A unified classification system for HIV-1 5' long terminal repeats.

The HIV-1 provirus mainly consists of internal coding region flanked by 1 long terminal repeats (LTRs) at each terminus. The LTRs play important roles in HIV-1 reverse transcription, integration, and transcription. However, despite of the significant study advances of the internal coding regions of HIV-1 by using definite reference classification, there are no systematic and phylogenetic classifications for HIV-1 5' LTRs, which hinders our elaboration on 5' LTR and a better understanding of the viral origin, spread and therapy. Here, by analyzing all available resources of 5' LTR sequences in public databases following 4 recognized principles for the reference classification, 83 representatives and 14 consensus sequences were identified as representatives of 2 groups, 6 subtypes, 6 sub-subtypes, and 9 CRFs. To test the reliability of the supplemented classification system, the constructed references were applied to identify the 5' LTR assignment of the 22 clinical isolates in China. The results revealed that 16 out of 22 tested strains showed a consistent subtype classification with the previous LTR-independent classification system. However, 6 strains, for which recombination events within 5' LTR were demonstrated, unexpectedly showed a different subtype classification, leading a significant change of binding sites for important transcription factors including SP1, p53, and NF-κB. The binding change of these transcriptional factors would probably affect the transcriptional activity of 5' LTR. This study supplemented a unified classification system for HIV-1 5' LTRs, which will facilitate HIV-1 characterization and be helpful for both basic and clinical research fields.

Paleo-geomorphic features of pre-Jurassic and its oil-controlling effect in Wuqi-Dingbian area.

The Fuxian-Yan10 layers are the main oil-producing reservoirs of Jurassic in Wuqi-Dingbian area of Ordos Basin. However, due to the lack of understanding of the pattern and distribution characteristics of oil reservoirs, the benefits of exploration and development are restricted. In order to provide theoretical guidance for the study of similar geological features, based on the analysis of paleogeomorphic features and evolution, the analysis focuses on the influence of palaeo-geomorphology on oil reservoir distribution, and summarizes the main types of reservoir models in the study area. The results show that there are four types of palaeo-geomorphic units in the Wuding area: palaeo-river, slope, highland and interriver hill. In the study area, the Jurassic paleogeomorphology controls the sedimentary development and distribution from Fuxian Formation to Yan 9 Formation. The compacted structure and lithologic barrier provide good trapping conditions for the paleogeomorphic oil. Moreover, the swampy coal measures and mudstone at the top of Yan 9 play a sealing role for oil accumulation, and the bottom water was obviously driven. In addition, the pre-Jurassic deep valley was the main channels for oil migration. On this basis, it is concluded that there are four reservoir-forming models in Wuding area: slope type, river hill type, ancient river type and highland type.

Integrating IASLC grading and radiomics for predicting postoperative outcomes in stage IA invasive lung adenocarcinoma.

