Nat Commun. 2025 Feb 7;16(1):1452. doi: 10.1038/s41467-025-56425-5.

ABSTRACT

The history of clinical resistance to tetracycline antibiotics is characterized by cycles whereby the deployment of a new generation of drug molecules is quickly followed by the discovery of a new mechanism of resistance. This suggests mechanism-specific selection by each tetracycline generation; however, the evolutionary dynamics of this remain unclear. Here, we evaluate 24 recombinant Escherichia coli strains expressing tetracycline resistance genes from each mechanism (efflux pumps, ribosomal protection proteins, and enzymatic inactivation) in the context of each tetracycline generation. We employ a high-throughput barcode sequencing protocol that can discriminate between strains in mixed culture and quantify their relative abundances. We find that each mechanism is preferentially selected for by specific antibiotic generations, leading to their expansion. Remarkably, the minimum inhibitory concentration associated with individual genes is secondary to resistance mechanism for inter-mechanism relative fitness, but it does explain intra-mechanism relative fitness. These patterns match the history of clinical deployment of tetracycline drugs and resistance discovery in pathogens.

PMID:39920134 | DOI:10.1038/s41467-025-56425-5

Nat Commun. 2025 Feb 7;16(1):1460. doi: 10.1038/s41467-025-56603-5.

ABSTRACT

Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work thus identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition.

PMID:39920132 | DOI:10.1038/s41467-025-56603-5

Stem Cell Reports. 2025 Jan 23:102398. doi: 10.1016/j.stemcr.2025.102398. Online ahead of print.

ABSTRACT

SOX17 directs the differentiation toward endoderm and acts as a human germline specifier. We previously found that the replacement of glutamate at position 57 of the high-mobility group (HMG) box with the basic lysine residue in SOX2 alters interactions with OCT4 and turns SOX17 into a pluripotency factor. Here, we systematically interrogated how mutations at this critical position affect the cellular reprogramming activity of SOX17 in mouse and human. We found that most mutations turn SOX17 into a pluripotency factor regardless of their biophysical properties except for acidic residues and proline. The conservative mutation to an aspartate allows the SOX17E57D protein to maintain a self-renewing endodermal state. We showed that only the glutamate in the wild-type protein blocks the formation of an SOX17/OCT4 dimer at composite DNA elements in pluripotency enhancers. Insights into how modifications of an ultra-conserved residue affect functions of developmental transcription factors provide avenues to advance cell fate engineering.

PMID:39919754 | DOI:10.1016/j.stemcr.2025.102398

Sci Total Environ. 2025 Feb 6;966:178713. doi: 10.1016/j.scitotenv.2025.178713. Online ahead of print.

ABSTRACT

In resource-limited producer-consumer systems, environmental variables such as weather, habitat structure, and resource availability interact to shape consumer dynamics. We conducted a comparative analysis on territorial Fremont's squirrel (Tamiasciurus fremonti) in Arizona mountain ranges (three sites) and non-territorial Eurasian red squirrel (Sciurus vulgaris) in the Italian Alps (five sites) to investigate the effects of forest composition, pulsed seed resources, weather, and climate change-induced forest disturbances on population density. We also explored potential synchrony in spatial and temporal dynamics between squirrel populations, driven by endogenous and exogenous processes. Our long-term, multi-site datasets revealed shared density-dependent patterns: annual oscillations in Fremont's squirrel populations and biennial oscillations in Eurasian red squirrels. Both species exhibited strong bottom-up responses, with higher densities following tree-seed production and warmer spring temperatures. Despite the absence of synchronized trends in population density across time or regions, we found consistent responses to resource availability and abiotic conditions, demonstrating shared mechanisms across ecologically distinct systems. By integrating field data, remotely sensed forest disturbances, and multi-factorial modeling, this study highlights the role of climate, forest dynamics, and climate change-induced forest disturbance in shaping population processes in pulsed resource systems. Our findings underscore the importance of understanding producer-consumer interactions under climate change, providing globally relevant insights into the interplay of abiotic drivers, species-specific behaviours, and ecological resilience. These results contribute to advancing strategies for wildlife conservation and forest management in the face of ongoing environmental change.

