Nat Methods. 2024 Mar 26. doi: 10.1038/s41592-024-02211-y. Online ahead of print.

ABSTRACT

Most proteins are organized in macromolecular assemblies, which represent key functional units regulating and catalyzing most cellular processes. Affinity purification of the protein of interest combined with liquid chromatography coupled to tandem mass spectrometry (AP-MS) represents the method of choice to identify interacting proteins. The composition of complex isoforms concurrently present in the AP sample can, however, not be resolved from a single AP-MS experiment but requires computational inference from multiple time- and resource-intensive reciprocal AP-MS experiments. Here we introduce deep interactome profiling by mass spectrometry (DIP-MS), which combines AP with blue-native-PAGE separation, data-independent acquisition with mass spectrometry and deep-learning-based signal processing to resolve complex isoforms sharing the same bait protein in a single experiment. We applied DIP-MS to probe the organization of the human prefoldin family of complexes, resolving distinct prefoldin holo- and subcomplex variants, complex-complex interactions and complex isoforms with new subunits that were experimentally validated. Our results demonstrate that DIP-MS can reveal proteome modularity at unprecedented depth and resolution.

PMID:38532014 | DOI:10.1038/s41592-024-02211-y

Nat Commun. 2024 Mar 26;15(1):2658. doi: 10.1038/s41467-024-47041-w.

NO ABSTRACT

PMID:38531897 | DOI:10.1038/s41467-024-47041-w

RNA Biol. 2024 Jan;21(1):1-10. doi: 10.1080/15476286.2024.2332856. Epub 2024 Mar 26.

ABSTRACT

Transgene silencing is a common phenomenon observed in Caenorhabditis elegans, particularly in the germline, but the precise mechanisms underlying this process remain elusive. Through an analysis of the transcription factors profile of C. elegans, we discovered that the expression of several transgenic reporter lines exhibited tissue-specific silencing, specifically in the intestine of C. elegans. Notably, this silencing could be reversed in mutants defective in endogenous RNA interference (RNAi). Further investigation using knock-in strains revealed that these intestine-silent genes were indeed expressed in vivo, indicating that the organism itself regulates the intestine-specific silencing. This tissue-specific silencing appears to be mediated through the endo-RNAi pathway, with the main factors of this pathway, mut-2 and mut-16, are significantly enriched in the intestine. Additionally, histone modification factors, such as met-2, are involved in this silencing mechanism. Given the crucial role of the intestine in reproduction alongside the germline, the transgene silencing observed in the intestine reflects the self-protective mechanisms employed by the organisms. In summary, our study proposed that compared to other tissues, the transgenic silencing of intestine is specifically regulated by the endo-RNAi pathway.

PMID:38531838 | DOI:10.1080/15476286.2024.2332856

Int J Sports Physiol Perform. 2024 Mar 26:1-5. doi: 10.1123/ijspp.2023-0451. Online ahead of print.

ABSTRACT

BACKGROUND: Durability (ie, the ability to attenuate the decline in performance after accumulated work) has been identified as a performance determinant in elite cyclists. The aim of the present study was to compare durability in elite cyclists of various performance levels, particularly after high-intensity work, referred to as "high-intensity durability."

METHODS: Forty-nine (N = 49) male road cyclists were categorized as either under 23 years of age (U23) (N = 11), Pro Team (N = 13), or World Tour (N = 24). The participants' critical power (CP) was assessed during the preseason. Thereafter, the participants' maximum mean power (MMP) values were determined for efforts of different durations (from 5 s to 30 min) after different levels of accumulated work above CP (from 0 to 7.5 kJ·kg-1).

RESULTS: U23 cyclists showed a significant reduction of all relative MMP values for durations ≥1 minute after ≥5 kJ·kg-1 above CP compared with the "fresh" state (0 kJ·kg-1), whereas in Pro Team and World Tour cyclists, a significant reduction was not observed until 7.5 kJ·kg-1 above CP. In the "fresh" state, both Pro Team and particularly World Tour cyclists attained higher MMP values for efforts ≥10 minutes than U23 riders. However, more differences emerged with greater previous work levels, and indeed after 7.5 kJ·kg-1 above CP World Tour cyclists attained higher MMP values than both U23 and Pro Team cyclists for most efforts (≥30 s).

