Frontiers in Molecular Biosciences最新文献

Advanced technologies to study protein biophysics, mRNA expression and protein-protein interactions at high throughput in physiological or pathological contexts are reshaping our view of the ARF family of GTPases. Most current knowledge arises from work on the classical members ARF1 and ARF6, with many ARF-like proteins (ARLs) remaining poorly characterized. Recent findings suggest that several ARLs deviate from the binary molecular switch paradigm, instead exhibiting atypical biochemical properties, highly restricted tissue-specific expression patterns, specialized subcellular localizations, and unique interaction networks. These observations raise fundamental questions about the breadth of ARF family functions, mechanisms that regulate them, and their potential impact on cellular and organismal biology. In this review, we highlight emerging insights into atypical ARF members, outline unresolved questions, and discuss how expanding our understanding beyond the classical ARF members could shed light on their unique roles in health and disease.

Preeclampsia is a leading cause of maternal and perinatal morbidity associated with systemic lipid metabolism disturbances, yet the underlying molecular mechanisms remain incompletely understood. In this study, we integrated single-cell RNA-seq data from preeclamptic placentas with an in vitro hypoxia model to analyze gene expression changes across distinct trophoblast subpopulations. While all trophoblast lineages exhibited hypoxia-driven metabolic reprogramming, the response was highly cell-type specific. In the syncytiotrophoblast (SCT), the primary maternal-fetal barrier, preeclampsia was associated with a significant downregulation of LDLR and cholesterol biosynthesis genes (OR = 4.991, p = 6.30e-04). Concurrently, we observed increased expression of genes governing transcytosis (SCARB1, CAV1). In contrast, the extravillous trophoblast (EVT) displayed a divergent adaptive response, characterized by elevated LDLR expression and downregulated cholesterol biosynthesis. In vitro hypoxia modeling in BeWo b30 cells recapitulated the SCT-specific phenotype and identified a potential regulatory mechanism: a fivefold increase in PCSK9 expression (padj = 3.53e-10) and a 1.5-fold decrease in SNX17 (padj = 1.76e-04)-key regulators that limit lipoprotein receptor recycling. This was accompanied by the suppression of lipid biosynthesis genes and the transcriptional activation of pathways associated with transcytosis and cholesterol efflux. Collectively, these results confirm the pivotal role of hypoxic stress in disrupting placental lipid metabolism and reveal a subpopulation-specific transcriptional program in preeclampsia-a shift from endocytosis to transcytosis-that likely serves as a compensatory mechanism to ensure fetal lipid supply under conditions of limited availability.

[This corrects the article DOI: 10.3389/fmolb.2024.1455890.].

Background: The Primary Ciliary Dyskinesia Rule (PICADAR) is a diagnostic predictive tool currently recommended by the European Respiratory Society (ERS) to assess the likelihood of a primary ciliary dyskinesia (PCD) diagnosis. Despite its recommendation according to the current ERS PCD diagnostic guideline, the performance of the PICADAR remains insufficiently studied.

Methods: We evaluated the sensitivity of PICADAR in 269 individuals with genetically confirmed PCD. Using an initial question, PICADAR rates all individuals without daily wet cough negative for PCD. PICADAR evaluates seven questions in the daily wet cough group. We here calculated test sensitivity based on the proportion of individuals scoring ≥5 points as recommended. Subgroup analyses examined the impact of laterality defects and predicted hallmark ultrastructural defects.

Results: 18 individuals (7%) reported no daily wet cough ruling out PCD according to PICADAR. The median PICADAR score was 7 (IQR: 5-9), with an overall sensitivity of 75% (202/269). Sensitivity was higher in individuals with laterality defects (95%; median score: 10; IQR 8-11) compared to those with situs solitus (61%, median score: 6; IQR 4-8; p*<0.0001). Further stratification by associated ciliary ultrastructure showed higher sensitivity in individuals with hallmark defects (83%) versus those without (59%, p*<0.0001).

Conclusion: The PICADAR has limited sensitivity, particularly in individuals without laterality defects (61%) or absent hallmark ultrastructural defects (59%). Therefore, PICADAR should not be the only factor to initiate diagnostic work-up for PCD. Alternative predictive tools are needed, particularly for PCD individuals with normal body composition and normal ultrastructure.

Background: Parkinson's disease (PD) shows considerable heterogeneity in motor and non motor features. The contribution of the salivary microbiome and its modification by sex remains unclear.

Methods: In a single center cross sectional case control study, we profiled unstimulated saliva from 24 patients with Parkinson's disease and 25 age and sex matched controls using 16S rRNA sequencing. Alpha and beta diversity were evaluated, group associated taxa were identified by indicator analysis, and community structure was related to clinical measures including Unified Parkinson's Disease Rating Scale part III in off and on medication states, the Non Motor Symptoms Scale, and the Hamilton Depression Rating Scale.

Results: Alpha diversity was broadly preserved, whereas richness was higher in men with Parkinson's disease than in women with PD. Beta diversity showed modest but significant separation across disease by sex groups at multiple taxonomic levels with PERMANOVA R ² about 0.13 and significant P values. Women with PD displayed higher Prevotella and Veillonella with lower Akkermansia, and men with PD showed a TM7 skewed profile typified by Candidatus Saccharimonas and reduced Haemophilus. The coupling between community structure and clinical burden was strongest for motor severity and was more evident in the on medication state.

Conclusion: The salivary microbiome in Parkinson's disease exhibits sex specific alterations that track clinical burden, supporting sex aware development of salivary biomarkers and microbiota focused strategies. Validation in larger longitudinal cohorts with multi omics and standardized oral and medication metadata is warranted.

