Immunometabolism (Cobham). 2025 Jan 10;7(1):e00053. doi: 10.1097/IN9.0000000000000053. eCollection 2025 Jan.

ABSTRACT

The nucleotide-binding domain, leucine-rich repeat, and pyrin domain containing-protein 3 (NLRP3) inflammasome is a multiprotein complex that plays a critical role in the innate immune response to both infections and sterile stressors. Dysregulated NLRP3 activation has been implicated in a variety of autoimmune and inflammatory diseases, including cryopyrin-associated periodic fever syndromes, diabetes, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, and cancer. Consequently, fine-tuning NLRP3 activity holds significant therapeutic potential. Studies have implicated several organelles, including mitochondria, lysosomes, the endoplasmic reticulum (ER), the Golgi apparatus, endosomes, and the centrosome, in NLRP3 localization and inflammasome assembly. However, reports of conflict and many factors regulating interactions between NLRP3 and subcellular organelles remain unknown. This review synthesizes the current understanding of NLRP3 spatiotemporal dynamics, focusing on recent literature that elucidates the roles of subcellular localization and organelle stress in NLRP3 signaling and its crosstalk with other innate immune pathways converging at these organelles.

PMID:39816134 | PMC:PMC11731036 | DOI:10.1097/IN9.0000000000000053

FEBS Open Bio. 2025 Jan 15. doi: 10.1002/2211-5463.13939. Online ahead of print.

ABSTRACT

Malaria, a life-threatening disease caused by Plasmodium parasites, continues to pose a significant global health threat, with nearly 250 million infections and over 600 000 deaths reported annually by the WHO. Fighting malaria is particularly challenging partly due to the complex life cycle of the parasite. However, technological breakthroughs such as the development of the nucleoside-modified mRNA lipid nanoparticle (mRNA-LNP) vaccine platform, along with the discovery of novel conserved Plasmodium antigens such as the E140 protein, present new opportunities in malaria prevention. Importantly, production of recombinant proteins for malaria vaccine evaluation by serological assays often represents an additional hurdle because many Plasmodium proteins are complex and often contain transmembrane domains that make production and purification particularly difficult. This research protocol provides a step-by-step guide for the production and purification of P. berghei and P. vivax E140 protein fragments that can be used to test humoral immune responses against this novel malaria vaccine target. We demonstrate that the purified proteins can be successfully used in enzyme-linked immunosorbent assay (ELISA) to evaluate antigen-specific binding antibody responses in sera obtained from E140 mRNA-LNP-vaccinated mice. Therefore, these proteins can contribute to the development and evaluation of E140-based malaria vaccines.

PMID:39815669 | DOI:10.1002/2211-5463.13939

Probiotics Antimicrob Proteins. 2025 Jan 16. doi: 10.1007/s12602-025-10451-3. Online ahead of print.

ABSTRACT

The emergence of multidrug-resistant pathogens presents a significant global health challenge, which is primarily fuelled by overuse and misuse of antibiotics. Bacteria-derived antimicrobial metabolites offer a promising alternative strategy for combating antimicrobial resistance issues. Bacillus velezensis PD9 (BvPD9), isolated from stingless bee propolis, has been reported to have antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to characterise and identify the antimicrobial compounds (AMCs) synthesised by BvPD9 through integration of genome mining and liquid chromatography-mass spectrometry (LC-MS) analysis. The whole-genome sequence of BvPD9 contained 4,263,351 base pairs and 4101 protein-coding sequences, with 12 potential AMC biosynthetic gene clusters. Comparative genomic analysis highlighted the unique profile of BvPD9 that possesses the largest number of unknown proteins, indicating significant potential for further exploration. The combined genomics-metabolic profiling uncovered five AMCs in BvPD9 extract, including bacillibactin, bacilysin, surfactin A, fengycin A, and bacillomycin D. The extract exhibited a broad antibacterial spectrum against 25 pathogenic bacteria, including both Gram-positive and Gram-negative bacteria, with the lowest minimum inhibitory concentration (MIC, 0.032 mg/ml) against S. epidermidis ATCC 12228, and the lowest minimum bactericidal concentration (MBC; 0.128 mg/ml) against MRSA ATCC 700699 and Aeromonas hydrophilia. The robust stability of BvPD9 extract was demonstrated at high temperatures, over a wide range of pH conditions (6 to 12) and in the presence of various hydrolytic enzymes. Additionally, the extract showed 50% haemolytic and cytotoxicity activity at 0.158 and 0.250 mg/ml, respectively. These characteristics suggest potential applications of BvPD9 metabolites for tackling antimicrobial resistance and its applicability across diverse industries.

