Int J Mol Sci. 2023 Nov 30;24(23):16999. doi: 10.3390/ijms242316999.

ABSTRACT

Presenilin 1 (PS1) forms, via its large cytosolic loop, a trimeric complex with N-cadherin and β-catenin, which is a key component of Wnt signaling. PS1 undergoes phosphorylation at 353 and 357 serines upon enhanced activity and elevated levels of the GSK3β isoform. PS1 mutations surrounding these serines may alter the stability of the β-catenin complex. Such mutations are found in some cases of familial early-onset Alzheimer's disease (fEOAD), but their functional impact remains obscure. One of such variants of PS1, the A360T substitution, is located close to GSK3β-targeted serine residues. This variant was recently demonstrated in the French population, but more detail is needed to understand its biological effects. To assess the significance of this variant, we employed functional studies using a fibroblast cell line from an Alzheimer's disease case (a female proband) carrying the A360T mutation. Based on functional transcriptomic, cellular, and biochemical assays, we demonstrated atypically impaired β-catenin/GSK3β signaling in the A360T patient's fibroblasts. In detail, this was characterized by a decreased level of active cytosolic β-catenin and bound by PS1, an increased level of nuclear β-catenin, an increased level of inhibited GSK3β phosphorylated on Ser9, and enhanced interaction of GSK3β(Ser9) with PS1. Based on the transcriptomic profile of the A360T fibroblasts, we proposed a dysregulated transcriptional activity of β-catenin, exemplified by increased expression of various cyclin-dependent kinases and cyclins, such as cyclin D1, potentially inducing neurons' cell cycle re-entry followed by apoptosis. The A360T cells did not exhibit significant amyloid pathology. Therefore, cell death in this PS1 cytosolic loop mutation may be attributed to impaired β-catenin/GSK3β signaling rather than amyloid deposition per se. We further estimated the biological and clinical relevance of the A360T variant by whole exome sequencing (WES). WES was performed on DNA from the blood of an A360T female proband, as well as an unrelated male patient carrying the A360T mutation and his mutation-free daughter (both unavailable for the derivation of the fibroblast cell lines). WES confirmed the highest-priority AD causality of the A360T variant in PS1 and also profiled the pathways and processes involved in the A360T case, highlighting the greatest importance of altered Wnt signaling.

PMID:38069323 | DOI:10.3390/ijms242316999

Int J Mol Sci. 2023 Nov 24;24(23):16701. doi: 10.3390/ijms242316701.

ABSTRACT

BACKGROUND: Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). Although it has been used for many years, its mechanism of action remains elusive. H295R cells are, in ACC, an essential tool to evaluate drug mechanisms, although they often lead to conflicting results.

METHODS: Using different in vitro biomolecular technologies and biochemical/biophysical experiments, we evaluated how the presence of "confounding factors" in culture media and patient sera could reduce the pharmacological effect of mitotane and its metabolites.

RESULTS: We discovered that albumin, the most abundant protein in the blood, was able to bind mitotane. This interaction altered the effect of the drug by blocking its biological activity. This blocking effect was independent of the albumin source or methodology used and altered the assessment of drug sensitivity of the cell lines.

CONCLUSIONS: In conclusion, we have for the first time demonstrated that albumin does not only act as an inert drug carrier when mitotane or its metabolites are present. Indeed, our experiments clearly indicated that both albumin and human serum were able to suppress the pharmacological effect of mitotane in vitro. These experiments could represent a first step towards the individualization of mitotane treatment in this rare tumor.

PMID:38069023 | DOI:10.3390/ijms242316701

Nutrients. 2023 Dec 4;15(23):5006. doi: 10.3390/nu15235006.

ABSTRACT

Worldwide, several food-based dietary guidelines, with diverse food-grouping methods in various countries, have been developed to maintain and promote public health. However, standardized international food-grouping methods are scarce. In this study, we used two-dimensional mapping to classify foods based on their nutrient composition. The Standard Tables of Food Composition in Japan were used for mapping with a novel technique-t-distributed stochastic neighbor embedding-to visualize high-dimensional data. The mapping results showed that most foods formed food group-based clusters in the Standard Tables of Food Composition in Japan. However, the beverages did not form large clusters and demonstrated scattered distribution on the map. Green tea, black tea, and coffee are located within or near the vegetable cluster whereas cocoa is near the pulse cluster. These results were ensured by the k-nearest neighbors. Thus, beverages made from natural materials can be categorized based on their origin. Visualization of food composition could enable an enhanced comprehensive understanding of the nutrients in foods, which could lead to novel aspects of nutrient-value-based food classifications.

