Integrated Dual-Channel Retrograde Signaling Directs Stress Responses by Degrading the HAT1/TPL/IMPα-9 Suppressor Complex and Activating CAMTA3.

The intricate communication between plastids and the nucleus, shaping stress-responsive gene expression, has long intrigued researchers. This study combines genetics, biochemical analysis, cellular biology, and protein modeling to uncover how the plastidial metabolite MEcPP activates the stress-response regulatory hub known as the Rapid Stress Response Element (RSRE). Specifically, we identify the HAT1/TPL/IMPα- 9 suppressor complex, where HAT1 directly binds to RSRE and its activator, CAMTA3, masking RSRE and sequestering the activator. Stress-induced MEcPP disrupts this complex, exposing RSRE and releasing CAMTA3, while enhancing Ca 2+ influx and raising nuclear Ca 2+ levels crucial for CAMTA3 activation and the initiation of RSRE- containing gene transcription. This coordinated breakdown of the suppressor complex and activation of the activator highlights the dual-channel role of MEcPP in plastid-to- nucleus signaling. It further signifies how this metabolite transcends its expected biochemical role, emerging as a crucial initiator of harmonious signaling cascades essential for maintaining cellular homeostasis under stress. Summary: This study uncovers how the stress-induced signaling metabolite MEcPP disrupts the HAT1/TPL/IMPα-9 suppressor complex, liberating the activator CAMTA3 and enabling Ca 2+ influx essential for CAMTA3 activation, thus orchestrating stress responses via repressor degradation and activator induction.

An updated resource for the detection of protein-coding circRNA with CircProPlus.

Protein-encoding circular RNAs (circRNAs) are newly identified RNA molecules characterized by intense interaction with translating ribosome. Emerging evidence has implicated physiological and pathological significance of these non-canonical RNAs, yet a large body of them remains unidentified. Due to limited tools at hand, we developed CircProPlus, an automated computational pipeline for de novo detection of translated circRNAs. In comparison to previously established CircPro, CircProPlus adjusts the overall workflow and integrates more robust implements for achieving easier accessibility, higher flexibility and productivity. In present study, we tested the performance of CircProPlus when using different circRNA-detecting implements (i.e., CIRI2, CirComPara2) in the evaluation of coding ability of circRNAs. Results showed that CirComPara2, a state-of-the-art algorithm, consistently outperformed CIRI2 when coupled with CircProPlus in testing real data collected from different RNA libraries and species, which highlighted its potency in data mining of circRNAs with protein-coding potential.

Clinical pathological significance and biological function of PLIN1 in hepatocellular carcinoma: bioinformatics analysis and in vitro experiments.

BACKGROUND & AIMS: Perilipin 1 (PLIN1) is an essential lipid droplet surface protein that participates in cell life activities by regulating energy balance and lipid metabolism. PLIN1 has been shown to be closely related to the development of numerous tumor types. The purpose of this work was to elucidate the clinicopathologic significance of PLIN1 in hepatocellular carcinoma (HCC), as well as its impact on the biological functions of HCC cells, and to investigate the underlying mechanisms involved. METHODS: Public high-throughput RNA microarray and RNA sequencing data were collected to examine PLIN1 levels and clinical significance in patients with HCC. Immunohistochemistry (IHC) and real-time quantitative reverse transcription polymerase chain reaction (RT‒qPCR) were conducted to assess the expression levels and the clinicopathological relevance of PLIN1 in HCC. Then, SK and Huh7 cells were transfected with a lentivirus overexpressing PLIN1. CCK8 assay, wound healing assay, transwell assay, and flow cytometric analysis were conducted to explore the effects of PLIN1 overexpression on HCC cell proliferation, migration, invasion, and cell cycle distribution. Ultimately, Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to investigate the underlying mechanisms of PLIN1 in HCC progression based on HCC differentially expressed genes and PLIN1 co-expressed genes. RESULTS: PLIN1 was markedly downregulated in HCC tissues, which correlated with a noticeably worse prognosis for HCC patients. Additionally, PLIN1 overexpression inhibited the proliferation, migration, and invasion of SK and Huh7 cells in vitro, as well as arresting the HCC cell cycle at the G0/G1 phase. More significantly, energy conversion-related biological processes, lipid metabolism, and cell cycle signalling pathways were the three most enriched molecular mechanisms. CONCLUSION: The present study revealed that PLIN1 downregulation is associated with poor prognosis in HCC patients and accelerated HCC progression by promoting cellular proliferation, migration, and metastasis, as well as the mechanisms underlying the regulation of lipid metabolism-related pathways in HCC.