PMID:39815115 | DOI:10.1007/s12602-025-10451-3

Nature. 2025 Jan 15. doi: 10.1038/s41586-024-08522-6. Online ahead of print.

NO ABSTRACT

PMID:39814901 | DOI:10.1038/s41586-024-08522-6

Nature. 2025 Jan 15. doi: 10.1038/s41586-024-08426-5. Online ahead of print.

ABSTRACT

Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)-LTβ receptor (LTβR) pathway1, the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues2, induces TLSs. In mice, Il33 deficiency severely attenuates inflammation- and LTβR-activation-induced TLSs in models of colitis and pancreatic ductal adenocarcinoma (PDAC). In PDAC, the alarmin domain of IL-33 activates group 2 innate lymphoid cells (ILC2s) expressing LT that engage putative LTβR+ myeloid organizer cells to initiate tertiary lymphoneogenesis. Notably, lymphoneogenic ILC2s migrate to PDACs from the gut, can be mobilized to PDACs in different tissues and are modulated by gut microbiota. Furthermore, we detect putative lymphoneogenic ILC2s and IL-33-expressing cells within TLSs in human PDAC that correlate with improved prognosis. To harness this lymphoneogenic pathway for immunotherapy, we engineer a recombinant human IL-33 protein that expands intratumoural lymphoneogenic ILC2s and TLSs and demonstrates enhanced anti-tumour activity in PDAC mice. In summary, we identify the molecules and cells of a druggable pathway that induces inflammation-triggered TLSs. More broadly, we reveal a lymphoneogenic function for alarmins and ILC2s.

PMID:39814891 | DOI:10.1038/s41586-024-08426-5

Nat Commun. 2025 Jan 15;16(1):684. doi: 10.1038/s41467-025-56017-3.

NO ABSTRACT

PMID:39814735 | DOI:10.1038/s41467-025-56017-3

Nat Commun. 2025 Jan 15;16(1):709. doi: 10.1038/s41467-025-56128-x.

ABSTRACT

Programmed-cell death is an antimicrobial defense mechanism that promotes clearance of intracellular pathogens. Toxoplasma counteracts host immune defenses by secreting effector proteins into host cells; however, how the parasite evades lytic cell death and the effectors involved remain poorly characterized. We identified ROP55, a rhoptry protein that promotes parasite survival by preventing lytic cell death in absence of IFN-γ stimulation. RNA-Seq analysis revealed that ROP55 acts as a repressor of host pro-inflammatory responses. In THP-1 monocytes ΔROP55 infection increased NF-κB p65 nuclear translocation, IL-1β production, and GSDMD cleavage compared to wild type or complemented parasites. ΔROP55 infection also induced RIPK3-dependent necroptosis in human and mouse primary macrophages. Moreover, ΔROP55 parasites were significantly impaired in virulence in female mice and prevented NF-κB activation and parasite clearance in mBMDM. These findings place ROP55 as a major virulence factor, dampening lytic cell death and enabling Toxoplasma to evade clearance from infected cells.

PMID:39814722 | DOI:10.1038/s41467-025-56128-x

Nat Commun. 2025 Jan 16;16(1):710. doi: 10.1038/s41467-025-55928-5.