PMID:38068864 | DOI:10.3390/nu15235006

Plants (Basel). 2023 Nov 29;12(23):4012. doi: 10.3390/plants12234012.

ABSTRACT

Phytoremediation, an environmentally friendly and sustainable approach for addressing Cu-contaminated environments, remains underutilized in mine tailings. Arbuscular mycorrhizal fungi (AMF) play a vital role in reducing Cu levels in plants through various mechanisms, including glomalin stabilization, immobilization within fungal structures, and enhancing plant tolerance to oxidative stress. Yeasts also contribute to plant growth and metal tolerance by producing phytohormones, solubilizing phosphates, generating exopolysaccharides, and facilitating AMF colonization. This study aimed to assess the impact of AMF and yeast inoculation on the growth and antioxidant response of Oenothera picensis plants growing in Cu mine tailings amended with compost. Plants were either non-inoculated (NY) or inoculated with Meyerozyma guilliermondii (MG), Rhodotorula mucilaginosa (RM), or a combination of both (MIX). Plants were also inoculated with Claroideoglomus claroideum (CC), while others remained non-AMF inoculated (NM). The results indicated significantly higher shoot biomass in the MG-NM treatment, showing a 3.4-fold increase compared to the NY-NM treatment. The MG-CC treatment exhibited the most substantial increase in root biomass, reaching 5-fold that in the NY-NM treatment. Co-inoculation of AMF and yeast influenced antioxidant activity, particularly catalase and ascorbate peroxidase. Furthermore, AMF and yeast inoculation individually led to a 2-fold decrease in total phenols in the roots. Yeast inoculation notably reduced non-enzymatic antioxidant activity in the ABTS and CUPRAC assays. Both AMF and yeast inoculation promoted the production of photosynthetic pigments, further emphasizing their importance in phytoremediation programs for mine tailings.

PMID:38068648 | DOI:10.3390/plants12234012

Materials (Basel). 2023 Dec 2;16(23):7486. doi: 10.3390/ma16237486.

ABSTRACT

The objective of this study was to formulate dip coatings, incorporating casein, NaOH, and nanocrystalline hydroxyapatite (nanoHAp), with self-healing properties for application on ZnMg3.2 wt.% alloy in the field of biomedical applications. This study hypothesizes that the self-healing mechanism within the layer will impede substrate degradation by progressively filling defects where chlorides from simulated body fluids intervene. Furthermore, it aims to mitigate potential damage effects during the implantation process by the layer's self-healing capabilities. The research focused on the dip-coating process parameters and chemical composition of baths for producing casein coatings on Zn alloy surfaces. This study investigated the impact of casein and NaOH concentration, along with the immersion time of ZnMg3.2 wt.% samples in the coating bath, on the self-healing capability of the coating under simulated human body fluid conditions (Ringer's solution, temperature: 37 °C). Effective technology was developed by selecting specific chemical compositions and immersion times in the coating bath, enhancing the self-healing progress against coating damage in Ringer's solution at 37 °C. The most significant self-healing effect was observed when the ZnMg3.2 wt.% substrate underwent a 1 h immersion in a coating bath containing 2 g of casein, 4 g of NaOH, and 0.1 g of nanoHAp powder. Electrochemical tests were instrumental in determining the optimal casein concentration and immersion time of the Zn alloy in the coating bath.

PMID:38068230 | DOI:10.3390/ma16237486

Molecules. 2023 Nov 30;28(23):7870. doi: 10.3390/molecules28237870.

ABSTRACT

The Guest Editors Federica Sodano, Elena Gazzano, and Roberta Fruttero are pleased to present this editorial overview of the Special Issue entitled "Nitric Oxide Donors for Biomedical Applications: A Themed Issue Dedicated to Professor Alberto Gasco" [...].

PMID:38067600 | DOI:10.3390/molecules28237870

Cancers (Basel). 2023 Nov 30;15(23):5660. doi: 10.3390/cancers15235660.

ABSTRACT

PURPOSE: In recent years, mathematical models have become instrumental in cancer research, offering insights into tumor growth dynamics, and guiding the development of pharmacological strategies. These models, encompassing diverse biological and physical processes, are increasingly used in clinical settings, showing remarkable predictive precision for individual patient outcomes and therapeutic responses.

