 at Ser555 and FUNDC1 at Ser17. The application of ULK1 agonist BL-918 reversely verified the effect of THP on reducing the phosphorylation of ULK1 and FUNDC1. In summary, THP inhibited mitophagy through the ULK1/FUNDC1 pathway to reduce H/R injury in H9c2 cells.

An elastic competitive and discriminative collaborative representation method for image classification.

Collaborative representation-based (CR) methods have become prevalent for pattern classification tasks, achieving formidable performance. Theoretically, we expect the learned class-specific representation of the correct class to be discriminative against others, with the representation of the correct class contributing dominantly in CR. However, most existing CR methods focus on improving discrimination while having a limited impact on enhancing the representation contribution of the correct category. In this work, we propose a novel CR approach for image classification called the elastic competitive and discriminative collaborative representation-based classifier (ECDCRC) to simultaneously strengthen representation contribution and discrimination of the correct class. The ECDCRC objective function penalizes two key terms by fully incorporating label information. The competitive term integrates the nearest subspace representation with corresponding elastic factors into the model, allowing each class to have varying competition intensities based on similarity with the query sample. This enhances the representation contribution of the correct class in CR. To further improve discrimination, the discriminative term introduces an elastic factor as a weight in the model to represent the gap between the query sample and the representation of each class. Moreover, instead of focusing on representation coefficients, the designed ECDCRC weights associated with representation components directly relate to the representation of each class, enabling more direct and precise discrimination improvement. Concurrently, sparsity is also enhanced through the two terms, further boosting model performance. Additionally, we propose a robust ECDCRC (R-ECDCRC) to handle image classification with noise. Extensive experiments on seven public databases demonstrate the proposed method's superior performance over related state-of-the-art CR methods.

Pattern classification of interstitial lung diseases from computed tomography images using a ResNet-based network with a split-transform-merge strategy and split attention.

In patients with interstitial lung disease (ILD), accurate pattern assessment from their computed tomography (CT) images could help track lung abnormalities and evaluate treatment efficacy. Based on excellent image classification performance, convolutional neural networks (CNNs) have been massively investigated for classifying and labeling pathological patterns in the CT images of ILD patients. However, previous studies rarely considered the three-dimensional (3D) structure of the pathological patterns of ILD and used two-dimensional network input. In addition, ResNet-based networks such as SE-ResNet and ResNeXt with high classification performance have not been used for pattern classification of ILD. This study proposed a SE-ResNeXt-SA-18 for classifying pathological patterns of ILD. The SE-ResNeXt-SA-18 integrated the multipath design of the ResNeXt and the feature weighting of the squeeze-and-excitation network with split attention. The classification performance of the SE-ResNeXt-SA-18 was compared with the ResNet-18 and SE-ResNeXt-18. The influence of the input patch size on classification performance was also evaluated. Results show that the classification accuracy was increased with the increase of the patch size. With a 32 × 32 × 16 input, the SE-ResNeXt-SA-18 presented the highest performance with average accuracy, sensitivity, and specificity of 0.991, 0.979, and 0.994. High-weight regions in the class activation maps of the SE-ResNeXt-SA-18 also matched the specific pattern features. In comparison, the performance of the SE-ResNeXt-SA-18 is superior to the previously reported CNNs in classifying the ILD patterns. We concluded that the SE-ResNeXt-SA-18 could help track or monitor the progress of ILD through accuracy pattern classification.

In-depth theoretical analysis of the influence of an external electric field on charge transport parameters.