PMID:39919654 | DOI:10.1016/j.scitotenv.2025.178713

J Hazard Mater. 2025 Feb 3;488:137490. doi: 10.1016/j.jhazmat.2025.137490. Online ahead of print.

ABSTRACT

Mine waste disposal in dumps and stockpiles causes environmental pollution, particularly through microbe-assisted acid mine drainage (AMD) generation and groundwater contamination with hazardous heavy metal(loid)s. Metal hyper-resistance in acidophilic microorganisms remains an underexplored intriguing phenomenon. Using a multi-level approach, we provide the first data on extreme zinc resistance mechanisms in Sulfobacillus thermotolerans, recognized as one of the most metal-resistant organisms known. Under high zinc levels, Sb. thermotolerans cells exhibited efficient zinc sorption and low intracellular accumulation. Remarkably, mechanisms involved the upregulation of stress response and metabolic pathway proteins, including different GroEL chaperonin forms. Moreover, overexpression of the Sb. thermotolerans StGroEL chaperonin in Escherichia coli enhanced its growth and zinc resistance under zinc stress. 3D structure modeling and ion binding site prediction in StGroEL revealed 46 amino acid residues potentially involved in zinc docking. Thriving in natural and engineered environments, such as sulfide mines, mine waste disposal sites, and AMD, Sb. thermotolerans is a key member of acidophilic microbial communities used in commercial biotechnologies for sulfidic raw material processing. These findings, beyond their fundamental scientific relevance, have important implications for environmental protection, including AMD management, safe hazardous waste disposal, and a broader application of eco-friendly biomining technologies using metal-resistant microbial communities.

PMID:39919630 | DOI:10.1016/j.jhazmat.2025.137490

Drug Metab Dispos. 2024 Dec 12;53(2):100029. doi: 10.1016/j.dmd.2024.100029. Online ahead of print.

ABSTRACT

The liver contains multiple cell types, including resident cell types and immune cells. The liver is also categorized into 3 zones: periportal (zone 1), midzonal (zone 2), and centrilobular (zone 3). The goal of this study was to characterize the distribution of drug-processing genes (DPGs) in mouse liver using published single-cell and nuclei transcriptomic datasets, which were subjected to zonal deconvolution. Filtering, normalization, clustering, and differential expression analyses were performed using Seurat V5 in R. Hepatocytes were assigned to 3 zones based on known zonal markers and validated with published spatial transcriptomics data. Among the 195 DPGs profiled, most were expressed highest in hepatocytes (61.3%). Interestingly, certain DPGs were expressed most highly in nonparenchymal cells, such as in cholangiocytes (11.2%, eg, carboxylesterase [Ces] 2e, Ces2g), endothelial cells (7.2%, eg, aldo-keto reductase [Akr] 1c19, Akr1e1), Kupffer cells (5.3%, eg, Akr1a1, Akr1b10), stellate cells (5.1%, eg, retinoic acid receptor [Rar] α, Rarβ), myofibroblasts (2.9%, RAR-related orphan receptor [Rar] α), and a few were expressed in immune cell types. In hepatocytes, 72.4% of phase-I enzymes were enriched in zone 3. Phase-II conjugation enzymes such as UDP-glucuronosyltransferases (75%) were enriched in zone 3, whereas sulfotransferases (40%) were enriched in zone 1. Hepatic xenobiotic transporters were enriched in zone 3. The xenobiotic biotransformation-regulating transcription factors were enriched in zone 3 hepatocytes. The enrichment of DPGs in liver cell types, including non-parenchymal cells and zone 1 hepatocytes, may serve as an additional repertoire for xenobiotic biotransformation. SIGNIFICANCE STATEMENT: Our study is among the first to systematically characterize the baseline mRNA enrichment of important drug-processing genes in different cell types and zones in the liver. This finding will aid in further understanding the mechanisms of chemical-induced liver injury with improved resolution and precision.