CONCLUSION: Pro Team and particularly World Tour cyclists tolerate greater levels of accumulated work at high intensity, which might support the importance of high-intensity durability for performance.

PMID:38531349 | DOI:10.1123/ijspp.2023-0451

Emerg Microbes Infect. 2024 Dec;13(1):2320929. doi: 10.1080/22221751.2024.2320929. Epub 2024 Mar 26.

ABSTRACT

The multi-drug resistant pathogen Acinetobacter baumannii has gained global attention as an important clinical challenge. Owing to its ability to survive on surfaces, its capacity for horizontal gene transfer, and its resistance to front-line antibiotics, A. baumannii has established itself as a successful pathogen. Bacterial conjugation is a central mechanism for pathogen evolution. The epidemic multidrug-resistant A. baumannii ACICU harbours a plasmid encoding a Type IV Secretion System (T4SS) with homology to the E. coli F-plasmid, and plasmids with homologous gene clusters have been identified in several A. baumannii sequence types. However the genetic and host strain diversity, global distribution, and functional ability of this group of plasmids is not fully understood. Using systematic analysis, we show that pACICU2 belongs to a group of almost 120 T4SS-encoding plasmids within four different species of Acinetobacter and one strain of Klebsiella pneumoniae from human and environmental origin, and globally distributed across 20 countries spanning 4 continents. Genetic diversity was observed both outside and within the T4SS-encoding cluster, and 47% of plasmids harboured resistance determinants, with two plasmids harbouring eleven. Conjugation studies with an extensively drug-resistant (XDR) strain showed that the XDR plasmid could be successfully transferred to a more divergent A. baumanii, and transconjugants exhibited the resistance phenotype of the plasmid. Collectively, this demonstrates that these T4SS-encoding plasmids are globally distributed and more widespread among Acinetobacter than previously thought, and that they represent an important potential reservoir for future clinical concern.

PMID:38530969 | DOI:10.1080/22221751.2024.2320929

PLoS One. 2024 Mar 26;19(3):e0298330. doi: 10.1371/journal.pone.0298330. eCollection 2024.

ABSTRACT

The bright colors of Alpine leaf beetles (Coleoptera, Chrysomelidae) are thought to act as aposematic signals against predation. Within the European Alps, at least six species display a basal color of either blue or green, likely configuring a classic case of müllerian mimicry. In this context, intra-population color polymorphism is paradoxical as the existence of numerous color morphs might hamper the establishment of a search image in visual predators. Assortative mating may be one of the main factors contributing to the maintenance of polymorphic populations. Due to the marked iridescence of these leaf beetles, the perceived color may change as the viewing or illumination angle changes. The present study, conducted over three years, involved intensive sampling of a population of Oreina gloriosa from the Italian Alps and applied colorimetry and a decision tree method to identify the color morphs in an objective manner. The tertiary sex ratio of the population was biased in favor of males, suggesting that viviparous females hide to give birth. Seven color morphs were identified, and their frequencies varied significantly over the course of the study. Three different analyses of mating (JMating, QInfomating, and Montecarlo simulations) recognized a general trend for random mating which coexists with some instances of positive and negative assortative mating. This could help explain the pre-eminence of one morph (which would be favored because of positive selection due to positive assortative mating) in parallel with the persistence of six other morphs (maintained due to negative assortative mating).

PMID:38530852 | DOI:10.1371/journal.pone.0298330

World J Microbiol Biotechnol. 2024 Mar 26;40(5):143. doi: 10.1007/s11274-024-03932-0.

