Nat Commun. 2024 Jan 8;15(1):363. doi: 10.1038/s41467-023-44210-1.

ABSTRACT

In the complex tumor microenvironment (TME), mesenchymal cells are key players, yet their specific roles in prostate cancer (PCa) progression remain to be fully deciphered. This study employs single-cell RNA sequencing to delineate molecular changes in tumor stroma that influence PCa progression and metastasis. Analyzing mesenchymal cells from four genetically engineered mouse models (GEMMs) and correlating these findings with human tumors, we identify eight stromal cell populations with distinct transcriptional identities consistent across both species. Notably, stromal signatures in advanced mouse disease reflect those in human bone metastases, highlighting periostin's role in invasion and differentiation. From these insights, we derive a gene signature that predicts metastatic progression in localized disease beyond traditional Gleason scores. Our results illuminate the critical influence of stromal dynamics on PCa progression, suggesting new prognostic tools and therapeutic targets.

PMID:38191471 | DOI:10.1038/s41467-023-44210-1

J Phys Chem B. 2024 Jan 8. doi: 10.1021/acs.jpcb.3c06258. Online ahead of print.

ABSTRACT

It is not well understood why severe acute respiratory syndrome (SARS)-CoV-2 spreads much faster than other β-coronaviruses such as SARS-CoV and Middle East respiratory syndrome (MERS)-CoV. In a previous publication, we predicted the binding of the N-terminal domain (NTD) of SARS-CoV-2 spike to sialic acids (SAs). Here, we experimentally validate this interaction and present simulations that reveal a second possible interaction between SAs and the spike protein via a binding site located in the receptor-binding domain (RBD). The predictions from molecular-dynamics simulations and the previously-published 2D-Zernike binding-site recognition approach were validated through flow-induced dispersion analysis (FIDA)─which reveals the capability of the SARS-CoV-2 spike to bind to SA-containing (glyco)lipid vesicles, and flow-cytometry measurements─which show that spike binding is strongly decreased upon inhibition of SA expression on the membranes of angiotensin converting enzyme-2 (ACE2)-expressing HEK cells. Our analyses reveal that the SA binding of the NTD and RBD strongly enhances the infection-inducing ACE2 binding. Altogether, our work provides in silico, in vitro, and cellular evidence that the SARS-CoV-2 virus utilizes a two-receptor (SA and ACE2) strategy. This allows the SARS-CoV-2 spike to use SA moieties on the cell membrane as a binding anchor, which increases the residence time of the virus on the cell surface and aids in the binding of the main receptor, ACE2, via 2D diffusion.

PMID:38190651 | DOI:10.1021/acs.jpcb.3c06258

Plant Cell Physiol. 2023 Dec 8:pcad154. doi: 10.1093/pcp/pcad154. Online ahead of print.

ABSTRACT

Pectin methylesterases (PMEs) modify homogalacturonan's chemistry and play a key role in regulating primary cell wall mechanical properties. Here, we report on Arabidopsis AtPME2, which we found to be highly expressed during lateral root emergence and dark-grown hypocotyl elongation. We showed that dark-grown hypocotyl elongation was reduced in knock-out mutant lines as compared to the control. The latter was related to the decreased total PME activity as well as increased stiffness of the cell wall in the apical part of the hypocotyl. To relate phenotypic analyses to the biochemical specificity of the enzyme, we produced the mature active enzyme using heterologous expression in Pichia pastoris and characterized it through the use of a generic plant PME antiserum. AtPME2 is more active at neutral compared to acidic pH, on pectins with a degree of 55-70% methylesterification. We further showed that the mode of action of AtPME2 can vary according to pH, from high processivity (at pH8) to low processivity (at pH5), and relate these observations to the differences in electrostatic potential of the protein. Our study brings insights into how the pH-dependent regulation by PME activity could affect the pectin structure and associated cell wall mechanical properties.

PMID:38190549 | DOI:10.1093/pcp/pcad154

PLoS Genet. 2024 Jan 8;20(1):e1010155. doi: 10.1371/journal.pgen.1010155. Online ahead of print.