PMID:39919554 | DOI:10.1016/j.dmd.2024.100029

Int Immunopharmacol. 2025 Feb 6;149:114204. doi: 10.1016/j.intimp.2025.114204. Online ahead of print.

ABSTRACT

BACKGROUND: Alkylating cellular DNA, sulfur mustard (SM) is a chemical warfare agent that causes severe damage to the skin, eyes, and respiratory tract. Exposure can result in painful burns, chronic lung disease, immune system suppression, and an increased chance of developing cancer. The symptoms of itching, redness, and blistering are frequently followed by long-term genetic and psychological damage. By exploring the interaction between microRNA (miRNA), mRNA, and long non-coding RNA (lncRNA) in these patients, it is possible to identify gene expression patterns that could reduce cancer risk or improve treatment outcomes.

METHODS: The purpose of this study is to examine transcriptome data from PBMC samples obtained from sulfur mustard exposed patients (Mild, Moderate, Severe) and healthy Control, separated into six groups (SC, SMo, SMi, MoMi, MoC, and MiC). miRNA, lncRNA, and mRNA interactions were explored using miRNA, lncRNA, and mRNA tools and databases, such as miRTarBase, miRDB, miRNET, miRcode, and DIANA. A tripartite mRNA-miRNA-lncRNA network was modeled with the aid of Cytoscape software, and functional analyses were performed to gain an understanding of molecular pathways using GO and KEGG functional analyses.

RESULTS: By extracting miRNAs shared between lncRNAs and mRNAs, six groups were identified and Cytoscape software was used to visualize the lncRNA-miRNA-mRNA network. Betweenness, closeness, and degree filters identified key genes, with INO80D and lncRNAs MINCR, LINC00662, NEAT1, and DHRS4-AS1, along with miRNAs hsa-miR-1-3p, hsa-miR-124-3p, and hsa-let-7b-5p as the main players in all groups.

CONCLUSION: The interaction between key genes involved in chemical injuries and their association with genes implicated in lung cancer is highlighted in this study. By targeting these genes and their proteins, we can improve treatment strategies for sulfur mustard exposed patients and potentially reduce lung cancer risk.

PMID:39919453 | DOI:10.1016/j.intimp.2025.114204

Mol Pharmacol. 2025 Jan;107(1):100010. doi: 10.1016/j.molpha.2024.100010. Epub 2024 Dec 12.

ABSTRACT

Chemokine receptors CCR3, CCR4, and CCR5 are G protein-coupled receptors implicated in diseases like cancer, Alzheimer's, asthma, human immunodeficiency virus (HIV), and macular degeneration. Recently, CCR3 and CCR4 have emerged as potential stroke targets. Although only the CCR5 antagonist maraviroc is US Food and Drug Administration-approved (for HIV), we curated data on CCR3, CCR4, and CCR5 antagonists from ChEMBL to develop and validate machine learning models. The top 5-fold cross-validation statistics for these models were high for both classification and regression models for CCR3 (receiver operating characteristic [ROC], 0.94; R2 = 0.8), CCR4 (ROC, 0.98; R2 = 0.57), and CCR5 (ROC, 0.96; R2 = 0.78). The models for CCR3/4 were used to screen a small library of US Food and Drug Administration-approved drugs and 17 were initially tested in vitro against both CCR3/4 receptors. A promising compound lapatinib, a dual tyrosine kinase inhibitor, was identified as an antagonist for CCR3 (IC50, 0.7 μM) and CCR4 (IC50, 1.8 μM). Additional testing also identified it as an CCR5 antagonist (IC50, 0.9 μM), and it showed moderate in vitro HIV I inhibition. We demonstrated how machine learning can be used to identify molecules for repurposing as antagonists for G protein-coupled receptors such as CCR3, CCR4, and CCR5. Lapatinib may represent a new orally available chemical probe for these 3 receptors, and it provides a starting point for further chemical optimization for multiple diseases impacting human health. SIGNIFICANCE STATEMENT: We describe the building of machine learning models for the chemokine receptors CCR3, CCR4, and CCR5 trained on data from the ChEMBL database. Using these models, we identified lapatinib as a potent inhibitor of CCR3, CCR4, and CCR5. Our study illustrates the potential of machine learning in identifying molecules for repurposing as antagonists for G protein-coupled receptors, including CCR3, CCR4, and CCR5, which have various therapeutic applications.