ABSTRACT

Polystyrene (PS) is frequently used in the plastics industry. However, its structural stability and difficulty to break down lead to an abundance of plastic waste in the environment, resulting in micro-nano plastics (MNPs). As MNPs are severe hazards to both human and environmental health, it is crucial to develop innovative treatment technologies to degrade plastic waste. The biodegradation of plastics by insect gut microorganisms has gained attention as it is environmentally friendly, efficient, and safe. However, our knowledge of the biodegradation of PS is still limited. This review summarizes recent research advances on PS biodegradation by gut microorganisms/enzymes from insect larvae of different species, and schematic pathways of the degradation process are discussed in depth. Additionally, the prospect of using modern biotechnology, such as genetic engineering and systems biology, to identify novel PS-degrading microbes/functional genes/enzymes and to realize new strategies for PS biodegradation is highlighted. Challenges and limitations faced by the application of genetically engineered microorganisms (GEMs) and multiomics technologies in the field of plastic pollution bioremediation are also discussed. This review encourages the further exploration of the biodegradation of PS by insect gut microbes/enzymes, offering a cutting-edge perspective to identify PS biodegradation pathways and create effective biodegradation strategies.

PMID:38530548 | DOI:10.1007/s11274-024-03932-0

Sci Immunol. 2024 Mar 26:eadn1452. doi: 10.1126/sciimmunol.adn1452. Online ahead of print.

ABSTRACT

Plasma membrane perforation elicited by caspase cleavage of the gasdermin D (GSDMD) N-terminal domain (GSDMD-NT) triggers pyroptosis. The mechanisms underlying GSDMD membrane translocation and pore formation are not fully understood. Here, using a proteomics approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner. S-palmitoylation of GSDMD at Cys191/192 (human/mouse), catalyzed by palmitoyl acyltransferases ZDHHC5 and ZDHHC9 and facilitated by reactive oxygen species (ROS), directly mediated membrane translocation of GSDMD-NT but not full-length GSDMD (GSDMD-FL). Palmitoylation of GSDMD-FL could be induced before inflammasome activation by stimuli such as lipopolysaccharide (LPS), consequently serving as an essential molecular event in macrophage priming. Inhibition of GSDMD palmitoylation suppressed macrophage pyroptosis and IL-1β release, mitigated organ damage, and enhanced the survival of septic mice. Thus, GSDMD-NT palmitoylation is a key regulatory mechanism controlling GSDMD membrane localization and activation, which may offer an additional target for modulating immune activity in infectious and inflammatory diseases.

PMID:38530158 | DOI:10.1126/sciimmunol.adn1452

J Proteome Res. 2024 Mar 26. doi: 10.1021/acs.jproteome.4c00018. Online ahead of print.

ABSTRACT

We studied the effect of the column temperature on the selectivity of reversed-phase peptide separation in bottom-up proteomics. The number of peptide identifications from 2 h liquid chromatography with tandem mass spectrometry (LC-MS/MS) acquisitions reaches a plateau at 45-55 °C, driven simultaneously by improved separation efficiency, a gradual decrease in peptide retention, and possible on-column degradation of peptides at elevated temperatures. Performing 2D LC-MS/MS acquisitions at 25, 35, 45, and 55 °C resulted in the identification of ∼100,000 and ∼120,000 unique peptides for nonmodified and tandem mass tags (TMT)-labeled samples, respectively. These peptide collections were used to investigate the temperature-driven retention features. The latter is governed by the specific temperature response of individual residues, peptide hydrophobicity and length, and amphipathic helicity. On average, peptide retention decreased by 0.56 and 0.5% acetonitrile for each 10 °C increase for label-free and TMT-labeled peptides, respectively. This generally linear response of retention shifts allowed the extrapolation of predictive models beyond the studied temperature range. Thus, (trap) column cooling from room temperature to 0 °C will allow the retention of an additional 3% of detectable tryptic peptides. Meanwhile, the application of 90 °C would result in the loss of ∼20% of tryptic peptides that were amenable to MS/MS-based identification.

PMID:38530092 | DOI:10.1021/acs.jproteome.4c00018

Elife. 2024 Mar 26;12:RP90390. doi: 10.7554/eLife.90390.

