Biochim Biophys Acta Mol Basis Dis. 2025 Jan 23:167688. doi: 10.1016/j.bbadis.2025.167688. Online ahead of print.

ABSTRACT

Cancer, a heterogeneous disease, presents significant challenges for drug development due to its complex etiology. Drug repurposing, particularly through network medicine approaches, offers a promising avenue for cancer treatment by analyzing how drugs influence cellular networks on a systemic scale. The advent of large-scale proteomics data provides new opportunities to elucidate regulatory mechanisms specific to cancer subtypes. Herein, we present NetSDR, a Network-based Subtype-specific Drug Repurposing framework for prioritizing repurposed drugs specific to certain cancer subtypes, guided by subtype-specific proteomic signatures and network perturbations. First, by integrating cancer subtype information into a network-based method, we developed a pipeline to recognize subtype-specific functional modules. Next, we conducted drug response analysis for each module to identify the "therapeutic module" and then used deep learning to construct weighted drug response network for the particular subtype. Finally, we employed a perturbation response scanning-based drug repurposing method, which incorporates dynamic information, to facilitate the prioritization of candidate drugs. Applying the framework to gastric cancer, we attested the significance of the extracellular matrix module in treatment strategies and discovered a promising potential drug target, LAMB2, as well as a series of possible repurposed drugs. This study demonstrates a systems biology framework for precise drug repurposing in cancer and other complex diseases.

PMID:39862994 | DOI:10.1016/j.bbadis.2025.167688

Cell. 2025 Jan 22:S0092-8674(25)00032-7. doi: 10.1016/j.cell.2025.01.003. Online ahead of print.

ABSTRACT

Knowledge of protein-metabolite interactions can enhance mechanistic understanding and chemical probing of biochemical processes, but the discovery of endogenous ligands remains challenging. Here, we combined rapid affinity purification with precision mass spectrometry and high-resolution molecular docking to precisely map the physical associations of 296 chemically diverse small-molecule metabolite ligands with 69 distinct essential enzymes and 45 transcription factors in the gram-negative bacterium Escherichia coli. We then conducted systematic metabolic pathway integration, pan-microbial evolutionary projections, and independent in-depth biophysical characterization experiments to define the functional significance of ligand interfaces. This effort revealed principles governing functional crosstalk on a network level, divergent patterns of binding pocket conservation, and scaffolds for designing selective chemical probes. This structurally resolved ligand interactome mapping pipeline can be scaled to illuminate the native small-molecule networks of complete cells and potentially entire multi-cellular communities.

PMID:39862855 | DOI:10.1016/j.cell.2025.01.003

EBioMedicine. 2025 Jan 24;112:105558. doi: 10.1016/j.ebiom.2025.105558. Online ahead of print.

ABSTRACT

BACKGROUND: Aging increases disease susceptibility and reduces vaccine responsiveness, highlighting the need to better understand the aging immune system and its clinical associations. Studying the human immune system, however, remains challenging due to its complexity and significant inter-individual variability.

METHODS: We conducted an immune profiling study of 550 elderly participants (≥60 years) and 100 young controls (20-40 years) from the RESIST Senior Individuals (SI) cohort. Extensive demographic, clinical, and laboratory data were collected. Multi-color spectral flow cytometry and 48-plex plasma cytokine assays were used for deep immune phenotyping. Data were analyzed using unsupervised clustering and multi-dataset integration approaches.

FINDINGS: We studied 97 innate and adaptive immune cell populations, revealing intricate age- and sex-related changes in the elderly immune system. Our large sample size allowed detection of even subtle changes in cytokines and immune cell clusters. Integrative analysis combining clinical, laboratory, and immunological data revealed systems-level aging signatures, including shifts in specific immune cell subpopulations and cytokine concentrations (e.g., HGF and CCL27). Additionally, we identified unique immune signatures associated with smoking, obesity, and diseases such as osteoporosis, heart failure, and gout.

INTERPRETATION: This study provides one of the most comprehensive immune profiles of elderly individuals, uncovering high-resolution immune changes associated with aging. Our findings highlight clinically relevant immune signatures that enhance our understanding of aging-related diseases and could guide future research into new treatments, offering translational insights into human health and aging.

FUNDING: Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC 2155-project number 390874280.