Activation of stress-response genes by retrograde signaling-mediated destabilization of nuclear importin IMPα-9 and its interactor TPR2.

Stress-induced retrograde signal transmission from the plastids to the nucleus has long puzzled plant biologists. To address this, we performed a suppressor screen of the ceh1 mutant, which contains elevated 2-C-methyl-d-erythritol-2,4-cyclopyrophosphate (MEcPP) levels, and identified the gain-of-function mutant impα-9, which shows reversed dwarfism and suppressed expression of stress-response genes in the ceh1 background despite heightened MEcPP. Subsequent genetic and biochemical analyses established that the accumulation of MEcPP initiates an upsurge in Arabidopsis SKP1-like 1 (ASK1) abundance, a pivotal component in the proteasome degradation pathway. This increase in ASK1 prompts the degradation of IMPα-9. Moreover, we uncovered a protein-protein interaction between IMPα-9 and TPR2, a transcriptional co-suppressor and found that a reduction in IMPα-9 levels coincides with a decrease in TPR2 abundance. Significantly, the interaction between IMPα-9 and TPR2 was disrupted in impα-9 mutants, highlighting the critical role of a single amino acid alteration in maintaining their association. Disruption of their interaction results in the reversal of MEcPP-associated phenotypes. Chromatin immunoprecipitation coupled with sequencing analyses revealed that TPR2 binds globally to stress-response genes and suggested that IMPα-9 associates with the chromatin. They function together to suppress the expression of stress-response genes under normal conditions, but this suppression is alleviated in response to stress through the degradation of the suppressing machinery. The biological relevance of our discoveries was validated under high light stress, marked by MEcPP accumulation, elevated ASK1 levels, IMPα-9 degredation, reduced TPR2 abundance, and subsequent activation of a network of stress-response genes. In summary, our study collectively unveils fresh insights into plant adaptive mechanisms, highlighting intricate interactions among retrograde signaling, the proteasome, and nuclear transport machinery.

Time-Restricted Feeding Attenuates Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma in Obese Male Mice.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has surpassed the hepatitis B virus and hepatitis C virus as the leading cause of chronic liver disease in most parts of the Western world. MASLD (formerly known as NAFLD) encompasses both simple steatosis and more aggressive metabolic dysfunction-associated steatohepatitis (MASH), which is accompanied by inflammation, fibrosis, and cirrhosis, and ultimately can lead to hepatocellular carcinoma (HCC). There are currently very few approved therapies for MASH. Weight loss strategies such as caloric restriction can ameliorate the harmful metabolic effect of MASH and inhibit HCC; however, it is difficult to implement and maintain in daily life, especially in individuals diagnosed with HCC. In this study, we tested a time-restricted feeding (TRF) nutritional intervention in mouse models of MASH and HCC. We show that TRF abrogated metabolic dysregulation induced by a Western diet without any calorie restriction or weight loss. TRF improved insulin sensitivity and reduced hyperinsulinemia, liver steatosis, inflammation, and fibrosis. Importantly, TRF inhibited liver tumors in two mouse models of obesity-driven HCC. Our data suggest that TRF is likely to be effective in abrogating MASH and HCC and warrant further studies of time-restricted eating in humans with MASH who are at higher risk of developing HCC.