METHODS: Motivated by these advancements, our study introduces an innovative in silico model for simulating tumor growth and invasiveness. The automated hybrid cell emulates critical tumor cell characteristics, including rapid proliferation, heightened motility, reduced cell adhesion, and increased responsiveness to chemotactic signals. This model explores the potential evolution of 3D tumor spheroids by manipulating biological parameters and microenvironment factors, focusing on nutrient availability.

RESULTS: Our comprehensive global and local sensitivity analysis reveals that tumor growth primarily depends on cell duplication speed and cell-to-cell adhesion, rather than external chemical gradients. Conversely, tumor invasiveness is predominantly driven by chemotaxis. These insights illuminate tumor development mechanisms, providing vital guidance for effective strategies against tumor progression. Our proposed model is a valuable tool for advancing cancer biology research and exploring potential therapeutic interventions.

PMID:38067364 | DOI:10.3390/cancers15235660

Cancers (Basel). 2023 Nov 29;15(23):5645. doi: 10.3390/cancers15235645.

ABSTRACT

Understanding the complex dynamics of tumor growth to develop more efficient therapeutic strategies is one of the most challenging problems in biomedicine. Three-dimensional (3D) tumor spheroids, reflecting avascular microregions within a tumor, are an advanced in vitro model system to assess the curative effect of combinatorial radio(chemo)therapy. Tumor spheroids exhibit particular crucial pathophysiological characteristics such as a radial oxygen gradient that critically affect the sensitivity of the malignant cell population to treatment. However, spheroid experiments remain laborious, and determining long-term radio(chemo)therapy outcomes is challenging. Mathematical models of spheroid dynamics have the potential to enhance the informative value of experimental data, and can support study design; however, they typically face one of two limitations: while non-spatial models are computationally cheap, they lack the spatial resolution to predict oxygen-dependent radioresponse, whereas models that describe spatial cell dynamics are computationally expensive and often heavily parameterized, impeding the required calibration to experimental data. Here, we present an effectively one-dimensional mathematical model based on the cell dynamics within and across radial spheres which fully incorporates the 3D dynamics of tumor spheroids by exploiting their approximate rotational symmetry. We demonstrate that this radial-shell (RS) model reproduces experimental spheroid growth curves of several cell lines with and without radiotherapy, showing equal or better performance than published models such as 3D agent-based models. Notably, the RS model is sufficiently efficient to enable multi-parametric optimization within previously reported and/or physiologically reasonable ranges based on experimental data. Analysis of the model reveals that the characteristic change of dynamics observed in experiments at small spheroid volume originates from the spatial scale of cell interactions. Based on the calibrated parameters, we predict the spheroid volumes at which this behavior should be observable. Finally, we demonstrate how the generic parameterization of the model allows direct parameter transfer to 3D agent-based models.

PMID:38067348 | DOI:10.3390/cancers15235645

Cancers (Basel). 2023 Nov 26;15(23):5595. doi: 10.3390/cancers15235595.

ABSTRACT

Cervical cancer represents a significant global health concern, stemming from persistent infections with high-risk types of human papillomavirus (HPV). The understanding of cervical cancer's clinical correlates, risk factors, molecular mechanisms, stages, and associated genetic mutations is important for early detection and improved treatment strategies. Through integrated analysis of clinical and molecular datasets, this study aims to identify key factors that are overlapping and distinct across four cohorts of different races and regions. Here, datasets from four distinct cohorts of patients from Uganda (N = 212), the United States of America (USA) (N = 228), China (N = 106), and Venezuela (N = 858) were examined to comprehensively explore the relationships between cervical cancer stages, HPV types (clades), productive HPV integration, and malignant genetic mutations. Cohort-specific findings included the occurrence frequencies of cervical cancer stages and grades. The majority of patients from the USA and China were diagnosed with stages I and II, while those from Uganda were diagnosed with stages II and III, reflecting levels of awareness and the availability of HPV vaccines and screening services. Conversely, cervical cancer and its stages were positively correlated with HPV types (clades), HPV integration, and risk-factor habits across the cohorts. Our findings indicate that the more common squamous cervical cancer can be potentially due to productive HPV16 (clade 9) integration. At the molecular level, pathways related to HPV infection, cancer-related conditions, and viral carcinogenesis were among the most significant pathways associated with mutated genes in cervical cancer (across cohorts). These findings collectively corroborate the prominent role of HPV infection and integration leading to genetic mutation and hence to the development of cervical cancer and its stages across patients of distinct races and regions.