BACKGROUND: The International Association for the Study of Lung Cancer (IASLC) Pathology Committee introduced a histologic grading system for invasive lung adenocarcinoma (LUAD) in 2020. The IASLC grading system, hinging on the evaluation of predominant and high-grade histologic patterns, has proven to be practical and prognostic for invasive LUAD. However, there are still limitations in evaluating the prognosis of stage IA LUAD. Radiomics may serve as a valuable complement. PURPOSE: To establish a model that integrates IASLC grading and radiomics, aimed at predicting the prognosis of stage IA LUAD. METHODS: We conducted a retrospective analysis of 628 patients diagnosed with stage IA LUAD who underwent surgical resection between January 2015 and December 2018 at our institution. The patients were randomly divided into the training set (n = 439) and testing set (n = 189) at a ratio of 7:3. Overall survival (OS) and disease-free survival (DFS) were taken as the end points. Radiomics features were obtained by PyRadiomics. Feature selection was performed using the least absolute shrinkage and selection operator (LASSO). The prediction models for OS and DFS were developed using multivariate Cox regression analysis, and the models were visualized through nomogram plots. The model's performance was evaluated using area under the curves (AUC), concordance index (C-index), calibration curves, and survival decision curve analysis (DCA). RESULTS: In total, nine radiomics features were selected for the OS prediction model, and 15 radiomics features were selected for the DFS prediction model. Patients with high radiomics scores were associated with a worse prognosis (p < 0.001). We built separate prediction models using radiomics or IASLC alone, as well as a combined prediction model. In the prediction of OS, we observed that the combined model (C-index: 0.812 ± 0.024, 3 years AUC: 0.692, 5 years AUC: 0.792) achieved superior predictive performance than the radiomics (C-index: 0.743 ± 0.038, 3 years AUC: 0.633, 5 years AUC: 0.768) and IASLC grading (C-index: 0.765 ± 0.042, 3 years AUC: 0.658, 5 years AUC: 0.743) models alone. Similar results were obtained in the models for DFS. CONCLUSION: The combination of radiomics and IASLC pathological grading proves to be an effective approach for predicting the prognosis of stage IA LUAD. This has substantial clinical relevance in guiding treatment decisions for early-stage LUAD.

Dynamic performance of combined biochar from co-pyrolysis of pig manure with invasive weed: Effect of natural aging on Pb and As mobilization in polluted mining soil.

Due to the natural biochar aging, the improvement of soil quality and immobilization of soil pollutants achieved by biochar may change; understanding the dynamic evolution of the in situ performance of biochar in these roles is essential to discuss the long-term sustainability of biochar remediation. Therefore, in this study, combined biochar from co-pyrolysis of pig manure and invasive Japanese knotweed - P1J1, as well as pure pig manure - PM - and pure Japanese knotweed - JK - derived biochar were applied to investigate their remediation performance in a high As- and Pb-polluted soil with prolonged incubation periods (up to 360 days). Biochar application, especially P1J1 and PM, initially promoted soil pH, dissolved organic carbon, and EC, but the improvements were not constant through time. The JK-treated soil exhibited the highest increase of soil organic matter (OM), followed by P1J1 and then PM, and OM did not change with aging. Biochar, especially P1J1, was a comprehensive nutrient source of Ca, K, Mg, and P to improve soil fertility. However, while soluble cationic Ca, K, and Mg increased with time, anionic P decreased over time, indicating that continuous P availability might not be guaranteed with the aging process. The total microorganism content declined with time; adding biochars slowed down this tendency, which was more remarkable at the later incubation stage. Biochar significantly impeded soil Pb mobility but mobilized soil As, especially in PM- and P1J1-treated soils. However, mobilized As gradually re-fixed in the long run; meanwhile, the excellent Pb immobilization achieved by biochars was slightly reduced with time. The findings of this study offer fresh insights into the alterations in metal(loid)s mobility over an extended duration, suggesting that the potential mobilization risk of As is reduced while Pb mobility slightly increases over time.

[Inaugural Scalp Metastasis of Pulmonary Squamous Cell Carcinoma: 
A Rare Case Report and Literature Review].

Distant cutaneous metastasis of primary lung squamous cell carcinoma is an exceedingly rare event, with scalp metastasis as the initial clinical presentation even rarer. Scalp skin metastases are prone to be misdiagnosed as other scalp disorders, yet their appearance signifies the deterioration and poor prognosis of lung cancer. This case report documents a female patient presenting initially with scalp folliculitis in dermatology, who was subsequently diagnosed with malignant lung tumor through radiological imaging and referred to Department of Thoracic Surgery. Pathological examination of the excised lesion from the scalp revealed distant metastasis of lung cancer. A review of similar cases reported in literature was conducted. This article aims to enhance understanding and awareness of skin metastasis in lung cancer, to emphasize the importance of this condition, and to improve early recognition and precise diagnosis. It is crucial to prevent clinical misdiagnosis and ensure appropriate treatment, finally leading to improve the prognosis of the patients.
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Development and validation of a nomogram to predict postoperative delirium in older patients after major abdominal surgery: a retrospective case-control study.