Loureirin A is a narrow-spectrum antimicrobial agent against Helicobacter pylori.

Currently, Helicobacter pylori eradication by antibiotic therapy faces various challenges, including antibiotic resistance, side effects on intestinal commensal bacteria, and patient compliance. In this study, loureirin A (LrA), a traditional Chinese medicine monomer extracted from Sanguis Draconis flavones, was found to possess specific antibacterial activity against H. pylori without the bacteria displaying a tendency to develop resistance in vitro. LrA demonstrated a synergistic or additive effect when combined with omeprazole (a proton pump inhibitor) against H. pylori. The combination of LrA and omeprazole showed promising anti-H. pylori potential, exhibiting notable in vivo efficacy comparable to standard triple therapy in mouse models infected with both drug-sensitive and drug-resistant H. pylori strains. Moreover, the narrow-spectrum antibacterial profile of LrA is reflected in its minimal effect on the diversity and composition of the mouse gut microbiota. The underlying mechanism of action of LrA against H. pylori involves the generation of bactericidal levels of reactive oxygen species, resulting in apoptosis-like cell death. These findings indicate that LrA is a promising lead compound targeting H. pylori without harming the commensal bacteria.

Optomechanical Microwave-to-Optical Photon Transducer Chips: Empowering the Quantum Internet Revolution.

The first quantum revolution has brought us the classical Internet and information technology. Today, as technology advances rapidly, the second quantum revolution quietly arrives, with a crucial moment for quantum technology to establish large-scale quantum networks. However, solid-state quantum bits (such as superconducting and semiconductor qubits) typically operate in the microwave frequency range, making it challenging to transmit signals over long distances. Therefore, there is an urgent need to develop quantum transducer chips capable of converting microwaves into optical photons in the communication band, since the thermal noise of optical photons at room temperature is negligible, rendering them an ideal information carrier for large-scale spatial communication. Such devices are important for connecting different physical platforms and efficiently transmitting quantum information. This paper focuses on the fast-developing field of optomechanical quantum transducers, which has flourished over the past decade, yielding numerous advanced achievements. We categorize transducers based on various mechanical resonators and discuss their principles of operation and their achievements. Based on existing research on optomechanical transducers, we compare the parameters of several mechanical resonators and analyze their advantages and limitations, as well as provide prospects for the future development of quantum transducers.

The role of iron-rich hydrosaline liquids in the formation of Kiruna-type iron oxide-apatite deposits.

Kiruna-type iron oxide-apatite (IOA) deposits, an important source of iron, show close associations with andesitic subvolcanic intrusions. However, the processes of ore formation and the mechanism controlling iron concentration remain uncertain. Here, we report the widespread presence of high-temperature (>800°C) water-poor multisolid hydrosaline liquid inclusions in pre- and syn-ore minerals from IOA deposits of eastern China. These inclusions consistently homogenize to a liquid phase by vapor disappearance and mostly contain 3 to 10 wt % Fe, signifying a substantial capacity for iron transportation by such hydrosaline liquids. We propose that the hydrosaline liquids were likely immiscible from the dioritic magmas with high Cl/H2O in subvolcanic settings. Subsequent reaction with host rocks and/or decompression and cooling of the hydrosaline liquids is deemed responsible for the simultaneous formation of high-temperature alteration and magnetite ores, thereby providing important insights into the distinctive characteristics of IOA deposits in shallow magmatic-hydrothermal systems.

Evaluating the potency of zoliflodacin against Helicobacter pylori: In vitro activity and conserved GyrB target.