ABSTRACT

Introgression is a common evolutionary phenomenon that results in shared genetic material across non-sister taxa. Existing statistical methods such as Patterson's D statistic can detect introgression by measuring an excess of shared derived alleles between populations. The D statistic is effective to detect genome-wide patterns of introgression but can give spurious inferences of introgression when applied to local regions. We propose a new statistic, D+, that leverages both shared ancestral and derived alleles to infer local introgressed regions. Incorporating both shared derived and ancestral alleles increases the number of informative sites per region, improving our ability to identify local introgression. We use a coalescent framework to derive the expected value of this statistic as a function of different demographic parameters under an instantaneous admixture model and use coalescent simulations to compute the power and precision of D+. While the power of D and D+ is comparable, D+ has better precision than D. We apply D+ to empirical data from the 1000 Genome Project and Heliconius butterflies to infer local targets of introgression in humans and in butterflies.

PMID:38190420 | DOI:10.1371/journal.pgen.1010155

PLoS Comput Biol. 2024 Jan 8;20(1):e1011735. doi: 10.1371/journal.pcbi.1011735. Online ahead of print.

ABSTRACT

Bacteria like E. coli grow at vastly different rates on different substrates, however, the precise reason for this variability is poorly understood. Different growth rates have been attributed to 'nutrient quality', a key parameter in bacterial growth laws. However, it remains unclear to what extent nutrient quality is rooted in fundamental biochemical constraints like the energy content of nutrients, the protein cost required for their uptake and catabolism, or the capacity of the plasma membrane for nutrient transporters. Here, we show that while nutrient quality is indeed reflected in protein investment in substrate-specific transporters and enzymes, this is not a fundamental limitation on growth rate, at least for certain 'poor' substrates. We show that it is possible to turn mannose, one of the 'poorest' substrates of E. coli, into one of the 'best' substrates by reengineering chromosomal promoters of the mannose transporter and metabolic enzymes required for mannose degradation. This result falls in line with previous observations of more subtle growth rate improvement for many other carbon sources. However, we show that this faster growth rate comes at the cost of diverse cellular capabilities, reflected in longer lag phases, worse starvation survival and lower motility. We show that addition of cAMP to the medium can rescue these phenotypes but imposes a corresponding growth cost. Based on these data, we propose that nutrient quality is largely a self-determined, plastic property that can be modulated by the fraction of proteomic resources devoted to a specific substrate in the much larger proteome sector of catabolically activated genes. Rather than a fundamental biochemical limitation, nutrient quality reflects resource allocation decisions that are shaped by evolution in specific ecological niches and can be quickly adapted if necessary.

PMID:38190385 | DOI:10.1371/journal.pcbi.1011735

OMICS. 2024 Jan 8. doi: 10.1089/omi.2023.0163. Online ahead of print.

ABSTRACT

Checkpoint kinase 1 (CHK1), a serine/threonine kinase, plays a crucial role in cell cycle arrest and is a promising therapeutic target for drug development against cancers. CHK1 coordinates cell cycle checkpoints in response to DNA damage, facilitating repair of single-strand breaks, and maintains the genome integrity in response to replication stress. In this study, we employed an integrated computational and experimental approach to drug discovery and repurposing, aiming to identify a potent CHK1 inhibitor among existing drugs. An e-pharmacophore model was developed based on the three-dimensional crystal structure of the CHK1 protein in complex with CCT245737. This model, characterized by seven key molecular features, guided the screening of a library of drugs through molecular docking. The top 10% of scored ligands were further examined, with procaterol emerging as the leading candidate. Procaterol demonstrated interaction patterns with the CHK1 active site similar to CHK1 inhibitor (CCT245737), as shown by molecular dynamics analysis. Subsequent in vitro assays, including cell proliferation, colony formation, and cell cycle analysis, were conducted on gastric adenocarcinoma cells treated with procaterol, both as a monotherapy and in combination with cisplatin. Procaterol, in synergy with cisplatin, significantly inhibited cell growth, suggesting a potentiated therapeutic effect. Thus, we propose the combined application of cisplatin and procaterol as a novel potential therapeutic strategy against human gastric cancer. The findings also highlight the relevance of CHK1 kinase as a drug target for enhancing the sensitivity of cytotoxic agents in cancer.

PMID:38190280 | DOI:10.1089/omi.2023.0163

OMICS. 2024 Jan 8. doi: 10.1089/omi.2023.0241. Online ahead of print.