BACKGROUND: Postoperative delirium is a common complication in older patients, with poor long-term outcomes. This study aimed to investigate risk factors and develop a predictive model for postoperative delirium in older patients after major abdominal surgery. METHODS: This study retrospectively recruited 7577 patients aged ≥ 65 years who underwent major abdominal surgery between January 2014 and December 2018 in a single hospital in Beijing, China. Patients were divided into a training cohort (n = 5303) and a validation cohort (n = 2224) for univariate and multivariate logistic regression analyses and to build a nomogram. Data were collected for 43 perioperative variables, including demographics, medical history, preoperative laboratory results, imaging, and anesthesia information. RESULTS: Age, chronic obstructive pulmonary disease, white blood cell count, glucose, total protein, creatinine, emergency surgery, and anesthesia time were associated with postoperative delirium in multivariate analysis. We developed a nomogram based on the above 8 variables. The nomogram achieved areas under the curve of 0.731 and 0.735 for the training and validation cohorts, respectively. The discriminatory ability of the nomogram was further assessed by dividing the cases into three risk groups (low-risk, nomogram score < 175; medium-risk, nomogram score 175~199; high-risk, nomogram score > 199; P < 0.001). Decision curve analysis revealed that the nomogram provided a good net clinical benefit. CONCLUSIONS: We developed a nomogram that could predict postoperative delirium with high accuracy and stability in older patients after major abdominal surgery.

Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells.

Background & Aims: Reactive oxygen species (ROS) act as modulators triggering cellular dysfunctions and organ damage including liver fibrosis in which hepatic stellate cell (HSC) activation plays a key role. Previous studies suggest that microRNA-144 (miR-144) acts as a pro-oxidant molecule; however, whether and how miR-144 affects HSC activation and liver fibrosis remain unknown. Methods: Carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced experimental liver fibrosis models were used. Hepatic miR-144 expression was analyzed by miRNA in situ hybridization with RNAscope probe. The in vivo effects of silencing or overexpressing miR-144 were examined with an adeno-associated virus 6 (AAV6) carrying miR-144 inhibitor or mimics in fibrotic mouse experimental models. Results: In this study, we demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro. Interestingly, miR-144 was preferentially elevated in HSCs of experimental liver fibrosis in mice and in human liver fibrotic tissues. Furthermore, in vivo loss or gain-of-function experiments via AAV6 carrying miR-144 antagomir or agomir revealed that blockade of miR-144 in HSCs mitigated, while overexpression of miR-144 in HSCs accelerated the development of experimental liver fibrosis. Mechanistically, SIN3 transcription regulator family member A (SIN3A), a transcriptional repressor, was identified to be the target of miR-144 in HSCs. MiR-144 downregulated Sin3A, and in line with this result, specific knockdown of Sin3a in HSCs remarkedly activated p38 MAPK signaling pathway to promote HSC activation, eventually exacerbating liver fibrosis. Conclusions: Oxidative stress-driven miR-144 fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis. Thus, a specific inhibition of miR-144 in HSCs could be a novel therapeutic strategy for the treatment of liver fibrosis.

Detoxification and Activating Blood Circulation Decoction Promotes Reendothelialization of Damaged Blood Vessels via VEGF Signaling Pathway Activation by miRNA-126.