BACKGROUND: The current standard treatment for Helicobacter pylori infection, which involves a combination of two broad-spectrum antibiotics, faces significant challenges due to its detrimental impact on the gut microbiota and the emergence of drug-resistant strains. This underscores the urgent requirement for the development of novel anti-H. pylori drugs. Zoliflodacin, a novel bacterial gyrase inhibitor, is currently undergoing global phase III clinical trials for treating uncomplicated Neisseria gonorrhoeae. However, there is no available data regarding its activity against H. pylori. MATERIALS AND METHODS: We evaluated the in vitro activity of zoliflodacin against H. pylori clinical isolates (n = 123) with diverse multidrug resistance. We performed DNA gyrase supercoiling and microscale thermophoresis assays to identify the target of zoliflodacin in H. pylori. We analyzed 2262 H. pylori whole genome sequences to identify Asp424Asn and Lys445Asn mutations in DNA gyrase subunit B (GyrB) that are associated with zoliflodacin resistance. RESULTS: Zoliflodacin exhibits potent activity against all tested isolates, with minimal inhibitory concentration (MIC) values ranging from 0.008 to 1 µg/mL (MIC50: 0.125 µg/mL; MIC90: 0.25 µg/mL). Importantly, there was no evidence of cross-resistance to any of the four first-line antibiotics commonly used against H. pylori. We identified GyrB as the primary target of zoliflodacin, with Asp424Asn or Lys445Asn substitutions conferring resistance. Screening of 2262 available H. pylori genomes for the two mutations revealed only one clinical isolate carrying Asp424Asn substitution. CONCLUSION: These findings support the potential of zoliflodacin as a promising candidate for H. pylori treatment, warranting further development and evaluation.

The fertility-sparing treatment and outcome of epithelioid trophoblastic tumor isolated to lung: a case report and review literature.

Background: Epithelioid trophoblastic tumor (ETT) is the rarest gestational trophoblastic tumor, with poor response to chemotherapy. Hysterectomy, as the cornerstone therapy for early ETT, is particularly challenging in reproductive-age women who often have a strong desire for fertility preservation. The management of extra-uterine ETT could be even more complicated and inconsistent. Here we reported a case of isolated ETT lesions in lungs managed with thoracic surgery without hysterectomy. Case presentation: A 32-year-old woman presented with amenorrhea for 2 months. Her serum ß- human chorionic gonadotropin (hCG) levels fluctuated between 52 and 75 mIU/mL. The patient underwent removal of intrauterine device and suction and curettage, but only proliferative endometrium was found. Methotrexate was given for a provisional diagnosis of ectopic pregnancy of unknown location, while ß-hCG had no significant decline. She complained of mild chest pain during the past half year, and the chest computed tomography (CT) result showed two mixed ground-glass nodules of 24 mm × 14.2 mm in right upper lobe and 10 mm × 8 mm in the right lower lobe and a thin-walled cavity in the posterior segment of the left lower lobe. Right upper wedge resection and right lower segmentectomy were performed 3 months later. The result of the pathological examination of pulmonary mass indicated an epithelioid trophoblastic tumor. She was diagnosed with ETT at stage III (with right lung metastasis) according to FIGO 2000. Her menstrual cycle recovered within 1 month after the first thoracic surgery. However, ß-hCG was elevated again to 9 mIU/mL, and the positron emission tomography/computed tomography (PET/CT) scans revealed the consolidation of the nodule in the left lower lobe which enlarged to about 1.0 cm × 1.7 cm. Her second pulmonary surgery without hysterectomy was conducted. Followed for 12 months for postoperative monitoring, the patient was found to be disease-free with negative results of serial serum ß-hCG and chest CT. Conclusion: Our case highlights the efficacy of fertility-sparing surgery for isolated ETT in lungs. The surgical management of pulmonary isolated ETT could be individualized under long-term supervision. Sporadic reports on the favorable outcome of extra-uterine ETT with fertility-sparing surgery were described in the last decades. The safety of this surgical strategy might be warranted only if enough reliable data is accumulated.

Nisin and ε-polylysine combined treatment enhances quality of fresh-cut jackfruit at refrigerated storage.