ABSTRACT

Host-virus Protein-Protein Interactions (PPIs) play pivotal roles in biological processes crucial for viral pathogenesis and by extension, inform antiviral drug discovery and therapeutics innovations. Despite efforts to develop the Epstein-Barr virus (EBV)-host PPI network, there remain significant knowledge gaps and a limited number of interacting human proteins deciphered. Furthermore, understanding the dynamics of the EBV-host PPI network in the distinct lytic and latent viral stages remains elusive. In this study, we report a comprehensive map of the EBV-human protein interactions, encompassing 1752 human and 61 EBV proteins by integrating data from the public repository HPIDB (v3.0) as well as curated high-throughput proteomic data from the literature. To address the stage-specific nature of EBV infection, we generated two detailed subset networks representing the latent and lytic stages, comprising 747 and 481 human proteins, respectively. Functional and pathway enrichment analysis of these subsets uncovered the profound impact of EBV proteins on cancer. The identification of highly connected proteins and the characterization of intrinsically disordered and cancer-related proteins provide valuable insights into potential therapeutic targets. Moreover, the exploration of drug-protein interactions revealed notable associations between hub proteins and anticancer drugs, offering novel perspectives for controlling EBV pathogenesis. This study represents, to the best of our knowledge, the first comprehensive investigation of the two distinct stages of EBV infection using high-throughput datasets. This makes a contribution to our understanding of EBV-host interactions and provides a foundation for future drug discovery and therapeutic interventions.

PMID:38190109 | DOI:10.1089/omi.2023.0241

Appl Microbiol Biotechnol. 2024 Dec;108(1):1-18. doi: 10.1007/s00253-023-12918-1. Epub 2024 Jan 8.

ABSTRACT

Recently, we reported the discovery of a novel endoglucanase of the glycoside hydrolase family 12 (GH12), designated IfCelS12A, from the haloalkaliphilic anaerobic bacterium Iocasia fonsfrigidae strain SP3-1, which was isolated from a hypersaline pond in the Samut Sakhon province of Thailand (ca. 2017). IfCelS12A exhibits high substrate specificity on carboxymethyl cellulose and amorphous cellulose but low substrate specificity on b-1,3;1,4-glucan. Unlike some endoglucanases of the GH12 family, IfCelS12A does not exhibit hydrolytic activity on crystalline cellulose (i.e., Avicel™). High-Pressure Liquid Chromatography (HPLC) and Thin Layer Chromatography (TLC) analyses of products resulting from IfCelS12-mediated hydrolysis indicate mode of action for this enzyme. Notably, IfCelS12A preferentially hydrolyzes cellotetraoses, cellopentaoses, and cellohexaoses with negligible activity on cellobiose or cellotriose. Kinetic analysis with cellopentaose and barely b-D-glucan as cellulosic substrates were conducted. On cellopentaose, IfCelS12A demonstrates a 16-fold increase in activity (KM = 0.27 mM; kcat = 0.36 s-1; kcat/KM = 1.34 mM-1 s-1) compared to the enzymatic hydrolysis of barley b-D-glucan (KM: 0.04 mM, kcat: 0.51 s-1, kcat/KM = 0.08 mM-1 s-1). Moreover, IfCelS12A enzymatic efficacy is stable in hypersaline sodium chlorids (NaCl) solutions (up to 10% NaCl). Specifically, IfCel12A retains notable activity after 24 h at 2M NaCl (10% saline solution). IfCelS12A used as a cocktail component with other cellulolytic enzymes and in conjunction with mobile sequestration platform technology offers additional options for deconstruction of ionic liquid-pretreated cellulosic feedstock. KEY POINTS: • IfCelS12A from an anaerobic alkaliphile Iocasia fronsfrigidae shows salt tolerance • IfCelS12A in cocktails with other enzymes efficiently degrades cellulosic biomass • IfCelS12A used with mobile enzyme sequestration platforms enhances hydrolysis.

PMID:38189956 | DOI:10.1007/s00253-023-12918-1

Elife. 2024 Jan 8;12:RP88525. doi: 10.7554/eLife.88525.