ABSTRACT

Zygotic genome activation (ZGA) is crucial for maternal to zygotic transition at the 2-8-cell stage in order to overcome silencing of genes and enable transcription from the zygotic genome. In humans, ZGA is induced by DUX4, a pioneer factor that drives expression of downstream germline-specific genes and retroelements. Here we show that herpesviruses from all subfamilies, papillomaviruses and Merkel cell polyomavirus actively induce DUX4 expression to promote viral transcription and replication. Analysis of single-cell sequencing data sets from patients shows that viral DUX4 activation is of relevance in vivo. Herpes-simplex virus 1 (HSV-1) immediate early proteins directly induce expression of DUX4 and its target genes, which mimics zygotic genome activation. Upon HSV-1 infection, DUX4 directly binds to the viral genome and promotes viral transcription. DUX4 is functionally required for infection, since genetic depletion by CRISPR/Cas9 as well as degradation of DUX4 by nanobody constructs abrogates HSV-1 replication. Our results show that DNA viruses including herpesviruses mimic an embryonic-like transcriptional program that prevents epigenetic silencing of the viral genome and facilitates herpesviral gene expression.

PMID:39814710 | DOI:10.1038/s41467-025-55928-5

Nat Commun. 2025 Jan 15;16(1):700. doi: 10.1038/s41467-024-55735-4.

NO ABSTRACT

PMID:39814709 | DOI:10.1038/s41467-024-55735-4

Nat Commun. 2025 Jan 15;16(1):698. doi: 10.1038/s41467-025-56059-7.

ABSTRACT

The Drosophila visual system is a powerful model to study the development of neural circuits. Lobula columnar neurons-LCNs are visual output neurons that encode visual features relevant to natural behavior. There are ~20 classes of LCNs forming non-overlapping synaptic optic glomeruli in the brain. To address their origin, we used single-cell mRNA sequencing to define the transcriptome of LCN subtypes and identified lines that are expressed throughout their development. We show that LCNs originate from stem cells in four distinct brain regions exhibiting different modes of neurogenesis, including the ventral and dorsal tips of the outer proliferation center, the ventral superficial inner proliferation center and the central brain. We show that this convergence of similar neurons illustrates the complexity of generating neuronal diversity, and likely reflects the evolutionary origin of each subtype that detects a specific visual feature and might influence behaviors specific to each species.

PMID:39814708 | DOI:10.1038/s41467-025-56059-7

Trends Microbiol. 2025 Jan 14:S0966-842X(24)00323-8. doi: 10.1016/j.tim.2024.12.007. Online ahead of print.

ABSTRACT

Microbiology plays an important role in most sectors. Future progress in critical areas requires diverse workforce development. We outline a pathway program that aims to provide equitable exposure to high-impact research experiences and course-based instruction to provide crucial training in growing areas of microbiology (phage discovery, synthetic biology and data science/AI).

PMID:39814665 | DOI:10.1016/j.tim.2024.12.007

J Anat. 2025 Jan 15. doi: 10.1111/joa.14200. Online ahead of print.

ABSTRACT

Anecdotally, horses' gaits sound rhythmic. Are they really? In this study, we quantified the motor rhythmicity of horses across three different gaits (walk, trot, and canter). For the first time, we adopted quantitative tools from bioacoustics and music cognition to quantify locomotor rhythmicity. Specifically, we tested whether kinematics data contained rhythmic categories; these occur when adjacent temporal intervals are categorically, rather than randomly, distributed. We extracted the motion cycle duration (tk) of two ipsilateral hooves from motion data of 13 ridden horses and calculated the ratios from two successive tk values. We tested whether these ratios significantly fell within rhythmic categories and quantified how close they were to small-integer ratios, a rhythmic feature also present in animal vocalizations and human music. We found a strong isochronous pattern-a 1:1 rhythmic ratio, corresponding to the ticking of a clock-in the motion of single limbs for all gaits. We also analyzed the interlimb coordination of the two ipsilateral hooves' impacts to identify differences associated with the biomechanical patterns of the three gaits. We found an interlimb 1:1 rhythmic pattern for trot and 1:3 and 3:1 rhythmic categories for walk and canter. Our findings are a first step toward quantifying rhythmicity in horse locomotion and potentially the resulting rhythmic sounds, with possible implications as tools to detect gait irregularities. Overall, we show that rhythmic categories are a valuable tool for gait kinematic analysis and that they can be used to quantify temporal patterns in the motor domain.