PMID:38067297 | DOI:10.3390/cancers15235595

Cells. 2023 Nov 28;12(23):2721. doi: 10.3390/cells12232721.

ABSTRACT

Osteopontin (OPN)-CD44 signaling plays an important role in promoting tumor progression and metastasis. In cancer, OPN and CD44 overexpression is a marker of aggressive disease and poor prognosis, and correlates with therapy resistance. In this study, we aimed to evaluate the association of single nucleotide polymorphisms (SNPs) in the OPN and CD44 genes with clinical outcomes in 307 non-small cell lung cancer (NSCLC) patients treated with radiotherapy or chemoradiotherapy. The potential impact of the variants on plasma OPN levels was also investigated. Multivariate analysis showed that OPN rs11730582 CC carriers had a significantly increased risk of death (p = 0.029), while the CD44 rs187116 A allele correlated with a reduced risk of locoregional recurrence (p = 0.016) in the curative treatment subset. The rs11730582/rs187116 combination was associated with an elevated risk of metastasis in these patients (p = 0.016). Furthermore, the OPN rs1126772 G variant alone (p = 0.018) and in combination with rs11730582 CC (p = 7 × 10-5) was associated with poor overall survival (OS) in the squamous cell carcinoma subgroup. The rs11730582 CC, rs187116 GG, and rs1126772 G, as well as their respective combinations, were independent risk factors for unfavorable treatment outcomes. The impact of rs11730582-rs1126772 haplotypes on OS was also observed. These data suggest that OPN and CD44 germline variants may predict treatment effects in NSCLC.

PMID:38067149 | DOI:10.3390/cells12232721

Cells. 2023 Nov 21;12(23):2674. doi: 10.3390/cells12232674.

ABSTRACT

Bacterial membrane vesicles (BMVs) are produced by most bacteria and participate in various cellular processes, such as intercellular communication, nutrient exchange, and pathogenesis. Notably, these vesicles can contain virulence factors, including toxic proteins, DNA, and RNA. Such factors can contribute to the harmful effects of bacterial pathogens on host cells and tissues. Although the general effects of BMVs on host cellular physiology are well known, the underlying molecular mechanisms are less understood. In this study, we introduce a vesicle quantification method, leveraging the membrane dye FM4-64. We utilize a linear regression model to analyze the fluorescence emitted by stained vesicle membranes to ensure consistent and reproducible vesicle-host interaction studies using cultured cells. This method is particularly valuable for identifying host cellular processes impacted by vesicles and their specific cargo. Moreover, it outcompetes unreliable protein concentration-based methods. We (1) show a linear correlation between the number of vesicles and the fluorescence signal emitted from the FM4-64 dye; (2) introduce the "vesicle load" as a new semi-quantitative unit, facilitating more reproducible vesicle-cell culture interaction experiments; (3) show that a stable vesicle load yields consistent host responses when studying vesicles from Pseudomonas aeruginosa mutants; (4) demonstrate that typical vesicle isolation contaminants, such as flagella, do not significantly skew the metabolic response of lung epithelial cells to P. aeruginosa vesicles; and (5) identify inositol monophosphatase 1 (SuhB) as a pivotal regulator in the vesicle-mediated pathogenesis of P. aeruginosa.

PMID:38067103 | DOI:10.3390/cells12232674

Animals (Basel). 2023 Dec 4;13(23):3744. doi: 10.3390/ani13233744.

ABSTRACT

Environmental filtering shapes animal communities by preventing the colonization and persistence of certain species in a given habitat. More heterogenous environments are presumed to support a greater number of species and, consequently, increased species diversity, as environmental filters are also likely more heterogenous. Amphibians are especially sensitive to environmental influences due to distinct characteristics like permeable skin and low mobility. By analyzing the species richness and assemblage composition of tadpoles in 132 breeding ponds, we examined how the interplay of environmental variables shapes anuran species assemblages in breeding habitats of the dry forest of Western Madagascar. We found that environmental filtering is prevalent and habitat heterogeneity not only increases larval species richness but also alters species composition between these assemblages. Our study highlights the need for conserving heterogenous habitats to maintain local diversity. Furthermore, we recommend including multivariate modelling approaches to conservation efforts to acknowledge differences between specific habitats and beta diversity.