PMID:39862806 | DOI:10.1016/j.ebiom.2025.105558

Placenta. 2025 Jan 20;161:31-38. doi: 10.1016/j.placenta.2025.01.009. Online ahead of print.

ABSTRACT

INTRODUCTION: Fusion of mononucleated cytotrophoblasts into syncytium leads to trophoblast senescence. Yet, premature senescence is associated with preeclampsia, fetal growth restriction (FGR), and related obstetrical syndromes. A set of 28 transcripts that comprise senescence-associated secretory phenotype (SASP) was recently described in placentas from women with preeclampsia. We posited that this transcript set is uniquely regulated in late-term placentas or in placentas derived from participants with major obstetrical syndromes.

METHODS: Using our large placental RNAseq bank, we analyzed data from healthy participants (n = 33) with histologically normal placentas, representing delivery at 37-41 weeks. To represent diseases, we included RNAseq data from participants (n = 220) with severe preeclampsia, FGR, FGR with a hypertensive disorder (FGR + HDP), or spontaneous preterm delivery, and healthy controls (n = 129). We also assessed the expression of several SASPs in primary human trophoblasts that were exposed in vitro to hypoxia, reduced differentiation, or ferroptotic or apoptotic signals.

RESULTS: Among the 28 SASP transcripts analyzed, eight had a significant change between deliveries at <37 weeks vs ≥ 41 weeks, including upregulation of FSTL3, IL1RL1, INHBA, and VEGFA and downregulation of STC1, RARRES2, MRC2, and SELP. The expression of SASP mRNAs was enriched in the placentas from the assessed syndromes, with most expression changes in placentas from FGR/HDP. Our in vitro analysis associated hypoxia or apoptosis with altered expression of FSTL3, VEGFA, and DKK1.

DISCUSSION: A set of placental SASPs defines late-term placentas, placental dysfunction-related clinical syndromes, and in vitro-defined trophoblast injury. Trophoblastic SASP signatures may assist in characterizing placental senescence in health and disease.

PMID:39862734 | DOI:10.1016/j.placenta.2025.01.009

Genomics Proteomics Bioinformatics. 2025 Jan 25:qzaf002. doi: 10.1093/gpbjnl/qzaf002. Online ahead of print.

ABSTRACT

Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) techniques hold great value in evaluating the heterogeneity and spatial characteristics of hematopoietic cells within tissues. These two techniques are highly complementary, with scRNA-seq offering single-cell resolution and ST retaining spatial information. However, there is an urgent demand for well-organized and user-friendly toolkits capable of handling single-cell and spatial information. Here, we present HemaScope, a specialized bioinformatics toolkit featuring modular designs to analyze scRNA-seq and ST data generated from hematopoietic cells. It enables users to perform quality control, basic analysis, cell atlas construction, cellular heterogeneity exploration, and dynamical examination on scRNA-seq data. Also, it can perform spatial analysis and microenvironment analysis on ST data. Meanwhile, HemaScope takes into consideration hematopoietic cell-specific features, including lineage affiliation evaluation, cell cycle prediction, and marker gene collection. To enhance the user experience, we have deployed the toolkit in user-friendly forms: HemaScopeR (an R package), HemaScopeCloud (a web server), HemaScopeDocker (a Docker image), and HemaScopeShiny (a graphical interface). In case studies, we employed it to construct a cell atlas of human bone marrow, analyze age-related changes, and identify acute myeloid leukemia cells in mice. Moreover, we characterized the microenvironments in angioimmunoblastic T cell lymphoma and primary central nervous system lymphoma, elucidating tumor boundaries. HemaScope is freely available at https://zhenyiwangthu.github.io/HemaScope_Tutorial/.

PMID:39862439 | DOI:10.1093/gpbjnl/qzaf002

STAR Protoc. 2025 Jan 24;6(1):103589. doi: 10.1016/j.xpro.2024.103589. Online ahead of print.

ABSTRACT

The intestine features a two-front nutrient supply environment, comprising an enteral side enriched with microbial and dietary metabolites and a serosal side supplied by systemic nutrients, collectively supporting intestinal and systemic homeostasis, but there is currently no optimal approach for extracting and assessing the local intestinal microenvironment. Here, we present a protocol for constructing a nutrient supply model in mice and extracting gut interstitial fluid (GIF) via centrifugation. This model and the extracted GIF are suitable for downstream analyses. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.