ABSTRACT

Photosynthetic eukaryotes, such as microalgae and plants, foster fundamentally important relationships with their microbiome based on the reciprocal exchange of chemical currencies. Among these, the dicarboxylate metabolite azelaic acid (Aze) appears to play an important, but heterogeneous, role in modulating these microbiomes, as it is used as a carbon source for some heterotrophs but is toxic to others. However, the ability of Aze to promote or inhibit growth, as well as its uptake and assimilation mechanisms into bacterial cells are mostly unknown. Here, we use transcriptomics, transcriptional factor coexpression networks, uptake experiments, and metabolomics to unravel the uptake, catabolism, and toxicity of Aze on two microalgal-associated bacteria, Phycobacter and Alteromonas, whose growth is promoted or inhibited by Aze, respectively. We identify the first putative Aze transporter in bacteria, a 'C4-TRAP transporter', and show that Aze is assimilated through fatty acid degradation, with further catabolism occurring through the glyoxylate and butanoate metabolism pathways when used as a carbon source. Phycobacter took up Aze at an initial uptake rate of 3.8×10-9 nmol/cell/hr and utilized it as a carbon source in concentrations ranging from 10 μM to 1 mM, suggesting a broad range of acclimation to Aze availability. For growth-impeded bacteria, we infer that Aze inhibits the ribosome and/or protein synthesis and that a suite of efflux pumps is utilized to shuttle Aze outside the cytoplasm. We demonstrate that seawater amended with Aze becomes enriched in bacterial families that can catabolize Aze, which appears to be a different mechanism from that in soil, where modulation by the host plant is required. This study enhances our understanding of carbon cycling in the oceans and how microscale chemical interactions can structure marine microbial populations. In addition, our findings unravel the role of a key chemical currency in the modulation of eukaryote-microbiome interactions across diverse ecosystems.

PMID:38189382 | DOI:10.7554/eLife.88525

Infect Immun. 2024 Jan 8:e0031823. doi: 10.1128/iai.00318-23. Online ahead of print.

ABSTRACT

Inflammation has a pronounced impact on the intestinal ecosystem by driving an expansion of facultative anaerobic bacteria at the cost of obligate anaerobic microbiota. This pathogen "blooming" is also a hallmark of enteric Salmonella enterica serovar Typhimurium (S. Tm) infection. Here, we analyzed the contribution of bacterial and host factors to S. Tm "blooming" in a gnotobiotic mouse model for S. Tm-induced enterocolitis. Mice colonized with the Oligo-Mouse-Microbiota (OMM12), a minimal bacterial community, develop fulminant colitis by day 4 after oral infection with wild-type S. Tm but not with an avirulent mutant. Inflammation leads to a pronounced reduction in overall intestinal bacterial loads, distinct microbial community shifts, and pathogen blooming (relative abundance >50%). S. Tm mutants attenuated in inducing gut inflammation generally elicit less pronounced microbiota shifts and reduction in total bacterial loads. In contrast, S. Tm mutants in nitrate respiration, salmochelin production, and ethanolamine utilization induced strong inflammation and S. Tm "blooming." Therefore, individual Salmonella-specific inflammation-fitness factors seem to be of minor importance for competition against this minimal microbiota in the inflamed gut. Finally, we show that antibody-mediated neutrophil depletion normalized gut microbiota loads but not intestinal inflammation or microbiota shifts. This suggests that neutrophils equally reduce pathogen and commensal bacterial loads in the inflamed gut.

PMID:38189339 | DOI:10.1128/iai.00318-23

iScience. 2023 Dec 2;27(1):108631. doi: 10.1016/j.isci.2023.108631. eCollection 2024 Jan 19.

ABSTRACT

Idiopathic nephrotic syndrome (NS) is a common glomerular disease. Although glucocorticoids (GC) are the primary treatment, the PPARγ agonist pioglitazone (Pio) also reduces proteinuria in patients with NS and directly protects podocytes from injury. Because both drugs reduce proteinuria, we hypothesized these effects result from overlapping transcriptional patterns. Systems biology approaches compared glomerular transcriptomes from rats with PAN-induced NS treated with GC vs. Pio and identified 29 commonly regulated genes-of-interest, primarily involved in extracellular matrix (ECM) remodeling. Correlation with clinical idiopathic NS patient datasets confirmed glomerular ECM dysregulation as a potential mechanism of injury. Cellular deconvolution in silico revealed GC- and Pio-induced amelioration of altered genes primarily within podocytes and mesangial cells. While validation studies are indicated, these analyses identified molecular pathways involved in the early stages of NS (prior to scarring), suggesting that targeting glomerular ECM dysregulation may enable a future non-immunosuppressive approach for proteinuria reduction in idiopathic NS.