PMID:39814540 | DOI:10.1111/joa.14200

Vascul Pharmacol. 2025 Jan 13:107463. doi: 10.1016/j.vph.2025.107463. Online ahead of print.

ABSTRACT

The appropriate regulation of peripheral vascular tone is crucial for maintaining tissue perfusion. Myoendothelial junctions (MEJs), specialized connections between endothelial cells and vascular smooth muscle cells, are primarily located in peripheral resistance vessels. Therefore, these junctions, with their key membrane proteins, play a pivotal role in the physiological control of relaxation-contraction coupling in resistance arterioles, mainly mediated through endothelium-derived hyperpolarization (EDH). This review aims to illustrate the mechanisms involved in the initiation and propagation of EDH, emphasizing the role of membrane proteins involved in its generation (TRPV4, Piezo1, ASIC1a) and propagation (connexins, Notch). Finally, we discuss relevant studies on pathological events linked to EDH dysfunction and discuss novel approaches, including the effects of natural and dietary bioactive molecules, in modulating EDH-mediated vascular tone.

PMID:39814089 | DOI:10.1016/j.vph.2025.107463

Cell Rep Methods. 2025 Jan 5:100938. doi: 10.1016/j.crmeth.2024.100938. Online ahead of print.

ABSTRACT

Single-cell RNA sequencing (scRNA-seq) is invaluable for profiling cellular heterogeneity and transcriptional states, but transcriptomic profiles do not always delineate subsets defined by surface proteins. Cellular indexing of transcriptomes and epitopes (CITE-seq) enables simultaneous profiling of single-cell transcriptomes and surface proteomes; however, accurate cell-type annotation requires a classifier that integrates multimodal data. Here, we describe multimodal classifier hierarchy (MMoCHi), a marker-based approach for accurate cell-type classification across multiple single-cell modalities that does not rely on reference atlases. We benchmark MMoCHi using sorted T lymphocyte subsets and annotate a cross-tissue human immune cell dataset. MMoCHi outperforms leading transcriptome-based classifiers and multimodal unsupervised clustering in its ability to identify immune cell subsets that are not readily resolved and to reveal subset markers. MMoCHi is designed for adaptability and can integrate annotation of cell types and developmental states across diverse lineages, samples, or modalities.

PMID:39814026 | DOI:10.1016/j.crmeth.2024.100938

PLoS Biol. 2025 Jan 15;23(1):e3002984. doi: 10.1371/journal.pbio.3002984. eCollection 2025 Jan.

ABSTRACT

Noncoding satellite DNA repeats are abundant at the pericentromeric heterochromatin of eukaryotic chromosomes. During interphase, sequence-specific DNA-binding proteins cluster these repeats from multiple chromosomes into nuclear foci known as chromocenters. Despite the pivotal role of chromocenters in cellular processes like genome encapsulation and gene repression, the associated proteins remain incompletely characterized. Here, we use 2 satellite DNA-binding proteins, D1 and Prod, as baits to characterize the chromocenter-associated proteome in Drosophila embryos, ovaries, and testes through quantitative mass spectrometry. We identify D1- and Prod-associated proteins, including known heterochromatin proteins as well as proteins previously unlinked to satellite DNA or chromocenters, thereby laying the foundation for a comprehensive understanding of cellular functions enabled by satellite DNA repeats and their associated proteins. Interestingly, we find that multiple components of the transposon-silencing piRNA pathway are associated with D1 and Prod in embryos. Using genetics, transcriptomics, and small RNA profiling, we show that flies lacking D1 during embryogenesis exhibit transposon expression and gonadal atrophy as adults. We further demonstrate that this gonadal atrophy can be rescued by mutating the checkpoint kinase, Chk2, which mediates germ cell arrest in response to transposon mobilization. Thus, we reveal that a satellite DNA-binding protein functions during embryogenesis to silence transposons, in a manner that is heritable across later stages of development.