PMID:39862429 | DOI:10.1016/j.xpro.2024.103589

Bioinformatics. 2025 Jan 25:btaf043. doi: 10.1093/bioinformatics/btaf043. Online ahead of print.

ABSTRACT

SUMMARY: Gene and genome duplications are major evolutionary forces that shape the diversity and complexity of life. However, different duplication modes have distinct impacts on gene function, expression, and regulation. Existing tools for identifying and classifying duplicated genes are either outdated or not user-friendly. Here, we present doubletrouble, an R/Bioconductor package that provides a comprehensive and robust framework for analyzing duplicated genes from genomic data. doubletrouble can detect and classify gene pairs as derived from six duplication modes (segmental, tandem, proximal, retrotransposon-derived, DNA transposon-derived, and dispersed duplications), calculate substitution rates, detect signatures of putative whole-genome duplication events, and visualize results as publication-ready figures. We applied doubletrouble to classify the duplicated gene repertoire in 822 eukaryotic genomes, and results were made available through a user-friendly web interface.

AVAILABILITY AND IMPLEMENTATION: doubletrouble is available on Bioconductor (https://bioconductor.org/packages/doubletrouble), and the source code is available in a GitHub repository (https://github.com/almeidasilvaf/doubletrouble). doubletroubledb is available online at https://almeidasilvaf.github.io/doubletroubledb/.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online and at https://github.com/almeidasilvaf/doubletrouble_paper.

PMID:39862387 | DOI:10.1093/bioinformatics/btaf043

Pediatr Nephrol. 2025 Jan 25. doi: 10.1007/s00467-025-06656-x. Online ahead of print.

ABSTRACT

BACKGROUND: Limited research exists regarding the genetic profile, clinical characteristics, and outcomes of refractory rickets in children from India.

METHODS: Patients with refractory rickets aged ≤ 18 years were enrolled. Data regarding clinical features, etiology, genotype-phenotype correlation, and estimated glomerular filtration rate (eGFR) were recorded.

RESULTS: Seventy-two patients with refractory rickets (non-nutritional, with normal kidney function at presentation) from 65 families attending the pediatric nephrology clinic from 2005-2024 were included. Median (IQR) age at first presentation was 2 (1, 4) years. Clinical features included failure-to-thrive (49 [68.1%]), polyuria (37 [51.4%]), nephrocalcinosis (33 [45.8%]), fractures (10 [13.9%]), and hypokalemic paralysis (4 [5.6%]). Major etiologies included distal renal tubular acidosis (dRTA) [34(47.2%)], hereditary hypophosphatemic rickets (11 [15.3%]), cystinosis (9 [12.5%]), Lowe syndrome (3 [4.2%]), vitamin D-dependent rickets (4 [5.5%]), and Fanconi-Bickel syndrome (3 [4.2%]). Next-generation sequencing identified 61 variants among 71 children tested (85.9%), of which 56 variants (among 55 children) were pathogenic (P)/likely-pathogenic (LP) (77.5% diagnostic-yield). P/LP variants included SLC4A1 (n = 14), CTNS (n = 9), PHEX (n = 8), WDR72 (n = 5), OCRL (n = 2), SLC2A2 (n = 3), ATP6V0A4 (n = 4), VDR (n = 3), CLDN16 (n = 2), ATP6V1B1 (n = 1), SLC12A1 (n = 1), CLCN5 (n = 1), SLC34A3 (n = 1), ATP7B (n = 1), and KCNJ1 (n = 1). Fifteen novel P/LP variants and five novel variants-of-uncertain-significance (VUS) were identified. c.2573C > A in exon 19 among SLC4A1-dRTA (n = 14) was a recurrent mutation. Five patients with cystinosis, two patients with SLC4A1-dRTA, two with WDR72-dRTA, and two with Bartter syndrome showed progression to CKD stage 2 or greater during follow-up.

CONCLUSIONS: dRTA, X-linked hypophosphatemic rickets, and cystinosis were common causes of refractory rickets. The c.2573C > A variant in exon 19 was a recurrent mutation in SLC4A1-dRTA.