PMID:38188512 | PMC:PMC10770536 | DOI:10.1016/j.isci.2023.108631

Plant Phenomics. 2024 Jan 5;6:0131. doi: 10.34133/plantphenomics.0131. eCollection 2024.

ABSTRACT

Tree growth is the consequence of developmental interactions between above- and below-ground compartments. However, a comprehensive view of the genetic architecture of growth as a cohesive whole is poorly understood. We propose a systems biology approach for mapping growth trajectories in genome-wide association studies viewing growth as a complex (phenotypic) system in which above- and below-ground components (or traits) interact with each other to mediate systems behavior. We further assume that trait-trait interactions are controlled by a genetic system composed of many different interactive genes and integrate the Lotka-Volterra predator-prey model to dissect phenotypic and genetic systems into pleiotropic and epistatic interaction components by which the detailed genetic mechanism of above- and below-ground co-growth can be charted. We apply the approach to analyze linkage mapping data of Populus euphratica, which is the only tree species that can grow in the desert, and characterize several loci that govern how above- and below-ground growth is cooperated or competed over development. We reconstruct multilayer and multiplex genetic interactome networks for the developmental trajectories of each trait and their developmental covariation. Many significant loci and epistatic effects detected can be annotated to candidate genes for growth and developmental processes. The results from our model may potentially be useful for marker-assisted selection and genetic editing in applied tree breeding programs. The model provides a general tool to characterize a complete picture of pleiotropic and epistatic genetic architecture in growth traits in forest trees and any other organisms.

PMID:38188223 | PMC:PMC10769449 | DOI:10.34133/plantphenomics.0131

Front Immunol. 2023 Dec 21;14:1285345. doi: 10.3389/fimmu.2023.1285345. eCollection 2023.

ABSTRACT

INTRODUCTION: Pro-thrombotic events are one of the prevalent causes of intensive care unit (ICU) admissions among COVID-19 patients, although the signaling events in the stimulated platelets are still unclear.

METHODS: We conducted a comparative analysis of platelet transcriptome data from healthy donors, ICU, and non-ICU COVID-19 patients to elucidate these mechanisms. To surpass previous analyses, we constructed models of involved networks and control cascades by integrating a global human signaling network with transcriptome data. We investigated the control of platelet hyperactivation and the specific proteins involved.

RESULTS: Our study revealed that control of the platelet network in ICU patients is significantly higher than in non-ICU patients. Non-ICU patients require control over fewer proteins for managing platelet hyperactivity compared to ICU patients. Identification of indispensable proteins highlighted key subnetworks, that are targetable for system control in COVID-19-related platelet hyperactivity. We scrutinized FDA-approved drugs targeting indispensable proteins and identified fostamatinib as a potent candidate for preventing thrombosis in COVID-19 patients.

DISCUSSION: Our findings shed light on how SARS-CoV-2 efficiently affects host platelets by targeting indispensable and critical proteins involved in the control of platelet activity. We evaluated several drugs for specific control of platelet hyperactivity in ICU patients suffering from platelet hyperactivation. The focus of our approach is repurposing existing drugs for optimal control over the signaling network responsible for platelet hyperactivity in COVID-19 patients. Our study offers specific pharmacological recommendations, with drug prioritization tailored to the distinct network states observed in each patient condition. Interactive networks and detailed results can be accessed at https://fostamatinib.bioinfo-wuerz.eu/.

PMID:38187394 | PMC:PMC10768010 | DOI:10.3389/fimmu.2023.1285345

Front Immunol. 2023 Dec 20;14:1297577. doi: 10.3389/fimmu.2023.1297577. eCollection 2023.

ABSTRACT

INTRODUCTION: Tobacco smoking generates airway inflammation in chronic obstructive pulmonary disease (COPD), and its involvement in the development of lung cancer is still among the leading causes of early death. Therefore, we aimed to have a better understanding of the disbalance in immunoregulation in chronic inflammatory conditions in smoker subjects with stable COPD (stCOPD), exacerbating COPD (exCOPD), or non-small cell lung cancer (NSCLC).