ABSTRACT

Non-invasive early cancer diagnosis remains challenging due to the low sensitivity and specificity of current diagnostic approaches. Exosomes are membrane-bound nanovesicles secreted by all cells that contain DNA, RNA, and proteins that are representative of the parent cells. This property, along with the abundance of exosomes in biological fluids makes them compelling candidates as biomarkers. However, a rapid and flexible exosome-based diagnostic method to distinguish human cancers across cancer types in diverse biological fluids is yet to be defined. Here, we describe a novel machine learning-based computational method to distinguish cancers using a panel of proteins associated with exosomes. Employing datasets of exosome proteins from human cell lines, tissue, plasma, serum, and urine samples from a variety of cancers, we identify Clathrin Heavy Chain (CLTC), Ezrin, (EZR), Talin-1 (TLN1), Adenylyl cyclase-associated protein 1 (CAP1), and Moesin (MSN) as highly abundant universal biomarkers for exosomes and define three panels of pan-cancer exosome proteins that distinguish cancer exosomes from other exosomes and aid in classifying cancer subtypes employing random forest models. All the models using proteins from plasma, serum, or urine-derived exosomes yield AUROC scores higher than 0.91 and demonstrate superior performance compared to Support Vector Machine, K Nearest Neighbor Classifier and Gaussian Naive Bayes. This study provides a reliable protein biomarker signature associated with cancer exosomes with scalable machine learning capability for a sensitive and specific non-invasive method of cancer diagnosis.

PMID:38529947 | DOI:10.7554/eLife.90390

J Respir Biol Transl Med. 2024 Mar;1(1):10003. doi: 10.35534/jrbtm.2024.10003. Epub 2024 Feb 19.

ABSTRACT

Tissue lymphatic vessels network plays critical roles in immune surveillance and tissue homeostasis in response to pathogen invasion, but how lymphatic system per se is remolded during infection is less understood. Here, we observed that influenza infection induces a significant increase of lymphatic vessel numbers in the lung, accompanied with extensive proliferation of lymphatic endothelial cells (LECs). Single-cell RNA sequencing illustrated the heterogeneity of LECs, identifying a novel PD-L1+ subpopulation that is present during viral infection but not at steady state. Specific deletion of Pd-l1 in LECs elevated the expansion of lymphatic vessel numbers during viral infection. Together these findings elucidate a dramatic expansion of lung lymphatic network in response to viral infection, and reveal a PD-L1+ LEC subpopulation that potentially modulates lymphatic vessel remolding.

PMID:38529320 | PMC:PMC10962217 | DOI:10.35534/jrbtm.2024.10003

Front Plant Sci. 2024 Mar 11;15:1368260. doi: 10.3389/fpls.2024.1368260. eCollection 2024.

ABSTRACT

Anthocyanin is an important pigment that prevents oxidative stress and mediates adaptation of plants to salt stress. Peanuts with dark red and black testa are rich in anthocyanin. However, correlation between salt tolerance and anthocyanin content in black and dark red testa peanuts is unknown. In this study, three peanut cultivars namely YZ9102 (pink testa), JHR1 (red testa) and JHB1 (black testa) were subjected to sodium chloride (NaCl) stress. The plant growth, ion uptake, anthocyanin accumulation, oxidation resistance and photosynthetic traits were comparatively analyzed. We observed that the plant height, leaf area and biomass under salt stress was highly inhibited in pink color testa (YZ9102) as compare to black color testa (JHB1). JHB1, a black testa colored peanut was identified as the most salt-tolerance cultivar, followed by red (JHR1) and pink(YZ9102). During salt stress, JHB1 exhibited significantly higher levels of anthocyanin and flavonoid accumulation compared to JHR1 and YZ9102, along with increased relative activities of antioxidant protection and photosynthetic efficiency. However, the K+/Na+ and Ca2+/Na+ were consistently decreased among three cultivars under salt stress, suggesting that the salt tolerance of black testa peanut may not be related to ion absorption. Therefore, we predicted that salt tolerance of JHB1 may be attributed to the accumulation of the anthocyanin and flavonoids, which activated antioxidant protection against the oxidative damage to maintain the higher photosynthetic efficiency and plant growth. These findings will be useful for improving salt tolerance of peanuts.

PMID:38529061 | PMC:PMC10961369 | DOI:10.3389/fpls.2024.1368260

BMC Cancer. 2024 Mar 25;24(1):371. doi: 10.1186/s12885-024-12142-8.