Diabetic foot ulcer (DFU) is a severe complication resulting from diabetes mellitus (DM) that affects approximately 18.6 million individuals annually and has a lifetime incidence of up to 25% among DM patients. These ulcers often precede lower-extremity amputations and are associated with high mortality as well as economic burden that necessitate innovative therapeutic strategies beyond conventional methods. Recent research efforts have highlighted the potential of non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), that regulate gene expression and cellular functions critical for wound healing. Exosomes are the natural carriers of ncRNAs and offer a promising avenue for the treatment of DFU by enhancing the stabilities and bioavailabilities of these molecules. In this review, we explore the substantial potential of ncRNAs in DFU treatment by emphasizing the action mechanisms of ncRNAs, refinement of exosome-based delivery systems, and expansion of clinical trials to translate ncRNA-based therapies into clinical practice. The application of exosomal ncRNAs involves diverse strategies through different mechanisms, although there remain challenges in terms of exosome preparation consistency, functional enhancement, and efficient drug delivery. The future directions in this regard include optimizing isolation techniques, engineering exosomes for improved targeting, integrating with biomaterials, and conducting more clinical trials to validate safety and effectiveness, thereby paving the path for widespread clinical use.

Objectives: Alzheimer's disease (AD), a common neurodegenerative disorder, is characterized by its complex pathogenesis and challenging early diagnosis; however, the role of the glymphatic system and metabolism-related genes (GS&MetabolismRGs) in AD remains poorly understood. Therefore, this study aimed to explore a potential diagnostic model and the molecular mechanisms of GS&MetabolismRGs in AD.

Materials and methods: We obtained glymphatic system and metabolism-related differentially expressed genes (GS&MetabolismRDEGs) associated with AD by integrating of GEO and GeneCards databases. Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and gene set enrichment analysis were performed to investigate the roles of GS&metabolismRDEGs in AD-related biological processes. Hub genes were identified using machine learning methods, resulting in the construction and validation of AD diagnostic models. AD samples were further stratified into high-score and low-score groups based on the median value of glymphatic system and Metabolism Score to investigate the underlying pathogenesis. Finally, immune infiltration analysis was conducted to explore the relationship between immune cell frequencies and hub genes.

Results: Six GS&MetabolismRDEGs were identified, which were predominantly enriched in biological processes, such as the PD-L1 expression, hyaluronan metabolic process, and the PD-1 checkpoint pathway in cancer. Further analysis identified six hub genes that were used to construct an AD diagnostic model. Immune infiltration analysis of the disease and control groups revealed significant associations among all eight immune cell types. The strongest negative correlation was found between the resting memory CD4⁺ T cells and Tregs. Further analysis revealed a strong positive correlation between Tregs and NFKB1 in low-risk group and the most significant correlation between activated mast cells and TREM1 in high-risk group.

Conclusion: This study developed a novel diagnostic model based on six GS&MetabolismRDEGs, highlighting their potential as key biomarkers for early diagnosis and providing new insights into the molecular mechanisms driving AD.

Although natural spices are widely applied for their complex aromas and flavors, the molecular mechanisms that drive these sensory perceptions remain obscure, leaving the selection of compounds for specific taste or aromatic outcomes more art than science. In tobacco industry, this challenge has practical implications for the design and enhancements of tobacco formulations. This study employed liquid chromatography-high resolution mass spectrometry (LC-HRMS) with data-independent acquisition (DIA) to conduct a comprehensive nontargeted metabolite analysis of sensory-enhancing attributes. Fifty-seven natural spices were evaluated and categorized into three groups based on five sensory metrics obtained from smoked blank cigarette evaluations. The result showed astringency and nasal moistening scores exhibited the most significant differences. The analysis revealed 1,853 differential ion features enriched in groups of advantageous sensory perceptions. Among these, 89 metabolites were putatively identified through mass spectral matching, and 28 were confirmed using chemical standards. Sensory evaluations of artificial formulations containing these validated compounds corroborated the accuracy of the nontargeted approach in identifying flavor-enhancing metabolites. Notably, minor components were shown to play a pivotal role in enhancing sensory attributes. This study demonstrates the potential of nontargeted metabolite analysis and chemometrics as useful tools for optimizing spice formulations in the tobacco and flavor industries.

Most cancer and stem cells activate telomerase to preserve critical genetic material during cell division. Telomerase is a reverse transcriptase ribonucleoprotein that adds telomeric repeats to chromosome ends, thus overcoming the end-replication problem. Shortening of telomeric repeats, or telomeres, is associated with genomic instability, cancer, and aging. Telomerase dysfunction during early development leads to telomeropathies such as dyskeratosis congenita, pulmonary fibrosis, and aplastic anaemia. Recent advancements in cryo-electron microscopy and improved strategies for purifying human telomerase have laid a strong foundation in the structural biology of telomerase, advancing our understanding of its molecular interactome. In this report, we review the latest progress in human telomerase structure and outline emerging therapeutic strategies targeting telomerase.

Exposure biomarkers are measurable biological indicators that indicate whether or not the body has been exposed to a particular chemical and the extent of that exposure. Exposure biomarkers are widely used in smokers. Today, there is a growing number of users of various forms of tobacco, especially in the form of e-cigarettes and heated tobaccos. The method of tobacco delivery has an impact on toxicity and biomarker concentrations. Therefore, it is expedient to introduce new biomarkers of tobacco smoke exposure, in addition to existing markers. The ideal biomarker is characterized by non-invasive intake - therefore saliva and urine should be considered as ideal material for determination of biomarkers of exposure. This paper summarizes the existing knowledge of classical and modern biomarkers of tobacco smoke exposure determined from urine and saliva and a brief overview on exposure biomarkers. In addition, the paper provides a description of future developments of exposure biomarkers in different groups of cigarette users.