PMID:39862309 | DOI:10.1007/s00467-025-06656-x

Pharmaceutics. 2025 Jan 3;17(1):52. doi: 10.3390/pharmaceutics17010052.

ABSTRACT

BACKGROUND: The Epstein-Barr virus (EBV) is intricately linked to a range of human malignancies, with EBV latent membrane protein 2A (LMP2A) emerging as a potential target antigen for immunotherapeutic strategies in the treatment of nasopharyngeal carcinoma (NPC).

METHODS: The modified vaccinia virus Ankara (MVA) is universally used in vector vaccine research because of its excellent safety profile and highly efficient recombinant gene expression. Here, we constructed a novel MVA-LMP2A recombinant virus and investigated its specific immune response induction and oncolytic effect.

RESULTS: An immunization dose of 2 × 107 PFU induced the highest specific immune response, which was no longer increased by boost injections after four doses. Three weeks post-final immunization, the specific immune response reached its peak. The MVA-LMP2A vaccine-induced LMP2A-specific cytotoxic T lymphocytes (CTLs), which exhibited substantial efficacy against target cells and effectively inhibited tumor growth.

CONCLUSIONS: Thus, the MVA-LMP2A recombinant virus effectively induces strong LMP2A-specific cellular and humoral immune responses and anti-tumor activity. This work provides a promising therapeutic strategy for developing NPC candidate vaccines, as well as a reference for the treatment of EBV LMP2-associated malignancies.

PMID:39861700 | DOI:10.3390/pharmaceutics17010052

Pharmaceuticals (Basel). 2025 Jan 3;18(1):45. doi: 10.3390/ph18010045.

ABSTRACT

BACKGROUND: Osteoporosis is characterized by the microstructural depletion of bone tissue and decreased bone density, leading to an increased risk of fractures. Cotoneaster wilsonii Nakai, an endemic species of the Korean Peninsula, grows wild in Ulleungdo. In this study, we aimed to investigate the effects of C. wilsonii and its components on osteoporosis.

METHODS AND RESULTS: The alkaline phosphatase (ALP) activity of C. wilsonii extracts and fractions was evaluated in MC3T3-E1 pre-osteoblasts, and the n-hexane fraction (CWH) showed the best properties for ALP activity. The effects of the CWH on bone formation were assessed in MC3T3-E1 cells and ovariectomized mice. Biochemical assays and histological analyses focused on the signaling activation of osteoblast differentiation and osteogenic markers, such as ALP, collagen, and osterix. The CWH significantly activated TGF-β and Wnt signaling, enhancing osteoblast differentiation and bone matrix formation. Notably, CWH treatment improved micro-CT indices, such as femoral bone density, and restored serum osteocalcin levels compared to OVX controls.

CONCLUSIONS: These results highlight the potential of the C. wilsonii Nakai n-hexane fraction as a promising therapeutic agent for managing osteoporosis.

PMID:39861108 | DOI:10.3390/ph18010045

Molecules. 2025 Jan 7;30(2):214. doi: 10.3390/molecules30020214.

ABSTRACT

Knowing which residues of a protein are important for its function is of paramount importance for understanding the molecular basis of this function and devising ways of modifying it for medical or biotechnological applications. Due to the difficulty in detecting these residues experimentally, prediction methods are essential to cope with the sequence deluge that is filling databases with uncharacterized protein sequences. Deep learning approaches are especially well suited for this task due to the large amounts of protein sequences for training them, the trivial codification of this sequence data to feed into these systems, and the intrinsic sequential nature of the data that makes them suitable for language models. As a consequence, deep learning-based approaches are being applied to the prediction of different types of functional sites and regions in proteins. This review aims to give an overview of the current landscape of methodologies so that interested users can have an idea of which kind of approaches are available for their proteins of interest. We also try to give an idea of how these systems work, as well as explain their limitations and high dependence on the training set so that users are aware of the quality of expected results.

PMID:39860084 | DOI:10.3390/molecules30020214

Int J Mol Sci. 2025 Jan 18;26(2):793. doi: 10.3390/ijms26020793.