The occurrence of in-stent restenosis (ISR) poses a significant challenge for percutaneous coronary intervention (PCI). Thus, the promotion of vascular reendothelialization is essential to inhibit endothelial proliferation. In this study, we clarified the mechanism by which Detoxification and Activating Blood Circulation Decoction (DABCD) promotes vascular reendothelialization to avoid ISR by miRNA-126-mediated modulation of the vascular endothelial growth factor (VEGF) signaling pathway. A rat model of post-PCI restenosis was established by balloon injury. The injured aortic segment was collected 14 and 28 d after model establishment. Our findings indicate that on the 14th and 28th days following balloon injury, DABCD reduced intimal hyperplasia and inflammation and promoted vascular reendothelialization. Additionally, DABCD markedly increased nitric oxide (NO) expression and significantly decreased ET-1 production in rat serum. DABCD also increased the mRNA level of endothelial nitric oxide synthase (eNOS) and the protein expression of VEGF, p-Akt, and p-extracellular signal-regulated kinase (ERK)1/2 in vascular tissue. Unexpectedly, the expression of miR-126a-5p mRNA was significantly lower in the aortic tissue of balloon-injured rats than in the aortic tissue of control rats, and higher miR-126a-5p levels were observed in the DABCD groups. The results of this study indicated that the vascular reendothelialization effect of DABCD on arterial intimal injury is associated with the inhibition of neointimal formation and the enhancement of vascular endothelial activity. More specifically, the effects of DABCD were mediated, at least in part, through miR-126-mediated VEGF signaling pathway activation.

Identification and validation of tryptophan metabolism-related lncRNAs in lung adenocarcinoma prognosis and immune response.

BACKGROUND: Tryptophan (Trp) is an essential amino acid. Increasing evidence suggests that tryptophan metabolism plays a complex role in immune escape from Lung adenocarcinoma (LUAD). However, the role of long non-coding RNAs (lncRNAs) in tryptophan metabolism remains to be investigated. METHODS: This study uses The Cancer Genome Atlas (TCGA)-LUAD dataset as the training cohort, and several datasets from the Gene Expression Omnibus (GEO) database are merged into the validation cohort. Genes related to tryptophan metabolism were identified from the Molecular Signatures Database (MSigDB) database and further screened for lncRNAs with Trp-related expression. Subsequently, a prognostic signature of lncRNAs related to tryptophan metabolism was constructed using Cox regression analysis, (Least absolute shrinkage and selection operator regression) and LASSO analysis. The predictive performance of this risk score was validated by Kaplan-Meier (KM) survival analysis, (receiver operating characteristic) ROC curves, and nomograms. We also explored the differences in immune cell infiltration, immune cell function, tumor mutational load (TMB), tumor immune dysfunction and exclusion (TIDE), and anticancer drug sensitivity between high- and low-risk groups. Finally, we used real-time fluorescence quantitative PCR, CCK-8, colony formation, wound healing, transwell, flow cytometry, and nude mouse xenotransplantation models to elucidate the role of ZNF8-ERVK3-1 in LUAD. RESULTS: We constructed 16 tryptophan metabolism-associated lncRNA prognostic models in LUAD patients. The risk score could be used as an independent prognostic indicator for the prognosis of LUAD patients. Kaplan-Meier survival analysis, ROC curves, and risk maps validated the prognostic value of the risk score. The high-risk and low-risk groups showed significant differences in phenotypes, such as the percentage of immune cell infiltration, immune cell function, gene mutation frequency, and anticancer drug sensitivity. In addition, patients with high-risk scores had higher TMB and TIDE scores compared to patients with low-risk scores. Finally, we found that ZNF8-ERVK3-1 was highly expressed in LUAD tissues and cell lines. A series of in vitro experiments showed that knockdown of ZNF8-ERVK3-1 inhibited cell proliferation, migration, and invasion, leading to cell cycle arrest in the G0/G1 phase and increased apoptosis. In vivo experiments with xenografts have shown that knocking down ZNF8-ERVK3-1 can significantly inhibit tumor size and tumor proliferation. CONCLUSION: We constructed a new prognostic model for tryptophan metabolism-related lncRNA. The risk score was closely associated with common clinical features such as immune cell infiltration, immune-related function, TMB, and anticancer drug sensitivity. Knockdown of ZNF8-ERVK3-1 inhibited LUAD cell proliferation, migration, invasion, and G0/G1 phase blockade and promoted apoptosis.