ABSTRACT

BACKGROUND: The need for intelligent and effective treatment of diseases and the increase in drug design costs have raised drug repurposing as one of the effective strategies in biomedicine. There are various computational methods for drug repurposing, one of which is using transcription signatures, especially single-cell RNA sequencing (scRNA-seq) data, which show us a clear and comprehensive view of the inside of the cell to compare the state of disease and health.

METHODS: In this study, we used 91,103 scRNA-seq samples from 29 patients with colorectal cancer (GSE144735 and GSE132465). First, differential gene expression (DGE) analysis was done using the ASAP website. Then we reached a list of drugs that can reverse the gene signature pattern from cancer to normal using the iLINCS website. Further, by searching various databases and articles, we found 12 drugs that have FDA approval, and so far, no one has reported them as a drug in the treatment of any cancer. Then, to evaluate the cytotoxicity and performance of these drugs, the MTT assay and real-time PCR were performed on two colorectal cancer cell lines (HT29 and HCT116).

RESULTS: According to our approach, 12 drugs were suggested for the treatment of colorectal cancer. Four drugs were selected for biological evaluation. The results of the cytotoxicity analysis of these drugs are as follows: tezacaftor (IC10 = 19 µM for HCT-116 and IC10 = 2 µM for HT-29), fenticonazole (IC10 = 17 µM for HCT-116 and IC10 = 7 µM for HT-29), bempedoic acid (IC10 = 78 µM for HCT-116 and IC10 = 65 µM for HT-29), and famciclovir (IC10 = 422 µM for HCT-116 and IC10 = 959 µM for HT-29).

CONCLUSIONS: Cost, time, and effectiveness are the main challenges in finding new drugs for diseases. Computational approaches such as transcriptional signature-based drug repurposing methods open new horizons to solve these challenges. In this study, tezacaftor, fenticonazole, and bempedoic acid can be introduced as promising drug candidates for the treatment of colorectal cancer. These drugs were evaluated in silico and in vitro, but it is necessary to evaluate them in vivo.

PMID:38528462 | DOI:10.1186/s12885-024-12142-8

Nat Microbiol. 2024 Mar 25. doi: 10.1038/s41564-024-01645-6. Online ahead of print.

ABSTRACT

Research on microbial pathogens has traditionally relied on animal and cell culture models to mimic infection processes in the host. Over recent years, developments in microfluidics and bioengineering have led to organ-on-chip (OoC) technologies. These microfluidic systems create conditions that are more physiologically relevant and can be considered humanized in vitro models. Here we review various OoC models and how they have been applied for infectious disease research. We outline the properties that make them valuable tools in microbiology, such as dynamic microenvironments, vascularization, near-physiological tissue constitutions and partial integration of functional immune cells, as well as their limitations. Finally, we discuss the prospects for OoCs and their potential role in future infectious disease research.

PMID:38528150 | DOI:10.1038/s41564-024-01645-6

Nat Microbiol. 2024 Mar 25. doi: 10.1038/s41564-024-01642-9. Online ahead of print.

ABSTRACT

Plasticity in gene expression allows bacteria to adapt to diverse environments. This is particularly relevant in the dynamic niche of the human intestinal tract; however, transcriptional networks remain largely unknown for gut-resident bacteria. Here we apply differential RNA sequencing (RNA-seq) and conventional RNA-seq to the model gut bacterium Bacteroides thetaiotaomicron to map transcriptional units and profile their expression levels across 15 in vivo-relevant growth conditions. We infer stress- and carbon source-specific transcriptional regulons and expand the annotation of small RNAs (sRNAs). Integrating this expression atlas with published transposon mutant fitness data, we predict conditionally important sRNAs. These include MasB, which downregulates tetracycline tolerance. Using MS2 affinity purification and RNA-seq, we identify a putative MasB target and assess its role in the context of the MasB-associated phenotype. These data-publicly available through the Theta-Base web browser ( http://micromix.helmholtz-hiri.de/bacteroides/ )-constitute a valuable resource for the microbiome community.

PMID:38528147 | DOI:10.1038/s41564-024-01642-9

NPJ Syst Biol Appl. 2024 Mar 25;10(1):32. doi: 10.1038/s41540-024-00352-6.

