eLIMS: Ensemble Learning-Based Spatial Segmentation of Mass Spectrometry Imaging to Explore Metabolic Heterogeneity.

Spatial segmentation is an essential processing method for image analysis aiming to identify the characteristic suborgans or microregions from mass spectrometry imaging (MSI) data, which is critical for understanding the spatial heterogeneity of biological information and function and the underlying molecular signatures. Due to the intrinsic characteristics of MSI data including spectral nonlinearity, high-dimensionality, and large data size, the common segmentation methods lack the capability for capturing the accurate microregions associated with biological functions. Here we proposed an ensemble learning-based spatial segmentation strategy, named eLIMS, that combines a randomized unified manifold approximation and projection (r-UMAP) dimensionality reduction module for extracting significant features and an ensemble pixel clustering module for aggregating the clustering maps from r-UMAP. Three MSI datasets are used to evaluate the performance of eLIMS, including mouse fetus, human adenocarcinoma, and mouse brain. Experimental results demonstrate that the proposed method has potential in partitioning the heterogeneous tissues into several subregions associated with anatomical structure, i.e., the suborgans of the brain region in mouse fetus data are identified as dorsal pallium, midbrain, and brainstem. Furthermore, it effectively discovers critical microregions related to physiological and pathological variations offering new insight into metabolic heterogeneity.

Phenylhydrazone Alkaloids from the Deep-Sea Cold Seep Derived Fungus Talaromyces amestolkiae HDN21-0307.

Alkaloids with a phenylhydrazone architecture are rarely found in nature. Four unusual phenylhydrazone alkaloids named talarohydrazones A-D (1-4) were isolated from the deep-sea cold seep derived fungus Talaromyces amestolkiae HDN21-0307 using the one strain-many compounds (OSMAC) approach and MS/MS-based molecular networking (MN) combined with network annotation propagation (NAP) and the unsupervised substructure annotation method MS2LDA. Their structures were elucidated by spectroscopic data analysis, single-crystal X-ray diffraction, and quantum chemical calculations. Talarohydrazone A (1) possessed an unusual skeleton combining 2,4-pyridinedione and phenylhydrazone. Talarohydrazone B (2) represents the first natural phenylhydrazone-bearing azadophilone. Bioactivity evaluation revealed that compound 1 exhibited cytotoxic activity against NCI-H446 cells with an IC50 value of 4.1 µM. In addition, compound 1 displayed weak antibacterial activity toward Staphylococcus aureus with an MIC value of 32 µg/mL.

Discovery, Total Synthesis, and Anti-Inflammatory Evaluation of Naturally Occurring Naphthopyrone-Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors.

Numerous clinical disorders have been linked to the etiology of dysregulated NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome activation. Despite its potential as a pharmacological target, modulation of NLRP3 activity remains challenging. Only a sparse number of compounds have been reported that can modulate NLRP3 and none of them have been developed into a commercially available drug. In this research, we identified three potent NLRP3 inflammasome inhibitors, gymnoasins A-C (1-3), with unprecedented pentacyclic scaffolds, from an Antarctic fungus Pseudogymnoascus sp. HDN17-895, which represent the first naturally occurring naphthopyrone-macrolide hybrids. Additionally, biomimetic synthesis of gymnoasin A (1) was also achieved validating the chemical structure and affording ample amounts of material for exhaustive bioactivity assessments. Biological assays indicated that 1 could significantly inhibited in vitro NLRP3 inflammasome activation and in vivo pro-inflammatory cytokine IL-1ß release, representing a valuable new lead compound for the development of novel therapeutics with the potential to inhibit the NLRP3 inflammasome.

Multimodal Image Fusion Offers Better Spatial Resolution for Mass Spectrometry Imaging.

High-resolution reconstruction has attracted increasing research interest in mass spectrometry imaging (MSI), but it remains a challenging ill-posed problem. In the present study, we proposed a deep learning model to fuse multimodal images to enhance the spatial resolution of MSI data, namely, DeepFERE. Hematoxylin and eosin (H&E) stain microscopy imaging was used to pose constraints in the process of high-resolution reconstruction to alleviate the ill-posedness. A novel model architecture was designed to achieve multi-task optimization by incorporating multi-modal image registration and fusion in a mutually reinforced framework. Experimental results demonstrated that the proposed DeepFERE model is able to produce high-resolution reconstruction images with rich chemical information and a detailed structure on both visual inspection and quantitative evaluation. In addition, our method was found to be able to improve the delimitation of the boundary between cancerous and para-cancerous regions in the MSI image. Furthermore, the reconstruction of low-resolution spatial transcriptomics data demonstrated that the developed DeepFERE model may find wider applications in biomedical fields.

iSegMSI: An Interactive Strategy to Improve Spatial Segmentation of Mass Spectrometry Imaging Data.