This study investigated the effects of nisin combined with ε-polylysine on microorganisms and the refrigerated quality of fresh-cut jackfruit. After being treated with distilled water (control), nisin (0.5 g/L), ε-polylysine (0.5 g/L), and the combination of nisin (0.1 g/L) and ε-polylysine (0.4 g/L), microporous modified atmosphere packaging (MMAP) was carried out and stored at 10 ± 1°C for 8 days. The microorganisms and physicochemical indexes were measured every 2 days during storage. The results indicated that combined treatment (0.1 g/L nisin, 0.4 g/L ε-polylysine) had the best preservation on fresh-cut jackfruit. Compared with the control, combined treatment inhibited microbial growth (total bacterial count, mold and yeast), reduced the weight loss rate, respiratory intensity, polyphenol oxidase and peroxidase activities, and maintained higher sugar acid content, firmness, and color. Furthermore, it preserved higher levels of antioxidant compounds, reduced the accumulation of malondialdehyde and hydrogen peroxide, thereby reducing oxidative damage and maintaining high nutritional and sensory qualities. As a safe application of natural preservatives, nisin combined with ε-polylysine treatment has great application potential in the fresh-cut jackfruit industry.

Re-analysis of single-cell transcriptomics reveals a critical role of macrophage-like smooth muscle cells in advanced atherosclerotic plaque.

Aims: Smooth muscle cell (SMC) remodeling poses a critical feature in the development and progression of atherosclerosis. Although fate mapping and in silicon approaches have expanded SMC phenotypes in atherosclerosis, it still remains elusive about the contributions of individual SMC phenotypes and molecular dynamics to advanced atherosclerotic plaque. Methods: Using single-cell transcriptome, we investigated cellular compositions of human carotid plaque laden with atherosclerotic core, followed by in vivo experiments utilizing SMC-lineage tracing technology, bulk RNA sequencing (RNA-seq) and both in vivo and in vitro validation of the underlying molecular mechanism. Results: 5 functionally distinct SMC subtypes were uncovered based on transcriptional features (described as contractile, fibroblast-like, osteogenic, synthetic and macrophage-like) within the niche. A proinflammatory, macrophage-like SMC subtype displaying an intermediary phenotype between SMC and macrophage, exhibits prominent potential in destabilizing plaque. At the molecular level, we explored cluster-specific master regulons by algorithm, and identified interferon regulatory factor-8 (IRF8) as a potential stimulator of SMC-to-macrophage transdifferentiation via activating nuclear factor-κB (NF-κB) signaling. Conclusions: Our study illustrates a comprehensive cell atlas and molecular landscape of advanced atherosclerotic lesion, which might renovate current understanding of SMC biology in atherosclerosis.

Analysis of Individualized Silicone Rubber Bolus Using Fan Beam Computed Tomography in Postmastectomy Radiotherapy: A Dosimetric Evaluation and Skin Acute Radiation Dermatitis Survey.

Objective: To investigate the dosimetric effects of using individualized silicone rubber (SR) bolus on the target area and organs at risk (OARs) during postmastectomy radiotherapy (PMRT), as well as evaluate skin acute radiation dermatitis (ARD). Methods: A retrospective study was performed on 30 patients with breast cancer. Each patient was prepared with an individualized SR bolus of 3 mm thickness. Fan-beam computed tomography (FBCT) was performed at the first and second fractions, and then once a week for a total of 5 times. Dosimetric metrics such as homogeneity index (HI), conformity index (CI), skin dose (SD), and OARs including the heart, lungs, and spinal cord were compared between the original plan and the FBCTs. The acute side effects were recorded. Results: In targets' dosimetric metrics, there were no significant differences in Dmean and V105% between planning computed tomography (CT) and actual treatments (P > .05), while the differences in D95%, V95%, HI, and CI were statistically significant (P < .05). In OARs, there were no significant differences between the Dmean, V5, and V20 of the affected lung, V5 of the heart and Dmax of the spinal cord (P > .05) except the V30 of affected lung, which was slightly lower than the planning CT (P < .05). In SD, both Dmax and Dmean in actual treatments were increased than plan A, and the difference was statistically significant (P < .05), while the skin-V20 and skin-V30 has no difference. Among the 30 patients, only one patient had no skin ARD, and 5 patients developed ARD of grade 2, while the remaining 24 patients were grade 1. Conclusion: The OR bolus showed good anastomoses and high interfraction reproducibility with the chest wall, and did not cause deformation during irradiation. It ensured accurate dose delivery of the target and OARs during the treatment, which may increase SD by over 101%. In this study, no cases of grade 3 skin ARD were observed. However, the potential of using OR bolus to reduce grade 1 and 2 skin ARD warrants further investigation with a larger sample size.