PMID:39813297 | DOI:10.1371/journal.pbio.3002984

PLoS One. 2025 Jan 15;20(1):e0316584. doi: 10.1371/journal.pone.0316584. eCollection 2025.

ABSTRACT

BACKGROUND: Rheumatoid arthritis (RA) is a degenerative autoimmune disease, often managed through symptomatic treatment. The co-occurrence of the reported extra-articular comorbidities such as inflammatory bowel disease (IBD), and dementia may complicate the pathology of the disease as well as the treatment strategies. Therefore, in our study, we aim to elucidate the key genes, and regulatory elements implicated in the progression and association of these diseases, thereby highlighting the linked potential therapeutic targets.

METHODOLOGY: Ten microarray datasets each for RA, and IBD, and nine datasets for dementia were obtained from Gene Expression Omnibus. We identified common differentially expressed genes (DEGs) and constructed a gene-gene interaction network. Subsequently, topology analysis for hub gene identification, cluster and functional enrichment, and regulatory network analysis were performed. The hub genes were then validated using independent microarray datasets from Gene Expression Omnibus.

RESULTS: A total of 198 common DEGs were identified from which CD44, FN1, IGF1, COL1A2, and POSTN were identified as the hub genes in our study. These hub genes were mostly enriched in significant processes and pathways like tissue development, collagen binding, cell adhesion, regulation of ERK1/2 cascade, PI3K-AKT signaling, and cell surface receptor signaling. Key transcription factors TWIST2, CEBPA, EP300, HDAC1, HDAC2, NFKB1, RELA, TWIST1, and YY1 along with the miRNA hsa-miR-29 were found to regulate the expression of the hub genes significantly. Among these regulatory molecules, miR-29 emerged as a significant linker molecule, bridging the molecular mechanisms of RA, IBD, and dementia. Validation of our hub genes demonstrated a similar expression trend in the independent datasets used for our study.

CONCLUSION: Our study underscores the significant role of miR-29 in modulating the expression of hub genes and the associated transcription factors, which are crucial in the comorbidity status of RA, dementia, and IBD. This regulatory mechanism highlights miR-29 as a key player in the pathogenesis of these comorbid diseases.

PMID:39813219 | DOI:10.1371/journal.pone.0316584

Anal Chem. 2025 Jan 15. doi: 10.1021/acs.analchem.4c03855. Online ahead of print.

ABSTRACT

The role of peripheral blood platelets as indicators of cancer progression is increasingly recognized, and the significance of abnormal glycosylation in platelet function and related disorders is gaining attention. However, the potential of platelets as a source of protein site-specific glycosylation for cancer diagnosis remains underexplored. In this study, we proposed a general pipeline that integrates quantitative proteomics with site-specific glycoproteomics, allowing for an in-depth investigation of the platelet glycoproteome. With this pipeline, we generated a data set comprising 3,466 proteins with qualitative information, 3,199 proteins with quantitative information, 3,419 site-specific glycans with qualitative information and 3,377 site-specific glycans with quantitative information from peripheral blood platelets of hepatocellular carcinoma (HCC) patients, metastatic liver cancer (mLC) patients, and healthy controls. The integrated analysis revealed significant changes in platelet protein N-glycosylation in liver cancer patients. Further systems biology analysis and lectin pull-down-coupled ELISA assays in independent clinical samples confirmed two N-glycoproteins with specific glycan types, complement C3 (C3) with oligomannose modification and integrin β-3 (ITGB3) with sialylation, as potential biomarkers distinguishing liver cancer patients from healthy individuals, without differentiating between HCC and mLC patient group. These findings highlight the potential of platelet protein glycosylation as biomarkers.

PMID:39813102 | DOI:10.1021/acs.analchem.4c03855

Methods Mol Biol. 2025;2891:1-14. doi: 10.1007/978-1-0716-4334-1_1.