ABSTRACT

Acute myeloid leukemia (AML) is prevalent in both adult and pediatric patients. Despite advances in patient categorization, the heterogeneity of AML remains a challenge. Recent studies have explored the use of gene expression data to enhance AML diagnosis and prognosis, however, alternative approaches rooted in physics and chemistry may provide another level of insight into AML transformation. Utilizing publicly available databases, we analyze 884 human and mouse blood and bone marrow samples. We employ a personalized medicine strategy, combining state-transition theory and surprisal analysis, to assess the RNA transcriptome of individual patients. The transcriptome is transformed into physical parameters that represent each sample's steady state and the free energy change (FEC) from that steady state, which is the state with the lowest free energy.We found the transcriptome steady state was invariant across normal and AML samples. FEC, representing active molecular processes, varied significantly between samples and was used to create patient-specific barcodes to characterize the biology of the disease. We discovered that AML samples that were in a transition state had the highest FEC. This disease state may be characterized as the most unstable and hence the most therapeutically targetable since a change in free energy is a thermodynamic requirement for disease progression. We also found that distinct sets of ongoing processes may be at the root of otherwise similar clinical phenotypes, implying that our integrated analysis of transcriptome profiles may facilitate a personalized medicine approach to cure AML and restore a steady state in each patient.

PMID:38527998 | DOI:10.1038/s41540-024-00352-6

Exp Gerontol. 2024 Mar 23:112410. doi: 10.1016/j.exger.2024.112410. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic low-grade inflammatory profile (CLIP) is one of the pathways involved in type 2 diabetes (T2D). Currently, there is limited evidence for ameliorating effects of combined lifestyle interventions on CLIP in type 2 diabetes. We investigated whether a 13-week combined lifestyle intervention, using hypocaloric diet and resistance exercise plus high-intensity interval training with or without consumption of a protein drink, affected CLIP in older adults with T2D.

METHODS: In this post-hoc analysis of the PROBE study 114 adults (≥55 years) with obesity and type 2 (pre-)diabetes had measurements of C-reactive protein (CRP), pro-inflammatory cytokines interleukin (IL)-6, tumor-necrosis-factor (TNF)-α, and monocyte chemoattractant protein (MCP)-1, anti-inflammatory cytokines IL-10, IL-1 receptor antagonist (RA), and soluble tumor-necrosis-factor receptor (sTNFR)1, adipokines leptin and adiponectin, and glycation biomarkers carboxymethyl-lysine (CML) and soluble receptor for advanced glycation end products (sRAGE) from fasting blood samples. A linear mixed model was used to evaluate change in inflammatory biomarkers after lifestyle intervention and effect of the protein drink. Linear regression analysis was performed with parameters of body composition (by dual-energy X-ray absorptiometry) and parameters of insulin resistance (by oral glucose tolerance test).

RESULTS: There were no significant differences in CLIP responses between the protein and the control groups. For all participants combined, IL-1RA, leptin and adiponectin decreased after 13 weeks (p = 0.002, p < 0.001 and p < 0.001), while ratios TNF-α/IL-10 and TNF-α/IL-1RA increased (p = 0.003 and p = 0.035). CRP increased by 12 % in participants with low to average CLIP (pre 1.91 ± 0.39 mg/L, post 2.13 ± 1.16 mg/L, p = 0.006) and decreased by 36 % in those with high CLIP (pre 5.14 mg/L ± 1.20, post 3.30 ± 2.29 mg/L, p < 0.001). Change in leptin and IL-1RA was positively associated with change in fat mass (β = 0.133, p < 0.001; β = 0.017, p < 0.001) and insulin resistance (β = 0.095, p = 0.024; β = 0.020, p = 0.001). Change in lean mass was not associated with any of the biomarkers.

CONCLUSION: 13 weeks of combined lifestyle intervention, either with or without protein drink, reduced circulating adipokines and anti-inflammatory cytokine IL-1RA, and increased inflammatory ratios TNF-α/IL-10 and TNF-α/IL-1RA in older adults with obesity and T2D. Effect on CLIP was inversely related to baseline inflammatory status.

PMID:38527636 | DOI:10.1016/j.exger.2024.112410

Cancer Discov. 2024 Mar 21:OF1-OF24. doi: 10.1158/2159-8290.CD-23-1161. Online ahead of print.