PMID:38067095 | DOI:10.3390/ani13233744

J Exp Bot. 2023 Dec 8:erad490. doi: 10.1093/jxb/erad490. Online ahead of print.

ABSTRACT

NRT2.1, the major high affinity nitrate transporter in roots, can be phosphorylated at five different sites within N- and C-terminus. Here, we characterized the functional relationship of two N-terminal phosphorylation sites, S21 and S28. Based on a site-specific correlation network we identified a receptor kinase (HPCAL1, AT5G49770), phosphorylating NRT2.1 at S21 and resulting in active nitrate uptake. HPCAL1 itself was regulated by phosphorylation at S839 and S870 within its kinase domain. In the active state, when S839 was dephosphorylated and S870 was phosphorylated, HPCAL1 was found to interact with the N-terminus of NRT2.1, mainly when S28 was dephosphorylated. Phosphorylation of NRT2.1 at S21 resulted in a reduced interaction of NRT2.1 with its activator NAR2.1, but nitrate transport activity remained. By contrast, phosphorylated NRT2.1 at S28 enhanced the interaction with NAR2.1, but reduced the interaction with HPCAL1. HPCAL1 here was identified as the kinase affecting this phospho-switch through phosphorylation of NRT2.1 at S21.

PMID:38066636 | DOI:10.1093/jxb/erad490

Cancer Cell Int. 2023 Dec 8;23(1):315. doi: 10.1186/s12935-023-03150-y.

ABSTRACT

Type I interferons (IFNs) play a central role not only in innate immunity against viral infection, but also in the antitumour response, e.g. through a direct impact on cell proliferation. Particularly for cancer arising in the context of chronic inflammation, constant exposure to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of neoplastic subclones resistant to the antiproliferative effects of IFNs may contribute to immunoediting of tumours, leading to more aggressive disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that six weeks exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines, most prominently in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours. In both, long-term IFN selection and in dedifferentiated tumour cell lines, we found IFNAR2 expression to be substantially reduced, suggesting the receptor complex to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.

PMID:38066598 | DOI:10.1186/s12935-023-03150-y

Acta Neuropathol Commun. 2023 Dec 8;11(1):193. doi: 10.1186/s40478-023-01662-2.

ABSTRACT

The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also in many cases of post-infectious syndromes, colloquially referred to as "long COVID". Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms. We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues. In addition, complement system related proteins were more abundant in the serum of patients with PCS, matching observations on the transcriptomic level in the muscle tissue. We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.

PMID:38066589 | DOI:10.1186/s40478-023-01662-2

BMC Psychiatry. 2023 Dec 8;23(1):922. doi: 10.1186/s12888-023-05433-0.

ABSTRACT

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can invade both the peripheral and central nervous systems and impact the function of the brain. Therefore, it is necessary to evaluate the mutual influences between COVID-19 outcomes and childhood mental disorders.

METHODS: We examined genetic correlations and potential causalities between three childhood mental disorders and three COVID-19 phenotypes by genetically proxied analyses. The three mental disorders included attention-deficit/hyperactivity disorder (ADHD, N = 292,548), Tourette's syndrome (TS, N = 14,307), and autism spectrum disorder (ASD, N = 46,350). The three COVID-19 traits included SARS-CoV-2 infection (N = 2,597,856), hospitalized COVID-19 (N = 2,095,324), and critical COVID-19 (N = 1,086,211). Literature-based analysis was used to build gene-based pathways connecting ADHD and COVID-19.

RESULTS: ADHD was positively correlated with the three COVID-19 outcomes (Rg: 0.22 ~ 0.30). Our Mendelian randomization (MR) analyses found that ADHD confers a causal effect on hospitalized COVID-19 (odds ratio (OR): 1.36, 95% confidence interval (CI): 1.10-1.69). TS confers a causal effect on critical COVID-19 (OR: 1.14, 95% CI: 1.04-1.25). Genetic liability to the COVID-19 outcomes may not increase the risk for the childhood mental disorders. Pathway analysis identified several immunity-related genes that may link ADHD to COVID-19, including CRP, OXT, IL6, PON1, AR, TNFSF12, and IL10.