PMID:39919162 | DOI:10.1016/j.molpha.2024.100010

PLoS Pathog. 2025 Feb 7;21(2):e1012562. doi: 10.1371/journal.ppat.1012562. eCollection 2025 Feb.

ABSTRACT

Infection by the liver fluke, Fasciola hepatica, places a substantial burden on the global agri-food industry and poses a significant threat to human health in endemic regions. Widespread resistance to a limited arsenal of chemotherapeutics, including the frontline flukicide triclabendazole (TCBZ), renders F. hepatica control unsustainable and accentuates the need for novel therapeutic target discovery. A key facet of F. hepatica biology is a population of specialised stem cells which drive growth and development - their dysregulation is hypothesised to represent an appealing avenue for control. The exploitation of this system as a therapeutic target is impeded by a lack of understanding of the molecular mechanisms underpinning F. hepatica growth and development. Wnt signalling pathways govern a myriad of stem cell processes during embryogenesis and drive tumorigenesis in adult tissues in animals. Here, we identify five putative Wnt ligands and five Frizzled receptors in liver fluke transcriptomic datasets and find that Wnt/β-catenin signalling is most active in juveniles, the most pathogenic life stage. FISH-mediated transcript localisation revealed partitioning of the five Wnt ligands, with each displaying a distinct expression pattern, consistent with each Wnt regulating the development of different cell/tissue types. The silencing of each individual Wnt or Frizzled gene yielded significant reductions in juvenile worm growth and, in select cases, blunted the proliferation of neoblast-like cells. Notably, silencing FhCTNNB1, the key effector of the Wnt/β-catenin signal cascade led to aberrant development of the neuromuscular system which ultimately proved lethal - the first report of a lethal RNAi-induced phenotype in F. hepatica. The absence of any discernible phenotypes following the silencing of the inhibitory Wnt/β-catenin destruction complex components is consistent with low destruction complex activity in rapidly developing juvenile worms, corroborates transcriptomic expression profiles and underscores the importance of Wnt signalling as a key molecular driver of growth and development in early-stage juvenile fluke. The putative pharmacological inhibition of Wnt/β-catenin signalling using commercially available inhibitors phenocopied RNAi results and provides impetus for drug repurposing. Taken together, these data functionally and chemically validate the targeting of Wnt signalling as a novel strategy to undermine the pathogenicity of juvenile F. hepatica.

PMID:39919127 | DOI:10.1371/journal.ppat.1012562

PLoS One. 2025 Feb 7;20(2):e0318657. doi: 10.1371/journal.pone.0318657. eCollection 2025.

ABSTRACT

BACKGROUND: Retinal problems are critical because they can cause severe vision loss if not treated. Traditional methods for diagnosing retinal disorders often rely heavily on manual interpretation of optical coherence tomography (OCT) images, which can be time-consuming and dependent on the expertise of ophthalmologists. This leads to challenges in early diagnosis, especially as retinal diseases like diabetic macular edema (DME), Drusen, and Choroidal neovascularization (CNV) become more prevalent. OCT helps ophthalmologists diagnose patients more accurately by allowing for early detection. This paper offers a hybrid SE (Squeeze-and-Excitation)-Enhanced Hybrid Model for detecting retinal disorders from OCT images, including DME, Drusen, and CNV, using artificial intelligence and deep learning.

METHODS: The model integrates SE blocks with EfficientNetB0 and Xception architectures, which provide high success in image classification tasks. EfficientNetB0 achieves high accuracy with fewer parameters through model scaling strategies, while Xception offers powerful feature extraction using deep separable convolutions. The combination of these architectures enhances both the efficiency and classification performance of the model, enabling more accurate detection of retinal disorders from OCT images. Additionally, SE blocks increase the representational ability of the network by adaptively recalibrating per-channel feature responses.