ABSTRACT

Metabolic profiling continues to develop, and research is now conducted on this topic globally in hundreds of laboratories, from small groups up to national centers and core facilities. Here we briefly provide a perspective on the current status and challenges facing metabolic phenotyping (metabonomics/metabolomics) and consider future directions for this important area of biomarker and systems biology research.

PMID:39812974 | DOI:10.1007/978-1-0716-4334-1_1

Am J Primatol. 2025 Jan;87(1):e23723. doi: 10.1002/ajp.23723.

ABSTRACT

It is under debate whether intersubjectivity-the capacity to experience a sense of togetherness around an action-is unique to humans. In humans, heavy tickling-a repeated body probing play that causes an automatic response including uncontrollable laughter (gargalesis)-has been linked to the emergence of intersubjectivity as it is aimed at making others laugh (self-generated responses are inhibited), it is often asymmetrical (older to younger subjects), and it elicits agent-dependent responses (pleasant/unpleasant depending on social bond). Intraspecific tickling and the related gargalesis response have been reported in humans, chimpanzees, and anecdotally in other great apes, potentially setting the line between hominids and other anthropoids. Here we investigated this phenomenon in bonobos and predicted that in this species (sharing with humans and chimpanzees the last common ancestor) the presence of tickling would be modulated depending on the players' age, play session initiators, and familiarity. In April-June 2018, we collected videos on play sessions-including tickling-on a bonobo group housed at La Vallée des Singes (France). We showed that tickling received decreased while tickling performed increased with age, with tickling being mostly directed from older to younger individuals. Moreover, tickling was mostly performed by the individuals that started the play interaction and most of it occurred in strongly bonded dyads, particularly mother-infant ones. Bonobo tickling features, especially age profile and social modulation, mirror those of heavy tickling in humans thus suggesting a common evolutionary origin and shared patterns of basic intersubjectivity in hominins.

PMID:39812349 | DOI:10.1002/ajp.23723

J Med Virol. 2025 Jan;97(1):e70130. doi: 10.1002/jmv.70130.

ABSTRACT

We investigated whether antibody concentrations measured in plasma using the Roche Elecsys® Anti-SARS-CoV-2 S assay (targeting the receptor binding domain, RBD) could estimate levels of Wuhan-Hu-1 and Omicron XBB.1.5 spike-directed antibodies with neutralizing ability (NtAb) or those mediating NK-cell activity. We analyzed 135 plasma samples from 39 vaccinated elderly nursing home residents. A strong correlation was found for NtAb against both Wuhan-Hu-1 (Rho = 0.73, p < 0.001) and Omicron XBB.1.5 (sub)variants (Rho = 0.73, p < 0.001). Moderate positive correlations were observed for NK-cell activity, based on lysosome-associated membrane protein 1 (LAMP1)-producing NK cells stimulated with Wuhan-Hu-1 (Rho = 0.43, p < 0.001) and Omicron XBB.1.5 spike proteins (Rho = 0.50, p < 0.001). Similarly, interferon-gamma (IFN-γ)-producing NK-cell frequencies showed moderate correlations (Wuhan-Hu-1: Rho = 0.43, p < 0.001; Omicron XBB.1.5: Rho = 0.50, p < 0.001). Random Forest models accurately predicted NtAb levels against Wuhan-Hu-1 (R2 = 0.72), though models for Omicron XBB.1.5 were less robust. Anti-RBD antibody concentrations of 4.73 and 5.02 log10 BAU/mL predicted high NtAb levels for Wuhan-Hu-1 and Omicron XBB.1.5, respectively. Antibody thresholds for predicting functional NK cell-mediated responses were 4.73 log10 and 4.54 log10 BAU/mL for Wuhan-Hu-1 and Omicron XBB.1.5, respectively. For LAMP1-producing NK cells, the thresholds were 4.94 and 4.75 log10 BAU/mL for Wuhan-Hu-1 and Omicron XBB.1.5, respectively. In summary, total anti-RBD antibody levels measured by the Roche assay may allow inference of NtAb levels and, to a lesser extent, Fc-mediated NK-cell responses against Omicron XBB.1.5.

PMID:39812228 | DOI:10.1002/jmv.70130