U2-Net and ResNet50-Based Automatic Pipeline for Bacterial Colony Counting.

In this paper, an automatic colony counting system based on an improved image preprocessing algorithm and convolutional neural network (CNN)-assisted automatic counting method was developed. Firstly, we assembled an LED backlighting illumination platform as an image capturing system to obtain photographs of laboratory cultures. Consequently, a dataset was introduced consisting of 390 photos of agar plate cultures, which included 8 microorganisms. Secondly, we implemented a new algorithm for image preprocessing based on light intensity correction, which facilitated clearer differentiation between colony and media areas. Thirdly, a U2-Net was used to predict the probability distribution of the edge of the Petri dish in images to locate region of interest (ROI), and then threshold segmentation was applied to separate it. This U2-Net achieved an F1 score of 99.5% and a mean absolute error (MAE) of 0.0033 on the validation set. Then, another U2-Net was used to separate the colony region within the ROI. This U2-Net achieved an F1 score of 96.5% and an MAE of 0.005 on the validation set. After that, the colony area was segmented into multiple components containing single or adhesive colonies. Finally, the colony components (CC) were innovatively rotated and the image crops were resized as the input (with 14,921 image crops in the training set and 4281 image crops in the validation set) for the ResNet50 network to automatically count the number of colonies. Our method achieved an overall recovery of 97.82% for colony counting and exhibited excellent performance in adhesion classification. To the best of our knowledge, the proposed "light intensity correction-based image preprocessing→U2-Net segmentation for Petri dish edge→U2-Net segmentation for colony region→ResNet50-based counting" scheme represents a new attempt and demonstrates a high degree of automation and accuracy in recognizing and counting single-colony and multi-colony targets.

Upregulation of CoQ shifts ferroptosis dependence from GPX4 to FSP1 in acquired radioresistance.

Acquired radioresistance is the primary contributor to treatment failure of radiotherapy, with ferroptosis is identified as a significant mechanism underlying cell death during radiotherapy. Although resistance to ferroptosis has been observed in both clinical samples of radioresistant cells and cell models, its mechanism remains unidentified. Herein, our investigation revealed that radioresistant cells exhibited greater tolerance to Glutathione Peroxidase 4 (GPX4) inhibitors and, conversely, increased sensitivity to ferroptosis suppressor protein 1 (FSP1) inhibitors compared to their sensitive counterparts. This observation suggested that FSP1 might play a dominant role in the development of radioresistance. Notably, the knockout of FSP1 demonstrated considerably superior efficacy in resensitizing cells to radiotherapy compared to the knockout of GPX4. To elucidate the driving force behind this functional shift, we conducted a metabolomic assay, which revealed an upregulation of Coenzyme Q (CoQ) synthesis and a downregulation of glutathione synthesis in the acquired radioresistance cells. Mechanistically, CoQ synthesis was found to be supported by aarF domain containing kinase 3-mediated phosphorylation of CoQ synthases, while the downregulation of Solute carrier family 7 member 11 led to decreased glutathione synthesis. Remarkably, our retrospective analysis of clinical response data further validated that the additional administration of statin during radiotherapy, which could impede CoQ production, effectively resensitized radioresistant cells to radiation. In summary, our findings demonstrate a dependency shift from GPX4 to FSP1 driven by altered metabolite synthesis during the acquisition of radioresistance. Moreover, we provide a promising therapeutic strategy for reversing radioresistance by inhibiting the FSP1-CoQ pathway.