RESULTS: The combined features from EfficientNetB0 and Xception are processed via fully connected layers and categorized using the Softmax algorithm. The methodology was tested on UCSD and Duke's OCT datasets and produced excellent results. The proposed SE-Improved Hybrid Model outperformed the current best-known approaches, with accuracy rates of 99.58% on the UCSD dataset and 99.18% on the Duke dataset.

CONCLUSION: These findings emphasize the model's ability to effectively diagnose retinal disorders using OCT images and indicate substantial promise for the development of computer-aided diagnostic tools in the field of ophthalmology.

PMID:39919140 | DOI:10.1371/journal.pone.0318657

PLoS One. 2025 Feb 7;20(2):e0318846. doi: 10.1371/journal.pone.0318846. eCollection 2025.

ABSTRACT

Perceptual recognition of tourist destinations is vital in representing the destination image, supporting destination management decision-making, and promoting tourism recommendations. However, previous studies on tourist destination perception have limitations regarding accuracy and completeness related to research methods. This study addresses these limitations by proposing an efficient strategy to achieve precise perceptual recognition of tourist destinations while ensuring the integrity of user-generated content (UGC) data and the completeness of perception dimensions. We integrated various types of UGC data, including images, texts, and spatiotemporal information, to create a comprehensive UGC dataset. Then, we adopted the improved Inception V3 model, the bidirectional long short-term memory network (BiLSTM) model with multi-head attention, and geographic information system (GIS) technology to recognize basic tourist feature information from the UGC dataset, such as the content, sentiment, and spatiotemporal perceptual dimensions of the data, achieving a recognition accuracy of over 97%. Finally, a progressive dimension combination method was proposed to visualize and analyze multiple perceptions. An experimental case study demonstrated the strategy's effectiveness, focusing on tourists' perceptions of Datong, China. Experimental results show that the approach is feasible for studying tourist destination perception. Content perception, sentiment perception, and the perception of Datong's spatial and temporal characteristics were recognized and analyzed efficiently. This study offers valuable guidance and a reference framework for selecting methods and technical routes in tourist destination perception.

PMID:39919101 | DOI:10.1371/journal.pone.0318846

Cell Rep. 2025 Feb 6;44(2):115270. doi: 10.1016/j.celrep.2025.115270. Online ahead of print.

ABSTRACT

Current deep-learning-based image-analysis solutions exhibit limitations in holistically capturing spatiotemporal cellular changes, particularly during aging. We present scCamAge, an advanced context-aware multimodal prediction engine that co-leverages image-based cellular spatiotemporal features at single-cell resolution alongside cellular morphometrics and aging-associated bioactivities such as genomic instability, mitochondrial dysfunction, vacuolar dynamics, reactive oxygen species levels, and epigenetic and proteasomal dysfunctions. scCamAge employed heterogeneous datasets comprising ∼1 million single yeast cells and was validated using pro-longevity drugs, genetic mutants, and stress-induced models. scCamAge also predicted a pro-longevity response in yeast cells under iterative thermal stress, confirmed using integrative omics analyses. Interestingly, scCamAge, trained solely on yeast images, without additional learning, surpasses generic models in predicting chemical and replication-induced senescence in human fibroblasts, indicating evolutionary conservation of aging-related morphometrics. Finally, we enhanced the generalizability of scCamAge by retraining it on human fibroblast senescence datasets, which improved its ability to predict senescent cells.

PMID:39918957 | DOI:10.1016/j.celrep.2025.115270

PLoS One. 2025 Feb 7;20(2):e0318877. doi: 10.1371/journal.pone.0318877. eCollection 2025.

ABSTRACT

BACKGROUND: The therapeutic role of antifibrotic therapy has been well-established in idiopathic pulmonary fibrosis (IPF). However, its efficacy and safety for interstitial lung diseases (ILDs) other than IPF are not fully understood.