Spatial segmentation is a critical procedure in mass spectrometry imaging (MSI)-based biochemical analysis. However, the commonly used unsupervised MSI segmentation methods may lead to inappropriate segmentation results as the MSI data is characterized by high dimensionality and low signal-to-noise ratio. This process can be improved by the incorporation of precise prior knowledge, which is hard to obtain in most cases. In this study, we show that the incorporation of partial or coarse prior knowledge from different sources such as reference images or biological knowledge may also help to improve MSI segmentation results. Here, we propose a novel interactive segmentation strategy for MSI data called iSegMSI, which incorporates prior information in the form of scribble-regularization of the unsupervised model to fine-tune the segmentation results. By using two typical MSI data sets (including a whole-body mouse fetus and human thyroid cancer), the present results demonstrate the effectiveness of the iSegMSI strategy in improving the MSI segmentations. Specifically, the method can be used to subdivide a region into several subregions specified by the user-defined scribbles or to merge several subregions into a single region. Additionally, these fine-tuned results are highly tolerant to the imprecision of the scribbles. Our results suggest that the proposed iSegMSI method may be an effective preprocessing strategy to facilitate the analysis of MSI data.

Dimeric Tetracenomycin Derivatives from a Taklamakan Desert-Derived Streptomyces sp. HDN154193.

Bitetracenomycin A (1) and its diastereomers [(±)-bitetracenomycin B, (±)-2] were discovered from the cultures of Streptomyces sp. HDN154193. Compounds 1 and (±)-2 were the first tetracenomycin dimers obtained from a natural source with sp3 methine protons at the bridge positions (C-12/12'), which also exhibited broad-spectrum antibacterial activity. The racemate (±)-2 was semisynthesized and separated into enantiomers (+)-2 and (-)-2, and the absolute configurations were determined by specific rotation and ECD data. These metabolites exhibited potent antibacterial activity especially against drug-resistant strains (MRSA and MRCNS) with MIC values ranging from 1.0 to 1.9 µg/mL.

Cytotoxic Nitrobenzoyl Sesquiterpenoids from an Antarctica Sponge-Derived Aspergillus insulicola.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplastic diseases of the pancreas with fatal proliferation and metastasis and no medicine available for treatment. From an Antarctica sponge-derived fungus, Aspergillus insulicola HDN151418, four new nitrobenzoyl sesquiterpenoids, namely, insulicolides D-G (1-4), were isolated. Compounds 3 and 4 exhibited selective inhibition against human PDAC cell lines. Further studies indicated that compound 4 could significantly suppress cell proliferation to induce apoptosis and blocked migration and invasion of PDAC cells. Compound 4 could also avoid resistance and improved the therapeutic effect of the chemotherapy drug gemcitabine. A preliminary mechanism study showed that compound 4 can significantly inhibit the expression of EGFR and XIAP in PDAC cells. Altogether, 4 is a potential lead compound for anti-PDAC drug research.

Polyhydroxy p-Terphenyls from a Mangrove Endophytic Fungus Aspergillus candidus LDJ-5.

Six undescribed polyhydroxy p-terphenyls, namely asperterphenyllins A-F, were isolated from an endophytic fungus Aspergillus candidus LDJ-5. Their structures were determined by NMR and MS data. Differing from the previously reported p-terphenyls, asperterphenyllin A represents the first p-terphenyl dimer connected by a C-C bond. Asperterphenyllin A displayed anti-influenza virus A (H1N1) activity and protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with IC50 values of 53 µM and 21 µM, respectively. The anti-influenza virus A (H1N1) activity and protein tyrosine phosphatase 1B (PTP1B) inhibitory activity of p-terphenyls are reported for the first time. Asperterphenyllin G exhibited cytotoxicity against nine cell lines with IC50 values ranging from 0.4 to 1.7 µM. Asperterphenyllin C showed antimicrobial activity against Proteus species with a MIC value of 19 µg/mL.

Antibacterial Polyketides from Antarctica Sponge-Derived Fungus Penicillium sp. HDN151272.

Three new polyketides, ketidocillinones A-C (1-3), were discovered from the extract of an Antarctica sponge-derived fungus Penicillium sp. HDN151272. All the structures were deduced by spectroscopic data, including NMR and HRESIMS. The absolute configuration of compound 3 was established by using ECD calculation. Compounds 1-3 can be slowly oxidized to quinone form when exposed to air. Ketidocillinones B and C (2 and 3) exhibited potent antibacterial activity against Pseudomonas aeurigenosa, Mycobacterium phlei, and MRCNS (methicillin-resistant coagulase-negative staphylococci) with MIC values ranging from 1.56 to 25.00 µg/mL.

Antibacterial Cyclic Tripeptides from Antarctica-Sponge-Derived Fungus Aspergillus insulicola HDN151418.