METHODS: Smoker controls without chronic illness were recruited as controls. Through extensive mapping of single cells, surface receptor quantification was achieved by single-cell mass cytometry (CyTOF) with 29 antibodies. The CyTOF characterized 14 main immune subsets such as CD4+, CD8+, CD4+/CD8+, CD4-/CD8-, and γ/δ T cells and other subsets such as CD4+ or CD8+ NKT cells, NK cells, B cells, plasmablasts, monocytes, CD11cdim, mDCs, and pDCs. The CD4+ central memory (CM) T cells (CD4+/CD45RA-/CD45RO+/CD197+) and CD4+ effector memory (EM) T cells (CD4+/CD45RA-/CD45RO+/CD197-) were FACS-sorted for RNA-Seq analysis. Plasma samples were assayed by Luminex MAGPIX® for the quantitative measurement of 17 soluble immuno-oncology mediators (BTLA, CD28, CD80, CD27, CD40, CD86, CTLA-4, GITR, GITRL, HVEM, ICOS, LAG-3, PD-1, PD-L1, PD-L2, TIM-3, TLR-2) in the four studied groups.

RESULTS: Our focus was on T-cell-dependent differences in COPD and NSCLC, where peripheral CD4+ central memory and CD4+ effector memory cells showed a significant reduction in exCOPD and CD4+ CM showed elevation in NSCLC. The transcriptome analysis delineated a perfect correlation of differentially expressed genes between exacerbating COPD and NSCLC-derived peripheral CD4+ CM or CD4+ EM cells. The measurement of 17 immuno-oncology soluble mediators revealed a disease-associated phenotype in the peripheral blood of stCOPD, exCOPD, and NSCLC patients.

DISCUSSION: The applied single-cell mass cytometry, the whole transcriptome profiling of peripheral CD4+ memory cells, and the quantification of 17 plasma mediators provided complex data that may contribute to the understanding of the disbalance in immune homeostasis generated or sustained by tobacco smoking in COPD and NSCLC.

PMID:38187374 | PMC:PMC10770259 | DOI:10.3389/fimmu.2023.1297577

Cogn Res Princ Implic. 2024 Jan 8;9(1):2. doi: 10.1186/s41235-023-00528-4.

ABSTRACT

Protective face masks were one of the central measures to counteract viral transmission in the COVID-19 pandemic. Prior research indicates that face masks impact various aspects of social cognition, such as emotion recognition and social evaluation. Whether protective masks also influence social avoidance behavior is less clear. Our project assessed direct and indirect measures of social avoidance tendencies towards masked and unmasked faces in two experiments with 311 participants during the first half of 2021. Two interventions were used in half of the participants from each sample (Experiment 1: protective face masks; Experiment 2: a disease prime video) to decrease or increase the salience of the immediate contagion threat. In the direct social avoidance measure, which asked for the deliberate decision to approach or avoid a person in a hypothetical social encounter, participants showed an increased willingness to approach masked as opposed to unmasked faces across experiments. This effect was further related to interindividual differences in pandemic threat perception in both samples. In the indirect measure, which assessed automatic social approach and avoidance tendencies, we neither observed an approach advantage towards masked faces nor an avoidance advantage for unmasked faces. Thus, while the absence of protective face masks may have led to increased deliberate social avoidance during the pandemic, no such effect was observed on automatic regulation of behavior, thus indicating the relative robustness of this latter behavior against changes in superordinate social norms.

PMID:38185759 | DOI:10.1186/s41235-023-00528-4

Biotechnol Adv. 2024 Jan 5:108307. doi: 10.1016/j.biotechadv.2024.108307. Online ahead of print.

ABSTRACT

Bioassays are the main tool to decipher bioactivities from natural resources thus their selection and quality are critical for optimal bioprospecting. They are used both in the early stages of compounds isolation/purification/identification, and in later stages to evaluate their safety and efficacy. In this review, we provide a comprehensive overview of the most common bioassays used in the discovery and development of new bioactive compounds with a focus on marine bioresources. We present a comprehensive list of practical considerations for selecting appropriate bioassays and discuss in detail the bioassays typically used to explore antimicrobial, antibiofilm, cytotoxic, antiviral, antioxidant, and anti-ageing potential. The concept of quality control and bioassay validation are introduced, followed by safety considerations, which are critical to advancing bioactive compounds to a higher stage of development. We conclude by providing an application-oriented view focused on the development of pharmaceuticals, food supplements, and cosmetics, the industrial pipelines where currently known marine natural products hold most potential. We highlight the importance of gaining reliable bioassay results, as these serve as a starting point for application-based development and further testing, as well as for consideration by regulatory authorities.