METHODS: We updated a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized controlled trials and prospective studies on antifibrotic drug (nintedanib or pirfenidone) vs other intervention (placebo, no intervention or conventional treatment) in non-IPF ILDs. The primary outcomes were absolute change in forced vital capacity (FVC), all-cause mortality and serious adverse events (SAEs). The risk of bias was rated with the RoB2 tool and certainty of evidence was assessed by the GRADE approach.

RESULTS: 17 studies with 1908 patients were included. For the primary outcomes, pooled analyses of four trials with low risk of bias showed that antifibrotic drugs significantly ameliorated FVC decline (mean difference 86.21; 95% CI 49.38 to 123.03; I2 = 64%; TSA-adjusted CI 40.86 to 131.56). Based on five trials with low risk of bias, no difference was observed in all-cause mortality (RR 0.87; 95% CI 0.53 to 1.43; I2 = 0%; TSA-adjusted CI 0.12 to 6.53) and SAEs (RR 0.97; 95% CI 0.83 to 1.13; I2 = 0%; TSA-adjusted CI 0.74 to 1.28) between groups. However, based on two studies with 324 patients, benefit of antifibrotic drugs in FVC was not shown in the subgroup taking mycophenolate (mean difference 17.08; 95% CI -56.22 to 90.37), which also had higher risk of SAEs (RR 1.71; 95% CI 1.09 to 2.70), although both were contested by TSA.

CONCLUSION: Our study suggests that antifibrotic drugs are beneficial for patients with non-IPF ILDs in slowing disease progression, whereas may not correlate to all-cause mortality and SAEs. However, for patients taking mycophenolate, antifibrotic drugs may do more harm than good. More investigations are warranted to validate current findings.

PMID:39919132 | DOI:10.1371/journal.pone.0318877

Cell Rep. 2025 Feb 6;44(2):115275. doi: 10.1016/j.celrep.2025.115275. Online ahead of print.

ABSTRACT

Mucosal-associated invariant T (MAIT) cells, the most abundant unconventional T cells in the lung, can exhibit a wide range of functional responses to different triggers via their T cell receptor (TCR) and/or cytokines. Their role, especially in sterile lung injury, is unknown. Using single-cell RNA sequencing (scRNA-seq), spectral analysis, and adoptive transfer in a bleomycin-induced sterile lung injury, we found that bleomycin activates murine pulmonary MAIT cells and is associated with a protective role against bleomycin-induced lung injury. MAIT cells drive the accumulation of type 1 conventional dendritic cells (cDC1s), limiting tissue damage in a DNGR-1-dependent manner. Human scRNA-seq data revealed that MAIT cells were activated, with increased cDC populations in idiopathic pulmonary fibrosis patients. Thus, MAIT cells enhance defense against sterile lung injury by fostering cDC1-driven anti-fibrotic pathways.

PMID:39918959 | DOI:10.1016/j.celrep.2025.115275

Sci Immunol. 2025 Feb 7;10(104):eadp6667. doi: 10.1126/sciimmunol.adp6667. Epub 2025 Feb 7.

ABSTRACT

The bone marrow microenvironment plays a crucial role in the development of multiple myeloma. As the disease progresses, malignant myeloma cells can evolve to survive outside the bone marrow. However, the processes underlying bone marrow independence and their consequences for immune control remain poorly understood. Here, we conducted single-cell and spatial multiomics analyses of bone marrow-confined intramedullary disease and paired breakout lesions that disrupt the cortical bone. These analyses revealed a distinct cellular microenvironment and architectural features of breakout lesions, characterized by extensive areas of malignant plasma cells interspersed with lesion-specific solitary natural killer and macrophage populations, as well as focal accumulations of immune cell agglomerates. Within these agglomerates, spatially confined T cell clones expanded alongside various immune cells, coinciding with the local genomic evolution of tumor cells. These analyses identify breakout lesions as a hotspot for tumor-immune cell interactions and diversification, representing a key event in myeloma pathogenesis.