3D Spheroids Facilitate Differentiation of Human Adipose-Derived Mesenchymal Stem Cells into Hepatocyte-Like Cells via p300-Mediated H3K56 Acetylation.

Hepatocyte-like cells (HLCs) that are differentiated from mesenchymal stem cells (MSCs) provide a valuable resource for drug screening and cell-based regeneration therapy. Differentiating HLCs into 3D spheroids enhances their phenotypes and functions. However, the molecular mechanisms underlying MSCs hepatogenic differentiation are not fully understood. In this study, we generated HLCs from human adipose-derived mesenchymal stem cells (hADMSCs) in both 2D and 3D cultures. We performed an acetyl-proteomics assay on the HLCs derived from both 2D and 3D differentiation and identified a differential change in H3K56 acetylation between the 2 differentiated cells. Our findings revealed that 3D differentiation activated ALB gene transcription by increasing the acetylation level of H3K56, thereby enhancing the phenotypes and functions of HLCs and further promoting their maturation. Notably, inhibiting p300 reduced the acetylation level of H3K56 during hepatogenic differentiation, leading to decreased phenotypes and functions of HLCs, whereas activation of p300 promoted hepatogenic differentiation, suggesting that p300 plays a critical role in this process. In summary, our study demonstrates a potential mechanism through which 3D spheroids differentiation facilitates hADMSCs differentiation into HLCs by promoting p300-mediated H3K56 acetylation, which could have significant clinical applications in liver regeneration and disease modeling.

Comprehensive scRNA-seq Model Reveals Artery Endothelial Cell Heterogeneity and Metabolic Preference in Human Vascular Disease.

Vascular disease is one of the major causes of death worldwide. Endothelial cells are important components of the vascular structure. A better understanding of the endothelial cell changes in the development of vascular disease may provide new targets for clinical treatment strategies. Single-cell RNA sequencing can serve as a powerful tool to explore transcription patterns, as well as cell type identity. Our current study is based on comprehensive scRNA-seq data of several types of human vascular disease datasets with deep-learning-based algorithm. A gene set scoring system, created based on cell clustering, may help to identify the relative stage of the development of vascular disease. Metabolic preference patterns were estimated using a graphic neural network model. Overall, our study may provide potential treatment targets for retaining normal endothelial function under pathological situations.

Repurposing a human acetyl-CoA carboxylase inhibitor firsocostat to treat fungal candidiasis alone and in combination.

Opportunistic fungal infections, particularly caused by Candida albicans, remain a common cause of high morbidity and mortality in immunocompromised patients. The escalating prevalence of antifungal drug resistance necessitates the immediate exploration of alternative treatment strategies to combat these life-threatening fungal diseases. In this study, we investigated the antifungal efficacy of firsocostat, a human acetyl-CoA carboxylase (ACC) inhibitor, against C. albicans. Firsocostat alone displayed moderate antifungal activity, while combining it with voriconazole, itraconazole, or amphotericin B exhibited synergistic effects across almost all drug-sensitive and drug-resistant C. albicans strains tested. These observed synergies were further validated in two mouse models of oropharyngeal and systemic candidiasis, where the combination therapies demonstrated superior fungicidal effects compared to monotherapy. Moreover, firsocostat was shown to directly bind to C. albicans ACC and inhibit its enzymatic activity. Sequencing spontaneous firsocostat-resistant mutants revealed mutations mapping to C. albicans ACC, confirming that firsocostat has retained its target in C. albicans. Overall, our findings suggest that repurposing firsocostat, either alone or in combination with other antifungal agents, holds promising potential in the development of antifungal drugs and the treatment of candidiasis.