ABSTRACT

Patients with estrogen receptor-positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients relapse even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late relapse patients and longitudinally profiled a rare cohort treated with long-term neoadjuvant ETs until progression. Next, we developed an in vitro evolutionary study to record the adaptive strategies of individual lineages in unperturbed parallel experiments. Our data demonstrate that ETs induce nongenetic cell state transitions into dormancy in a stochastic subset of cells via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably in the absence of recurrent genetic alterations. Targeting the dormant epigenome shows promising activity against adapting cancer cells. Overall, this study uncovers the contribution of epigenetic adaptation to the evolution of resistance to ETs.

SIGNIFICANCE: This study advances the understanding of therapy-induced dormancy with potential clinical implications for breast cancer. Estrogen receptor-positive breast cancer cells adapt to endocrine treatment by entering a dormant state characterized by strong heterochromatinization with no recurrent genetic changes. Targeting the epigenetic rewiring impairs the adaptation of cancer cells to ETs.

PMID:38527495 | DOI:10.1158/2159-8290.CD-23-1161

Wiley Interdiscip Rev RNA. 2024 Mar-Apr;15(2):e1839. doi: 10.1002/wrna.1839.

ABSTRACT

Spatially resolved transcriptomics has been dramatically transforming biological and medical research in various fields. It enables transcriptome profiling at single-cell, multi-cellular, or sub-cellular resolution, while retaining the information of geometric localizations of cells in complex tissues. The coupling of cell spatial information and its molecular characteristics generates a novel multi-modal high-throughput data source, which poses new challenges for the development of analytical methods for data-mining. Spatial transcriptomic data are often highly complex, noisy, and biased, presenting a series of difficulties, many unresolved, for data analysis and generation of biological insights. In addition, to keep pace with the ever-evolving spatial transcriptomic experimental technologies, the existing analytical theories and tools need to be updated and reformed accordingly. In this review, we provide an overview and discussion of the current computational approaches for mining of spatial transcriptomics data. Future directions and perspectives of methodology design are proposed to stimulate further discussions and advances in new analytical models and algorithms. This article is categorized under: RNA Methods > RNA Analyses in Cells RNA Evolution and Genomics > Computational Analyses of RNA RNA Export and Localization > RNA Localization.

PMID:38527900 | DOI:10.1002/wrna.1839

OMICS. 2024 Mar;28(3):125-137. doi: 10.1089/omi.2024.0002.

ABSTRACT

Nematode infections are common in both humans and livestock, with major adverse planetary health and economic impacts. Wuchereria bancrofti is a parasitic nematode that causes lymphatic filariasis, a neglected tropical disease that can lead to severe disability and deformity worldwide. For the long-term survival of the bancroftian parasites in the host, a complex immune invasion strategy is involved through immunomodulation. Therefore, immunomodulation can serve as a site of research and innovation for molecular targets. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine crucial to the host antimicrobial alarm system and stress response. Interestingly, the nematode parasite W. bancrofti also produces two homologs of MIF (Wba-MIF1 and 2). Using a mass spectrometry-based phosphoproteomics approach, we report new findings on the immunomodulatory effect and signaling mechanism of Wba-MIF2 in macrophage cells. Accordingly, we observed 1201 phosphorylated sites on 467 proteins. Out of the 1201 phosphorylated sites, 1075, 117, and 9 were found on serine (S), threonine (T), and tyrosine (Y) residues, respectively. Our bioinformatics analysis led to identification of major pathways, including spliceosomes, T cell receptor signaling pathway, Th17 differentiation pathway, interleukin-17 signaling pathway, and insulin signaling pathway upon Wba-MIF2 treatment. Wba-MIF2 treatment also enriched CDK4, CDK1, and DNAPK kinases. The comparison of the signaling pathway of Wba-MIF2 with that of human-MIF suggests both share similar signaling pathways. These findings collectively offer new insights into the role and mechanism of Wba-MIF2 as an immunomodulator and inform future diagnostics and drug discovery research for W. bancrofti.

PMID:38527276 | DOI:10.1089/omi.2024.0002