PMID:39919199 | DOI:10.1126/sciimmunol.adp6667

PLoS One. 2025 Feb 7;20(2):e0316368. doi: 10.1371/journal.pone.0316368. eCollection 2025.

ABSTRACT

The COVID-19 (SARS-CoV-2) pandemic has led to a significant mortality globally and persistent health challenges in many survivors. Early accurate diagnosis, surveillance, identification of cohorts, and prophylaxis are considered essential measures to reduce the spread of infectious viral pathogens such as SARS-CoV-2. A reliable, fast, high-throughput screening method that can detect viral particles and identify the pathogenic virus in infected individuals could help to reduce the spread of the next viral threat through quick knowledge and implementation of appropriate prevention strategies. Since respiratory viruses are typically present in nasal and oral secretions, saliva is a good target for testing for viral infections. Saliva testing has slowly gained popularity in the diagnostics based on biomarkers and other constituents ranging from organic compounds (e.g., food additives), peptides, and even microorganisms. Polymerase chain reaction (PCR) remains the gold standard for sensitive detection of SARS-CoV-2 infection in biological samples. However, while PCR testing for COVID is sensitive and widely used by hospitals, the method has a false-negative rate of 15-20% and is kit-based necessitating the development of alternative methods of detection that provide higher accuracy. This paper describes the use of a SpecID Mass Spectrometer that can detect the presence of viral particles in saliva at very low levels (<500 virions/0.5 ml). The main goal of this study was to demonstrate that our previously developed, portable, mass spectrometry based method, SpecID, could also be sued for detecting viruses in saliva, including but not limited to SARS-CoV-2; the SpecID method has the potential to provide a reliable solution that overcomes some of the challenges with molecular testing like PCR.

PMID:39919111 | DOI:10.1371/journal.pone.0316368

PLoS One. 2025 Feb 7;20(2):e0317672. doi: 10.1371/journal.pone.0317672. eCollection 2025.

ABSTRACT

Extreme temperatures associated with climate change are expected to impact the physiology and fertility of a variety of insects, including honey bees. Most previous work on this topic has focused on female honey bees (workers and queens), and comparatively little research has investigated how heat exposure affects males (drones). To address this gap, we tested body mass, viral infections, and population origin as predictors of drone survival and sperm viability in a series of heat challenge assays. We found that individual body mass was highly influential, with heavier drones being more likely to survive a heat challenge (4 h at 42°C) than smaller drones. In a separate experiment, we compared the survival of Northern California and Southern California drones in response to the same heat challenge (4 h at 42°C), and found that Southern Californian drones - which are enriched for African ancestry - were more likely to survive a heat challenge than drones originating from Northern California. To avoid survivor bias, we conducted sperm heat challenges using in vitro assays and found remarkable variation in sperm heat resilience among drones sourced from different commercial beekeeping operations, with some exhibiting no reduction in sperm viability after heat challenge and others exhibiting a 75% reduction in sperm viability. Further investigating potential causal factors for such variation, we found no association between drone mass and viability of sperm in in vitro sperm heat challenge assays, but virus inoculation (with Israeli acute paralysis virus) exacerbated the negative effect of heat on sperm viability. These experiments establish a vital framework for understanding the importance of population origin and comorbidities for drone heat sensitivity.

PMID:39919074 | DOI:10.1371/journal.pone.0317672

ALTEX. 2025 Jan 20. doi: 10.14573/altex.2412241. Online ahead of print.