It is important to develop materials with environmental stability and long device shelf life for use in organic field-effect transistors (OFETs). The microscopic, molecular-level nature of the organic layer in OFETs is not yet well understood. The stability of geometric and electronic structures and the regulation of the external electric field (EEF) on the charge transport properties of four typical homogeneous organic semiconductors (OSCs) were investigated by density functional theory (DFT). The results showed that under the EEF, the structural changes in single-bond linked oligomers were more sensitive and complex than those of condensed molecules, and there were non-monotonic changes in their reorganization energy (λ) during charge transport under an EEF consisting of decreases and then increases (Series D). The change in λ under an EEF can be preliminarily and qualitatively determined by the change in the frontier molecular orbitals (FMOs) - the number of C-atoms with nonbonding characteristics. For single-bonded molecules, the transfer integral is basically unchanged under a low EEF, but it will greatly change at a high EEF. Because the structure and properties of the molecule will greatly change under different EEFs, the effect of an EEF should be fully considered when determining the intrinsic mobility of OSCs, which could cause a deviation 0.3-20 times in mobility. According to detailed calculations, one heterogeneous oligomer, TH-BTz, was designed. Its λ can be greatly reduced under an EEF, and the change in the energy level of FMOs can be adjusted to different degrees. This study provides a reasonable idea for verification of the experimental mobility value and also provides guidance for the directional design of stable high-mobility OSCs.

Layperson assessment of smile lines and upper lip combined images in smile esthetics.

STATEMENT OF PROBLEM: The esthetic assessment of smile lines by laypersons is a subject of ongoing debate. However, smile lines often appear with different types of upper lip curvature, which further complicates the esthetic assessment process, and studies on this combination are lacking. PURPOSE: The purpose of this clinical study was to investigate a layperson's esthetic perception of smile lines and upper lip combined images. MATERIAL AND METHODS: Twenty-six smile images resulting from combinations of 3 upper lip types, 4 anterior smile line types, and 3 posterior smile line types were generated by an image editing software program. Eighty-three laypersons (39 men and 44 women; 18 to 35 years of age) completed rating images using a visual analog scale. Unattractive smiles were designated to be those with scores <50 and attractive ones with scores ≥50. Data were analyzed using 1-way analysis of variance and Bonferroni post hoc tests (α=.05). RESULTS: High anterior smile line with gingival display >4 mm obtained significantly lower scores of <50 when combined with all upper lip curvatures (upward: 28.29 ±22.79, straight: 38.74 ±23.00, downward: 30.67 ±22.25, P<.01). High anterior smile lines with gingival display ≤4 mm combined with upward and straight upper lip curvature images obtained significantly higher scores, and all were ≥50 (upward: 63.24 ±22.22, straight: 61.40 ±21.58, P<.01). CONCLUSIONS: From a layperson's perspective, high anterior smile lines with gingival display >4 mm combined with any lip type were determined to be unattractive. If gingival display was ≤4 mm combined with both upward and straight lip types, the smile was assessed as attractive.

Role of the GLP2-Wnt1 axis in silicon-rich alkaline mineral water maintaining intestinal epithelium regeneration in piglets under early-life stress.

Stress-induced intestinal epithelial injury (IEI) and a delay in repair in infancy are predisposing factors for refractory gut diseases in adulthood, such as irritable bowel syndrome (IBS). Hence, it is necessary to develop appropriate mitigation methods for mammals when experiencing early-life stress (ELS). Weaning, as we all know, is a vital procedure that all mammalian newborns, including humans, must go through. Maternal separation (MS) stress in infancy (regarded as weaning stress in animal science) is a commonly used ELS paradigm. Drinking silicon-rich alkaline mineral water (AMW) has a therapeutic effect on enteric disease, but the specific mechanisms involved have not been reported. Herein, we discover the molecular mechanism by which silicon-rich AMW repairs ELS-induced IEI by maintaining intestinal stem cell (ISC) proliferation and differentiation through the glucagon-like peptide (GLP)2-Wnt1 axis. Mechanistic study showed that silicon-rich AMW activates GLP2-dependent Wnt1/ß-catenin pathway, and drives ISC proliferation and differentiation by stimulating Lgr5+ ISC cell cycle passage through the G1-S-phase checkpoint, thereby maintaining intestinal epithelial regeneration and IEI repair. Using GLP2 antagonists (GLP23-33) and small interfering RNA (SiWnt1) in vitro, we found that the GLP2-Wnt1 axis is the target of silicon-rich AMW to promote intestinal epithelium regeneration. Therefore, silicon-rich AMW maintains intestinal epithelium regeneration through the GLP2-Wnt1 axis in piglets under ELS. Our research contributes to understanding the mechanism of silicon-rich AMW promoting gut epithelial regeneration and provides a new strategy for the alleviation of ELS-induced IEI.