CONCLUSIONS: Our study suggests that both ADHD and TS may augment the severity of COVID-19 through immunity-related pathways. However, our results did not support a causal role of COVID-19 in the risk for the childhood mental disorders.

PMID:38066446 | DOI:10.1186/s12888-023-05433-0

NPJ Biofilms Microbiomes. 2023 Dec 8;9(1):95. doi: 10.1038/s41522-023-00463-8.

ABSTRACT

The human microbiome has emerged as a key player in maintaining skin health, and dysbiosis has been linked to various skin disorders. Amidst growing concerns regarding the side effects of antibiotic treatments, the potential of live biotherapeutic products (LBPs) in restoring a healthy microbiome has garnered significant attention. This review aims to evaluate the current state of the art of the genetically or metabolically engineered LBPs, termed single-cell engineered LBPs (eLBPs), for skin repair and disease treatment. While some studies demonstrate promising outcomes, the translation of eLBPs into clinical applications remains a significant hurdle. Substantial concerns arise regarding the practical implementation and scalability of eLBPs, despite the evident potential they hold in targeting specific cells and delivering therapeutic agents. This review underscores the need for further research, robust clinical trials, and the exploration of current advances in eLBP-based bioengineered bacterial chassis and new outlooks to substantiate the viability and effectiveness of eLBPs as a transformative approach in skin repair and disease intervention.

PMID:38065982 | DOI:10.1038/s41522-023-00463-8

Genome Res. 2023 Dec 8. doi: 10.1101/gr.277061.122. Online ahead of print.

ABSTRACT

Recent studies have shown that the noncoding genome can produce unannotated proteins as antigens that induce immune response. One major source of this activity is the aberrant epigenetic reactivation of transposable elements (TEs). In tumors, TEs often provide cryptic or alternate promoters, which can generate transcripts that encode tumor-specific unannotated proteins. Thus, TE-derived transcripts (TE transcripts) have the potential to produce tumor-specific, but recurrent, antigens shared among many tumors. Identification of TE-derived tumor antigens holds the promise to improve cancer immunotherapy approaches; however, current genomics and computational tools are not optimized for their detection. Here we combined CAGE technology with full-length long-read transcriptome sequencing (long-read CAGE, or LRCAGE) and developed a suite of computational tools to significantly improve immunopeptidome detection by incorporating TE and other tumor transcripts into the proteome database. By applying our methods to human lung cancer cell line H1299 data, we show that long-read technology significantly improves mapping of promoters with low mappability scores and that LRCAGE guarantees accurate construction of uncharacterized 5' transcript structure. Augmenting a reference proteome database with newly characterized transcripts enabled us to detect noncanonical antigens from HLA-pulldown LC-MS/MS data. Lastly, we show that epigenetic treatment increased the number of noncanonical antigens, particularly those encoded by TE transcripts, which might expand the pool of targetable antigens for cancers with low mutational burden.

PMID:38065624 | DOI:10.1101/gr.277061.122

Nature. 2023 Dec 8. doi: 10.1038/s41586-023-06920-w. Online ahead of print.

NO ABSTRACT

PMID:38066327 | DOI:10.1038/s41586-023-06920-w

Cell Stem Cell. 2023 Dec 7;30(12):1658-1673.e10. doi: 10.1016/j.stem.2023.11.006.

ABSTRACT

Stem cells regulate their self-renewal and differentiation fate outcomes through both symmetric and asymmetric divisions. m6A RNA methylation controls symmetric commitment and inflammation of hematopoietic stem cells (HSCs) through unknown mechanisms. Here, we demonstrate that the nuclear speckle protein SON is an essential m6A target required for murine HSC self-renewal, symmetric commitment, and inflammation control. Global profiling of m6A identified that m6A mRNA methylation of Son increases during HSC commitment. Upon m6A depletion, Son mRNA increases, but its protein is depleted. Reintroduction of SON rescues defects in HSC symmetric commitment divisions and engraftment. Conversely, Son deletion results in a loss of HSC fitness, while overexpression of SON improves mouse and human HSC engraftment potential by increasing quiescence. Mechanistically, we found that SON rescues MYC and suppresses the METTL3-HSC inflammatory gene expression program, including CCL5, through transcriptional regulation. Thus, our findings define a m6A-SON-CCL5 axis that controls inflammation and HSC fate.

PMID:38065069 | DOI:10.1016/j.stem.2023.11.006