ABSTRACT

Chemical safety assessment still heavily relies on animal testing, presenting ethical dilemmas and limited human predictive value. New approach methodologies (NAMs), including in vitro and in silico techniques, offer alternative solutions. In silico toxicology has made progress in predicting chemical effects but frequently lacks biological mechanistic foundations. Recent developments focus on mechanistic understanding of adverse effects inflicted by chemicals, as embedded in (quantitative) adverse outcome pathways (AOPs). However, there is a demand for more detailed mechanistic insights at the gene and cell levels, encompassing both pathology and physiology. Drawing inspiration from the Disease Maps Project, this paper introduces Physiological Maps (PMs) as comprehensive graphical representations of biochemical processes related to specific organ functions. PMs are standardized using Systems Biology Graphical Notation and controlled vocabularies and annotations. Curation guidelines have been developed to ensure reproducibility and usability. This paper presents the methodology used to build PMs, emphasizing the essential collaboration between domain experts and curators. PMs offer user-friendly, standardized visualization for data analysis and educational purposes. Enabling a better understanding of (patho)physiology, they also complement and support the development of AOPs by providing detailed mechanistic information at the gene and cell level. Furthermore, PMs contribute to developing in vitro test batteries and to building (dynamic) in silico models aiming to predict the toxicity of chemicals. Collaborative efforts between the toxicology and systems biology communities are crucial for creating standardized and comprehensive PMs, supporting and accelerating the development of human-relevant NAMs for next-generation risk assessment.

PMID:39918919 | DOI:10.14573/altex.2412241

PLOS Glob Public Health. 2025 Feb 7;5(2):e0004110. doi: 10.1371/journal.pgph.0004110. eCollection 2025.

ABSTRACT

Drug-resistant tuberculosis remains a persistent public health threat. Maximizing successful treatment completion is a global health priority and a focus of the End TB strategy. Despite the implementation of programmatic management for drug-resistant tuberculosis in Ethiopia, there is limited understanding of the barriers related to successful treatment completion among Ethiopian patients. A qualitative study that is explorative, descriptive and contextual in nature was conducted to explore and describe the views and lived experiences of previously treated drug-resistant tuberculosis patients to gain an in-depth understanding of barriers to the successful completion of drug-resistant tuberculosis treatment. Six focus group discussion sessions with 42 purposively selected drug-resistant tuberculosis patients with previous treatment history and on retreatment regimens were conducted. The seven prominent themes revealed were: drug-related challenges encompassing adverse events and the lengthy treatment duration; clinical hurdles such as delayed consultation following prolonged illness, diagnostic delays, and suboptimal dosages; psycho-emotional difficulties including emotional trauma and facing stigma from both the community and healthcare professionals; socio-economic constraints; service-related issues such as interruptions in monitoring tests, inadequate follow-up, and accessibility barriers; patient-related factors such as a false sense of recovery and reverting to previously quit habits; and provider-related issues such as lack of responsiveness and ineffective communication. Addressing these factors demands policy-level decisions and programmatic guidance at the national level based on best practices, as well as good programmatic implementation from actors through regional and health facility-level structures.

PMID:39919126 | DOI:10.1371/journal.pgph.0004110

J Bras Nefrol. 2025 Apr-Jun;47(2):e20240087. doi: 10.1590/2175-8239-JBN-2024-0087en.

ABSTRACT

Atypical hemolytic uremic syndrome (aHUS) is a rare cause of thrombotic microangiopathy (TMA) caused by the dysregulation of the alternative complement pathway. The diagnosis of TMA is made clinically by the triad: microangiopathic hemolytic anemia, thrombocytopenia, and organ damage (mainly acute kidney injury). The heterogeneity of clinical manifestation and the lack of a gold standard diagnostic test makes the precise diagnosis of aHUS a challenging process that may impact patient management. Until one decade ago, there was no specific treatment for aHUS and patients were submitted to plasma therapy (plasma exchange and/or plasma infusion) and/or liver transplantation, procedures that are not free of serious complications and that do not address the underlying pathophysiology of the disease. Since 2011, an anti-C5 complement monoclonal antibody has been approved by the Food and Drug Administration (FDA) for aHUS patients beginning a new era in treatment. Clinical trials on new complement inhibitors may also add to the treatment portfolio in the future. The Brazilian population is a mixed race with a unique genetic and clinical profile. This consensus aims to offer recommendations for the diagnosis and treatment of patients with aHUS in this population based on expert experience, data from the aHUS Brazilian Registry and literature review. The GRADE system was used to classify the quality of the evidence.

PMID:39918340 | DOI:10.1590/2175-8239-JBN-2024-0087en