Sequence Note: Characterization of Two HIV-1 Strains with Novel Unique Recombinant Genome in Hebei, China.

In China, the proportion of HIV-1 infections due to men who have sex with men (MSM) has increased rapidly. More and more new subtypes are found among the MSM population besides known CRF01_AE, CRF07_BC, and B. The co-circulation of several HIV subtypes in the same population provides the opportunity to develop a new circulating recombinant form (CRF) and unique recombinant form (URF). Here we reported two new URFs from two HIV-1 positive subjects infected through homosexual contact in Hebei, China. Phylogenetic and recombinant analyses based on the near full-length genome (NFLG) of the two URFs are the second-generation recombinant strains that originated from B, CRF01_AE, and CRF07_BC. The CRF01_AE segments in the genome of two URFs originated from cluster 4 of CRF01_AE strains, while the CRF07_BC segments were clustered with 07BC_N in the phylogenetic tree. The emergence of the novel CRF01_AE/CRF07_BC and CRF01_AE/B recombinant forms indicated the importance of the continuous monitoring of the HIV-1 epidemic and new URFs among the MSM population.

Advancing musculoskeletal tumor diagnosis: Automated segmentation and predictive classification using deep learning and radiomics.

OBJECTIVES: Musculoskeletal (MSK) tumors, given their high mortality rate and heterogeneity, necessitate precise examination and diagnosis to guide clinical treatment effectively. Magnetic resonance imaging (MRI) is pivotal in detecting MSK tumors, as it offers exceptional image contrast between bone and soft tissue. This study aims to enhance the speed of detection and the diagnostic accuracy of MSK tumors through automated segmentation and grading utilizing MRI. MATERIALS AND METHODS: The research included 170 patients (mean age, 58 years ±12 (standard deviation), 84 men) with MSK lesions, who underwent MRI scans from April 2021 to May 2023. We proposed a deep learning (DL) segmentation model MSAPN based on multi-scale attention and pixel-level reconstruction, and compared it with existing algorithms. Using MSAPN-segmented lesions to extract their radiomic features for the benign and malignant classification of tumors. RESULTS: Compared to the most advanced segmentation algorithms, MSAPN demonstrates better performance. The Dice similarity coefficients (DSC) are 0.871 and 0.815 in the testing set and independent validation set, respectively. The radiomics model for classifying benign and malignant lesions achieves an accuracy of 0.890. Moreover, there is no statistically significant difference between the radiomics model based on manual segmentation and MSAPN segmentation. CONCLUSION: This research contributes to the advancement of MSK tumor diagnosis through automated segmentation and predictive classification. The integration of DL algorithms and radiomics shows promising results, and the visualization analysis of feature maps enhances clinical interpretability.

Systematic identification and characterization of exon-intron circRNAs.

Exon-intron circRNAs (EIciRNAs) are a circRNA subclass with retained introns. Global features of EIciRNAs remain largely unexplored, mainly owing to the lack of bioinformatic tools. The regulation of intron retention (IR) in EIciRNAs and the associated functionality also require further investigation. We developed a framework, FEICP, which efficiently detected EIciRNAs from high-throughput sequencing (HTS) data. EIciRNAs are distinct from exonic circRNAs (EcircRNAs) in aspects such as with larger length, localization in the nucleus, high tissue specificity, and enrichment mostly in the brain. Deep learning analyses revealed that compared with regular introns, the retained introns of circRNAs (CIRs) are shorter in length, have weaker splice site strength, and have higher GC content. Compared with retained introns in linear RNAs (LIRs), CIRs are more likely to form secondary structures and show greater sequence conservation. CIRs are closer to the 5'-end, whereas LIRs are closer to the 3'-end of transcripts. EIciRNA-generating genes are more actively transcribed and associated with epigenetic marks of gene activation. Computational analyses and genome-wide CRISPR screening revealed that SRSF1 binds to CIRs and inhibits the biogenesis of most EIciRNAs. SRSF1 regulates the biogenesis of EIciLIMK1, which enhances the expression of LIMK1 in cis to boost neuronal differentiation, exemplifying EIciRNA physiological function. Overall, our study has developed the FEICP pipeline to identify EIciRNAs from HTS data, and reveals multiple features of CIRs and EIciRNAs. SRSF1 has been identified to regulate EIciRNA biogenesis. EIciRNAs and the regulation of EIciRNA biogenesis play critical roles in neuronal differentiation.