ABSTRACT

The ubiquitin proteasome system (UPS) is implicated in protein homeostasis. One of the proteins involved in this system is HERC1 E3 ubiquitin ligase, which was associated with several processes including the normal development and neurotransmission at the neuromuscular junction (NMJ), autophagy in projection neurons, myelination of the peripheral nervous system, among others. The tambaleante (tbl) mouse model carries the spontaneous mutation Gly483Glu substitution in the HERC1 E3 protein. Using this model, we analyzed the implication of HERC1 E3 ubiquitin ligase in the activity of UPS, autophagy, and synaptic homeostasis in brain and muscle tissues. Regarding UPS, no differences were found in its activity nor in the specific gene expression in both brain and muscle tissues from tbl compared with the control littermates. Furthermore, the use of the specific UPS inhibitor (MG-132), did not alter the evoked neurotransmitter release in the levator auris longus (LAL) muscle. Interestingly, the expression of the autophagy-related gene p62 was significantly increased in the muscle of tbl compared to the control littermates. Indeed, impaired evoked neurotransmitter release was observed with the autophagy inhibitor Wortmannin. Finally, altered levels of Clathrin and Synaptophysin were detected in muscle tissues. Altogether, our findings show that HERC1 E3 ubiquitin ligase mutation found in tbl mice alters autophagy and vesicular recycling without affecting proteasomal function.

PMID:39859507 | DOI:10.3390/ijms26020793

Int J Mol Sci. 2025 Jan 15;26(2):686. doi: 10.3390/ijms26020686.

ABSTRACT

SARS-CoV-2 viral entry requires membrane fusion, which is facilitated by the fusion peptides within its spike protein. These predominantly hydrophobic peptides insert into target membranes; however, their precise mechanistic role in membrane fusion remains incompletely understood. Here, we investigate how FP1 (SFIEDLLFNKVTLADAGFIK), the N-terminal fusion peptide, modulates membrane stability and barrier function across various model membrane systems. Through a complementary suite of biophysical techniques-including electrophysiology, fluorescence spectroscopy, and atomic force microscopy-we demonstrate that FP1 significantly promotes pore formation and alters the membrane's mechanical properties. Our findings reveal that FP1 reduces the energy barrier for membrane defect formation and stimulates the appearance of stable conducting pores, with effects modulated by membrane composition and mechanical stress. The observed membrane-destabilizing activity suggests that, beyond its anchoring function, FP1 may facilitate viral fusion by locally disrupting membrane integrity. These results provide mechanistic insights into SARS-CoV-2 membrane fusion mechanisms and highlight the complex interplay between fusion peptides and target membranes during viral entry.

PMID:39859399 | DOI:10.3390/ijms26020686

Int J Mol Sci. 2025 Jan 7;26(2):448. doi: 10.3390/ijms26020448.

ABSTRACT

Mitophagy, an essential process within cellular autophagy, has a critical role in regulating key cellular functions such as reproduction, metabolism, and apoptosis. Its involvement in tumor development is complex and influenced by the cellular environment. Here, we conduct a comprehensive analysis of a mitophagy-related gene signature, composed of PRKN, PINK1, MAP1LC3A, SRC, BNIP3L, BECN1, and OPTN, across various cancer types, revealing significant differential expression patterns associated with molecular subtypes, stages, and patient outcomes. Pathway analysis revealed a complex interplay between the expression of the signature and potential effects on the activity of various cancer-related pathways in pan-cancer. Immune infiltration analysis linked the mitophagy signature with certain immune cell types, particularly OPTN with immune infiltration in melanoma. Methylation patterns correlated with gene expression and immune infiltration. Mutation analysis also showed frequent alterations in PRKN (34%), OPTN (21%), PINK1 (28%), and SRC (15%), with implications for the tumor microenvironment. We also found various correlations between the expression of the mitophagy-related genes and sensitivity in different drugs, suggesting that targeting this signature could improve therapy efficacy. Overall, our findings underscore the importance of mitophagy in cancer biology and drug resistance, as well as its potential for informing treatment strategies.

PMID:39859167 | DOI:10.3390/ijms26020448

Medicina (Kaunas). 2025 Jan 13;61(1):105. doi: 10.3390/medicina61010105.