PMID:38185432 | DOI:10.1016/j.biotechadv.2024.108307

Commun Biol. 2024 Jan 6;7(1):56. doi: 10.1038/s42003-023-05640-1.

ABSTRACT

Profiling spatial variations of cellular composition and transcriptomic characteristics is important for understanding the physiology and pathology of tissues. Spatial transcriptomics (ST) data depict spatial gene expression but the currently dominating high-throughput technology is yet not at single-cell resolution. Single-cell RNA-sequencing (SC) data provide high-throughput transcriptomic information at the single-cell level but lack spatial information. Integrating these two types of data would be ideal for revealing transcriptomic landscapes at single-cell resolution. We develop the method STEM (SpaTially aware EMbedding) for this purpose. It uses deep transfer learning to encode both ST and SC data into a unified spatially aware embedding space, and then uses the embeddings to infer SC-ST mapping and predict pseudo-spatial adjacency between cells in SC data. Semi-simulation and real data experiments verify that the embeddings preserved spatial information and eliminated technical biases between SC and ST data. We apply STEM to human squamous cell carcinoma and hepatic lobule datasets to uncover the localization of rare cell types and reveal cell-type-specific gene expression variation along a spatial axis. STEM is powerful for mapping SC and ST data to build single-cell level spatial transcriptomic landscapes, and can provide mechanistic insights into the spatial heterogeneity and microenvironments of tissues.

PMID:38184694 | DOI:10.1038/s42003-023-05640-1

Genome Med. 2024 Jan 6;16(1):6. doi: 10.1186/s13073-023-01278-0.

NO ABSTRACT

PMID:38184654 | DOI:10.1186/s13073-023-01278-0

J Control Release. 2024 Jan 4:S0168-3659(24)00001-4. doi: 10.1016/j.jconrel.2023.12.057. Online ahead of print.

ABSTRACT

Insufficient delivery of therapeutic agents into solid tumors by systemic administration remains a major challenge in cancer treatment. Secreted protein acidic and rich in cysteine (SPARC) has high binding affinity to albumin and has been shown to enhance the penetration and uptake of albumin-based drug carriers in tumors. Here, we developed a strategy to alter the tumor microenvironment (TME) by upregulating SPARC to enhance the delivery efficiency of albumin-based drug carriers into tumors. We prepared albumin nanoparticles encapsulating an NF-κB controllable CRISPR activation system (SP-NPs). SP-NPs achieved tumor-selective SPARC upregulation by responding to the highly activated NF-κB in tumor cells. Whereas a single dose of SP-NPs only modestly upregulated SPARC expression, serial administration of SP-NPs created a positive feedback loop that induced progressive increases in SPARC expression as well as tumor cell uptake and tumor penetration of the nanoparticles in vitro, in organoids, and in subcutaneous tumors in vivo. Additionally, pre-treatment with SP-NPs significantly enhanced the anti-tumor efficacy of Abraxane, a commercialized albumin-bound paclitaxel nanoformulation. Our data provide evidence that modulating SPARC in the TME can enhance the efficiency of albumin-based drug delivery to solid tumors, which may result in new strategies to increase the efficacy of nanoparticle-based cancer drugs.

PMID:38184232 | DOI:10.1016/j.jconrel.2023.12.057

J Genet Genomics. 2024 Jan 4:S1673-8527(24)00001-8. doi: 10.1016/j.jgg.2023.12.011. Online ahead of print.

ABSTRACT

PTEN is a multifunctional gene that is involved in a variety of physiological and pathological processes. Circular RNAs (circRNAs) are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins. However, PTEN-related circRNAs are largely unknown. Here we report that circPTEN-MT (hsa_circ_0002934) is a circular RNA encoded by exons 3, 4, and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism. CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), which regulates posttranscriptional gene expression in mitochondria. Knocking down circPTEN-MT reduces the interaction of LRPPRC and SRA stem-loop interacting RNA binding protein (SLIRP) and inhibits the polyadenylation of mitochondrial mRNA, which decreases the mRNA level of the mitochondrial complex Ι subunit and reduces mitochondrial membrane potential (MMP) and ATP production. Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism. This study expands our understanding of the role of PTEN which produces both linear and circular RNAs with different and independent functions.

PMID:38184105 | DOI:10.1016/j.jgg.2023.12.011