Heterosis of endophytic microbiomes in hybrid rice varieties improves seed germination.

Seed endophytic microbiomes are shaped by host and environmental factors and play a crucial role in their host growth and health. Studies have demonstrated that host genotype, including hybridization, affects seed microbiomes. Heterosis features are also observed in root-associated microbiomes. It remains unclear, however, whether heterosis exists in seed endophytic microbiomes and whether hybrid microbiota provide noticeable advantages to host plant growth, especially to seed germination. Here, we investigated the structure of seed endophytic bacterial and fungal communities from three hybrid rice varieties and their respective parents using amplicon sequencing targeting 16S rRNA and ITS2 genes. Heterosis was found in diversity and composition of seed endophytic microbiomes in hybrids, which hosted more diverse communities and significantly higher abundances of plant growth-promoting taxa, such as Pseudomonas and Rhizobium genera compared with their parental lines. Co-occurrence network analysis revealed that there are potentially tighter microbial interactions in the hybrid seeds compared with their parent seeds. Finally, inoculation of seed-cultivable endophytes, isolated from hybrids, resulted in a greater promotion of seed germination compared with those isolated from parent lines. These findings suggest that heterosis exists not only in plant traits but also in seed endophytic microbiota, the latter in turn promotes seed germination, which offers valuable guidance for microbiome-assisted rice breeding.IMPORTANCEGenetic and physiological changes associated with plant hybridization have been studied for many crop species. Still, little is known about the impact of hybridization on the seed microbiota. In this study, we indicate that hybridization has a significant impact on the endophytic bacterial and fungal communities in rice seeds. The seed endophytic microbiomes of hybrids displayed distinct characteristics from those of their parental lines and exhibited potential heterosis features. Furthermore, the inoculation of seed-cultivable endophytes isolated from hybrids exhibited a greater promotion effect on seed germination compared with those isolated from the parents. Our findings make a valuable contribution to the emerging field of microbiome-assisted plant breeding, highlighting the potential for a targeted approach that aims to achieve not only desired plant traits but also plant-beneficial microbial communities on the seeds.

Metabolic characterization of sphere-derived prostate cancer stem cells reveals aberrant urea cycle in stemness maintenance.

Alteration of cell metabolism is one of the essential characteristics of tumor growth. Cancer stem cells (CSCs) are the initiating cells of tumorigenesis, proliferation, recurrence, and other processes, and play an important role in therapeutic resistance and metastasis. Thus, identification of the metabolic profiles in prostate cancer stem cells (PCSCs) is critical to understanding prostate cancer progression. Using untargeted metabolomics and lipidomics methods, we show distinct metabolic differences between prostate cancer cells and PCSCs. Urea cycle is the most significantly altered metabolic pathway in PCSCs, the key metabolites arginine and proline are evidently elevated. Proline promotes cancer stem-like characteristics via the JAK2/STAT3 signaling pathway. Meanwhile, the enzyme pyrroline-5-carboxylate reductase 1 (PYCR1), which catalyzes the conversion of pyrroline-5-carboxylic acid to proline, is highly expressed in PCSCs, and the inhibition of PYCR1 suppresses the stem-like characteristics of prostate cancer cells and tumor growth. In addition, carnitine and free fatty acid levels are significantly increased, indicating reprogramming of fatty acid metabolism in PCSCs. Reduced sphingolipid levels and increased triglyceride levels are also observed. Collectively, our data illustrate the comprehensive landscape of the metabolic reprogramming of PCSCs and provide potential therapeutic strategies for prostate cancer.