ABSTRACT

Background and Objectives: The pathophysiology of arrhythmogenic cardiomyopathy (ACM), previously known as arrhythmogenic right ventricular cardiomyopathy (ARVC), and its specific biological features remain poorly understood. High-throughput plasma proteomic profiling, a powerful tool for gaining insights into disease pathophysiology at the systems biology level, has not been used to study ACM. This study aimed at characterizing plasmatic protein changes in patients with ACM, which were compared with those of healthy controls, and at exploring the potential role of the identified proteins as biomarkers for diagnosis and monitoring. Materials and Methods: Blood samples were collected from six ACM patients, four patients with other cardiomyopathies, and two healthy controls. Plasma was processed to remove high-abundance proteins and analyzed by two-dimensional gel electrophoresis. Differential protein expressions were assessed using PDQuest software, Bio-Rad US version 8.0.1. Results: The analysis revealed several proteins with altered expressions between ACM patients and controls, including plakophilin-2, junctional plakoglobin, desmoplakin, desmin, transmembrane protein 43, and lamin A/C. Conclusions: The plasma proteomic profiling of ACM suggests that ACM is a distinct disease entity characterized by a unique dysregulation of desmosomal proteins. The identification of plasma biomarkers associated with ACM underscores their potential to improve diagnostic accuracy and facilitate early intervention strategies. Further exploration of mutations in desmosomal proteins and their phosphorylation states may provide deeper insights into the pathophysiology of ACM.

PMID:39859087 | DOI:10.3390/medicina61010105

Microorganisms. 2025 Jan 16;13(1):176. doi: 10.3390/microorganisms13010176.

ABSTRACT

Antibiotic resistance is on the WHO's top 10 list of global public health threats due to its rapid emergence and spread but also because of the high morbidity and mortality associated with it. Amongst the main species driving this phenomenon is A. baumannii, a member of the ESKAPE group of medical assistance-associated infections causing species famous for its extensively drug-resistant phenotypes. Our findings note a 91.52% frequency of extensively drug-resistant carbapenem-resistant A. baumannii (XDR CRAB) phenotype amongst clinical isolates from multiple hospitals in two major cities from northwestern and central Romania, harboring multiple antibiotic resistance genes such as blaOXA-23-like in 108 (91.5%) isolates, blaOXA-24/40-like in 88 (74.6%) isolates, blaNDM in 29 (25%) isolates, ArmA in 75 (63.6%) isolates, and ant(3″)-I in 69 (58.5%) isolates and sul1 in 113 (95.76%) isolates. The isolates, although nearly identical in phenotype, displayed different genotypical profiles, with varying degrees of similarity across hospitals and cities, raising the possibility of both local outbreaks of a single clone and widespread dissemination of resistant isolates.

PMID:39858944 | DOI:10.3390/microorganisms13010176

Genes (Basel). 2024 Dec 29;16(1):37. doi: 10.3390/genes16010037.

ABSTRACT

Background/Objectives: Salivary gland carcinomas encompass a broad group of malignant lesions characterized by varied prognoses. Stem cells have been associated with the potential for self-renewal and differentiation to various subpopulations, resulting in histopathological variability and diverse biological behavior, features that characterize salivary gland carcinomas. This study aims to provide a thorough systematic review of immunohistochemical studies regarding the expression and prognostic significance of stem cell markers between different malignant salivary gland tumors (MSGTs). Methods: The English literature was searched via the databases MEDLINE/PubMed, EMBASE via OVID, Web of Science, Scopus, and CINHAL via EBSCO. The Joanna Briggs Institute Critical Appraisal Tool was used for risk of bias (RoB) assessment. Meta-analysis was conducted for markers evaluated in the same pair of diseases in at least two studies. Results: Fifty-four studies reported the expression of stem cell markers, e.g., c-KIT, CD44, CD133, CD24, ALDH1, BMI1, SOX2, OCT4, and NANOG, in various MSGTs. Low, moderate, and high RoB was observed in twenty-five, eleven, and eighteen studies, respectively. Meta-analysis revealed an outstanding discriminative ability of c-KIT for adenoid cystic carcinoma (AdCC) over polymorphous adenocarcinoma [P(LG)A] but did not confirm the prognostic significance of stem cell markers in MSGTs. Conclusions: This study indicated a possible link between stem cells and the histopathological heterogeneity and diverse biological behavior that characterize the MSGTs. c-KIT might be of diagnostic value in discriminating between AdCC and P(LG)A.

PMID:39858584 | DOI:10.3390/genes16010037

Genes (Basel). 2024 Dec 25;16(1):11. doi: 10.3390/genes16010011.