Three new aspochracin-type cyclic tripeptides, sclerotiotides M-O (1-3), together with three known analogues, sclerotiotide L (4), sclerotiotide F (5), and sclerotiotide B (6), were obtained from the ethyl acetate extract of the fungus Aspergillus insulicola HDN151418, which was isolated from an unidentified Antarctica sponge. Spectroscopic and chemical approaches were used to elucidate their structures. The absolute configuration of the side chain in compound 4 was elucidated for the first time. Compounds 1 and 2 showed broad antimicrobial activity against a panel of pathogenic strains, including Bacillus cereus, Proteus species, Mycobacterium phlei, Bacillus subtilis, Vibrio parahemolyticus, Edwardsiella tarda, MRCNS, and MRSA, with MIC values ranging from 1.56 to 25.0 µM.

New metabolites from a Mariana Trench-derived actinomycete Nocardiopsis sp. HDN 17-237.

One new ß,γ-butenoate derivative phenylbutenote (1), and one new α-pyrone nocapyrone T (2) were isolated from the deep-sea derived actinomycete Nocardiopsis sp. HDN 17-237. Their structures were elucidated by extensive HRMS, IR and NMR analyses. Among them, compound 1 is the first microbial natural products bearing a rare ß,γ-butenoate moiety, and compound 2 is the first α-pyrone isolated from strain of Mariana Trench. Compounds 1 and 2 were tested for antioxidant and antibacterial activities, while none of them showed significant activity.

Severe Central Nervous System and Respiratory Depression in a Neonate Following Accidental Oral Ingestion of Brimonidine Tartrate.

Brimonidine is a third-generation alpha-2 adrenergic agonist and is classified as an ocular hypotensive agent. It is used for chronic glaucoma treatment by lowering intraocular pressure, crucial for preventing blindness. Brimonidine works by reducing aqueous humor production and increasing uveoscleral outflow. The improper use of brimonidine in children can result in severe adverse effects. If brimonidine eye drops are ingested orally, it can cause significant depression of the cardiorespiratory and central nervous systems. This is a case report of a 27-day-old neonate, who presented with central nervous system and respiratory depression after accidental ingestion of one drop of brimonidine tartrate ophthalmic solution. On arrival, he was having shallow breathing, a low Glasgow Coma Scale score, pinpoint pupils, and absent deep tendon reflexes. Gastric lavage was performed and supportive treatment was started. The patient showed gradual improvement and completely recovered within 48 hours.

Seronegative Bilateral Pulmonary Hydatid Cysts in a 15-Year-Old Boy From Pakistan: Report of a Rare Case.

Hydatid disease, attributed to the tapeworm Echinococcus granulosus, poses a significant health threat in regions where it is endemic. Here, we present a case involving a 15-year-old boy from rural Pakistan who initially sought medical attention due to a persistent cough and hemoptysis. Despite initially testing negative for serological markers, imaging studies revealed well-defined cysts in both lungs. Confirmation of the diagnosis was achieved through histopathological examination. Management includes albendazole therapy and surgical excision of the cyst. Our case underscores the diagnostic challenges associated with seronegative cases and underscores the importance of considering hydatid disease in endemic regions, irrespective of typical serological markers. This report enhances understanding regarding the clinical presentation, diagnostic approach, and management strategies for pulmonary hydatid cysts.

Talaverrucin A, Heterodimeric Oxaphenalenone from Antarctica Sponge-Derived Fungus Talaromyces sp. HDN151403, Inhibits Wnt/ß-Catenin Signaling Pathway.

The Wnt/ß-catenin signaling pathway is an evolutionarily conserved signaling cascade involved in a broad range of biological roles. Dysregulation of the Wnt/ß-catenin pathway is implicated in congenital malformations and various kinds of cancers. We discovered a novel Wnt/ß-catenin inhibitor, talaverrucin A (1), featuring an unprecedented 6/6/6/5/5/5/6 fused ring system, from an Antarctica sponge-derived fungus Talaromyces sp. HDN151403. Talaverrucin A exhibits inhibitory activity on the Wnt/ß-catenin pathway in both zebrafish embryos in vivo and cultured mammalian cells in vitro, providing a naturally inspired small molecule therapeutic lead to target the Wnt/ß-catenin pathway.

Malignancies After Heart Transplant.

Along with graft vasculopathy, malignancies comprise a major complication after heart transplant, with a rate of occurrence of 39.1% in 10 years. Skin cancers and posttransplant lymphoproliferative disorder are more common in adults, whereas lymphoma is more often shown in children. A major cause of malignancies after heart transplant is the use of increased doses of prophylactics needed during immunosuppressive therapy. Data, however, are scarce regarding the association between a particular immunosuppressive drug and a posttransplant malignancy. Compared with the general population, recipients have a higher incidence of malignancies after heart transplant, with an early onset and more aggressive disease. Solid tumors known to occur in heart transplant recipients include lung cancer, bladder and prostate carcinoma, adenocarcinoma of the oral cavity, stomach cancer, and bowel cancer, although the incidence is rare. The risk factors for development of a malignancy after heart transplant are the same as for the nontransplant population.