Dysregulations of amino acid metabolism and lipid metabolism in urine of children and adolescents with major depressive disorder: a case-control study.

RATIONALE: The mechanisms underlying major depressive disorder (MDD) in children and adolescents are unclear. Metabolomics has been utilized to capture metabolic signatures of various psychiatric disorders; however, urinary metabolic profile of MDD in children and adolescents has not been studied. OBJECTIVES: We analyzed urinary metabolites in children and adolescents with MDD to identify potential biomarkers and metabolic signatures. METHODS: Here, liquid chromatography-mass spectrometry was used to profile metabolites in urine samples from 192 subjects, comprising 80 individuals with antidepressant-naïve MDD (AN-MDD), 37 with antidepressant-treated MDD (AT-MDD) and 75 healthy controls (HC). We performed orthogonal partial least squares discriminant analysis to identify differential metabolites and employed logistic regression and receiver operating characteristic analysis to establish a diagnostic panel. RESULTS: In total, 143 and 71 differential metabolites were identified in AN-MDD and AT-MDD, respectively. These were primarily linked to lipid metabolism, molecular transport, and small molecule biochemistry. AN-MDD additionally exhibited dysregulated amino acid metabolism. Compared to HC, a diagnostic panel of seven metabolites displayed area under the receiver operating characteristic curves of 0.792 for AN-MDD, 0.828 for AT-MDD, and 0.799 for all MDD. Furthermore, the urinary metabolic profiles of children and adolescents with MDD significantly differed from those of adult MDD. CONCLUSIONS: Our research suggests dysregulated amino acid metabolism and lipid metabolism in the urine of children and adolescents with MDD, similar to results in plasma metabolomics studies. This contributes to the comprehension of mechanisms underlying children and adolescents with MDD.

Replenishment of mitochondrial Na+ and H+ by ionophores potentiates cutaneous wound healing in diabetes.

Diabetic foot ulcer (DFU) is a highly morbid complication in patients with diabetes mellitus, necessitating the development of innovative pharmaceuticals to address unmet medical needs. Sodium ion (Na+) is a well-established mediator for membrane potential and osmotic equilibrium. Recently, Na+ transporters have been identified as a functional regulator of regeneration. However, the role of Na+ in the intricate healing process of mammalian wounds remains elusive. Here, we found that the skin wounds in hyponatremic mice display a hard-to-heal phenotype. Na+ ionophores that were employed to increase intracellular Na+ content could facilitate keratinocyte proliferation and migration, and promote angiogenesis, exhibiting diverse biological activities. Among of them, monensin A emerges as a promising agent for accelerating the healing dynamics of skin wounds in diabetes. Mechanistically, the elevated mitochondrial Na+ decelerates inner mitochondrial membrane fluidity, instigating the production of reactive oxygen species (ROS), which is identified as a critical effector on the monensin A-induced improvement of wound healing. Concurrently, Na+ ionophores replenish H+ to the mitochondrial matrix, causing an enhancement of mitochondrial energy metabolism to support productive wound healing programs. Our study unfolds a new role of Na+, which is a pivotal determinant in wound healing. Furthermore, it directs a roadmap for developing Na+ ionophores as innovative pharmaceuticals for treating chronic dermal wounds in diabetic patients.

Machine Learning Applied to Electron Beam Lithography to Accelerate Process Optimization of a Contact Hole Layer.