ABSTRACT

BACKGROUND/OBJECTIVES: A prominent endophenotype in Autism Spectrum Disorder (ASD) is the synaptic plasticity dysfunction, yet the molecular mechanism remains elusive. As a prototype, we investigate the postsynaptic signal transduction network in glutamatergic neurons and integrate single-cell nucleus transcriptomics data from the Prefrontal Cortex (PFC) to unveil the malfunction of translation control.

METHODS: We devise an innovative and highly dependable pipeline to transform our acquired signal transduction network into an mRNA Signaling-Regulatory Network (mSiReN) and analyze it at the RNA level. We employ Cell-Specific Network Inference via Integer Value Programming and Causal Reasoning (CS-NIVaCaR) to identify core modules and Cell-Specific Probabilistic Contextualization for mRNA Regulatory Networks (CS-ProComReN) to quantitatively reveal activated sub-pathways involving MAPK1, MKNK1, RPS6KA5, and MTOR across different cell types in ASD.

RESULTS: The results indicate that specific pivotal molecules, such as EIF4EBP1 and EIF4E, lacking Differential Expression (DE) characteristics and responsible for protein translation with long-term potentiation (LTP) or long-term depression (LTD), are dysregulated. We further uncover distinct activation patterns causally linked to the EIF4EBP1-EIF4E module in excitatory and inhibitory neurons.

CONCLUSIONS: Importantly, our work introduces a methodology for leveraging extensive transcriptomics data to parse the signal transduction network, transforming it into mSiReN, and mapping it back to the protein level. These algorithms can serve as potent tools in systems biology to analyze other omics and regulatory networks. Furthermore, the biomarkers within the activated sub-pathways, revealed by identifying convergent dysregulation, illuminate potential diagnostic and prognostic factors in ASD.

PMID:39858558 | DOI:10.3390/genes16010011

Biomolecules. 2025 Jan 9;15(1):89. doi: 10.3390/biom15010089.

ABSTRACT

Amylin and amyloid β belong to the same protein family and activate the same receptors. Amyloid β levels are elevated in Alzheimer's disease. Recent studies have demonstrated that amylin-based peptides can reduce the symptoms of Alzheimer's disease in animal models. Replica exchange molecular dynamics simulation machine learning, as well as other computational analyses, were applied to improve the understanding of the amino acid residues in these amylin-based peptides. Comparisons were made between amylin, amylin-based peptides, and amyloid β. These studies converged on amylin residues 10Q, 28S, 29S, 30T, 31N, 32V, 33G, 34S, and 35N (residues 10 and 28-35) being ranked highest, meaning that they were the most likely to be involved in activating the same targets as amyloid β. Surprisingly, the amyloid β signaling domain most closely matched amylin residues 29-35 in the simulated structures. These findings suggest important residues that are structurally similar between amylin and amyloid β and are thus implicated in the activation of the amylin receptor.

PMID:39858483 | DOI:10.3390/biom15010089

Biomolecules. 2024 Dec 24;15(1):1. doi: 10.3390/biom15010001.

ABSTRACT

This study examines the prevalence and the mechanisms of antibiotic resistance in Pseudomonas aeruginosa isolates collected from healthcare units in Northwestern Transylvania, Romania, between 2022 and 2023. Given the alarming rise in antibiotic resistance, the study screened 34 isolates for resistance to 10 antibiotics, 46 ARGs, and integrase genes using PCR analysis. The results reveal a concerning increase in multidrug-resistant (MDR) and extensively drug-resistant (XDR) isolates over the two-year period. Notably, the prevalence of ARGs encoding resistance to sulfonamides and beta-lactams, particularly sul1 and blaOXA-50, has shown a significant rise. Furthermore, the study detected the emergence of new resistance mechanisms in the same time interval. These include target protection and even more specific mechanisms, such as metallo-beta-lactamases or enzymes involved in the methylation of 23S rRNA. Statistical analysis further confirmed the correlation between Class I integrons and several ARGs, underscoring the role of horizontal gene transfer in the dissemination of resistance. These findings emphasize the urgent need for updated treatment strategies and monitoring programs to effectively combat the spread of ARGs in clinical settings.

PMID:39858396 | DOI:10.3390/biom15010001