Determining the lithographic process conditions with high-resolution patterning plays a crucial role in accelerating chip manufacturing. However, lithography imaging is an extremely complex nonlinear system, and obtaining suitable process conditions requires extensive experimental attempts. This severely creates a bottleneck in optimizing and controlling the lithographic process conditions. Herein, we report a process optimization solution for a contact layer of metal oxide nanoparticle photoresists by combining electron beam lithography (EBL) experiments with machine learning. In this solution, a long short-term memory (LSTM) network and a support vector machine (SVM) model are used to establish the contact hole imaging and process condition classification models, respectively. By combining SVM with the LSTM network, the process conditions that simultaneously satisfy the requirements of the contact hole width and local critical dimension uniformity tolerance can be screened. The verification results demonstrate that the horizontal and vertical contact widths predicted by the LSTM network are highly consistent with the EBL experimental results, and the classification model shows good accuracy, providing a reference for process optimization of a contact layer.

Discovery of ganoderic acid A (GAA) PROTACs as MDM2 protein degraders for the treatment of breast cancer.

Breast cancer is one of the most common female malignant tumors, with triple-negative breast cancer (TNBC) being the most specific, highly invasive, metastatic and associated with a poor prognosis. Our previous study showed that the natural product ganoderic acid A (GAA) has a certain affinity for MDM2. In this study, two series of novel GAA PROTACs C1-C10 and V1-V10 were designed and synthesized for the treatment of breast cancer. The antitumor activity of these compounds was evaluated against four human tumor cell lines (MCF-7, MDA-MB-231, SJSA-1, and HepG2). Among them, V9 and V10 showed stronger anti-proliferative effects against breast cancer cells, and V10 showed the best selectivity in MDA-MB-231 cells (TNBC), which was 5-fold higher than that of the lead compound GAA. Preliminary structure-activity analysis revealed that V-series GAA PROTACs had better effects than C-series, and the introduction of 2O-4O PEG linkers could significantly improve the antitumor activity. Molecular docking, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and Western blot researches showed that both V9 and V10 could bind with MDM2, and degrade the protein through the ubiquitin-proteasome system. Molecular dynamics simulation (MD) revealed that V10 is a bifunctional molecule that can bind to von Hippel-Lindau (VHL) at one end and target MDM2 at the other. In addition, V10 promoted the upregulation of p21 in p53-mutant MDA-MB-231 cells, and induced apoptosis via down-regulation of the bcl-2/bax ratio and the expression of cyclin B1. Finally, in vivo experiments showed that, V10 also exhibited good tumor inhibitory activity in xenografted TNBC zebrafish models, with an inhibition rate of 27.2% at 50 µg/mL. In conclusion, our results suggested that V10 has anti-tumor effects on p53-mutant breast cancer in vitro and in vivo, and may be used as a novel lead compound for the future development of TNBC.

New insights into pterosaur cranial anatomy: X-ray imaging reveals palatal structure and evolutionary trends.

Among the least studied portion of the pterosaur skeleton is the palate, which tends to be poorly preserved and commonly only visible from one side (the ventral portion). Even in well-preserved specimens, the bones tend to be fused, with the limits of individual palatal elements obscured. To shed new light on this region, we employed advanced X-ray imaging techniques on the non-pterodactyloid Kunpengopterus (Wukongopteridae), and the pterodactyloids Dsungaripterus (Dsungaripteridae), Hongshanopterus (Istiodactylidae), and Hamipterus (Hamipteridae). Our analyses revealed the presence of sutures between palatal bones in Dsungaripterus and Kunpengopterus, which resulted in different interpretations of the relation between palatine, ectopterygoid, and pterygoid, leading to a new identification of the palatal openings. Furthermore, our study shows six main observations such as the variation of the angle between the palatine rami and the variation in the relative sizes of the palatal openings. We also point out that the presence of a maxillopalatine fenestra (previously identified as postpalatine fenestra), is unique within Diapsida. Although much more work needs to be done, we showed that advanced X-ray imaging techniques open a window for understanding pterosaur cranial anatomy and provide a new perspective for investigating the evolutionary history of these flying reptiles.