Sensors (Basel). 2025 Mar 5;25(5):1589. doi: 10.3390/s25051589.

ABSTRACT

The health status of rotating machinery equipment in nuclear power plants is of paramount importance for ensuring the overall normal operation of the power plant system. In particular, significant failures in large rotating machinery equipment, such as main pumps, pose critical safety hazards to the system. Therefore, this paper takes pump equipment as a representative of rotating machinery in nuclear power plants and proposes a fault diagnosis method based on a multi-scale convolutional self-attention network for three types of faults: outer ring fracture, inner ring fracture, and rolling element pitting corrosion. Within the multi-scale convolutional self-attention network, a multi-scale hybrid feature complementarity mechanism is introduced. This mechanism leverages an adaptive encoder to capture deep feature information from the acoustic signals of rolling bearings and constructs a hybrid-scale feature set based on deep features and original signal characteristics in the time-frequency domain. This approach enriches the fault information present in the feature set and establishes a nonlinear mapping relationship between fault features and rolling bearing faults. The results demonstrate that, without significantly increasing model complexity or the volume of feature data, this method achieves a substantial increase in fault diagnosis accuracy, exceeding 99.5% under both vibration signal and acoustic signal conditions.

PMID:40096472 | DOI:10.3390/s25051589

Sensors (Basel). 2025 Mar 6;25(5):1615. doi: 10.3390/s25051615.

ABSTRACT

E-skin is an integrated electronic system that can mimic the perceptual ability of human skin. Traditional analysis methods struggle to handle complex e-skin data, which include time series and multiple patterns, especially when dealing with intricate signals and real-time responses. Recently, deep learning techniques, such as the convolutional neural network, recurrent neural network, and transformer methods, provide effective solutions that can automatically extract data features and recognize patterns, significantly improving the analysis of e-skin data. Deep learning is not only capable of handling multimodal data but can also provide real-time response and personalized predictions in dynamic environments. Nevertheless, problems such as insufficient data annotation and high demand for computational resources still limit the application of e-skin. Optimizing deep learning algorithms, improving computational efficiency, and exploring hardware-algorithm co-designing will be the key to future development. This review aims to present the deep learning techniques applied in e-skin and provide inspiration for subsequent researchers. We first summarize the sources and characteristics of e-skin data and review the deep learning models applicable to e-skin data and their applications in data analysis. Additionally, we discuss the use of deep learning in e-skin, particularly in health monitoring and human-machine interactions, and we explore the current challenges and future development directions.

PMID:40096464 | DOI:10.3390/s25051615

Sensors (Basel). 2025 Mar 4;25(5):1578. doi: 10.3390/s25051578.

ABSTRACT

This study proposes an enhanced network intrusion detection model, 1D-TCN-ResNet-BiGRU-Multi-Head Attention (TRBMA), aimed at addressing the issues of incomplete learning of temporal features and low accuracy in the classification of malicious traffic found in existing models. The TRBMA model utilizes Temporal Convolutional Networks (TCNs) to improve the ResNet18 architecture and incorporates Bidirectional Gated Recurrent Units (BiGRUs) and Multi-Head Self-Attention mechanisms to enhance the comprehensive learning of temporal features. Additionally, the ResNet network is adapted into a one-dimensional version that is more suitable for processing time-series data, while the AdamW optimizer is employed to improve the convergence speed and generalization ability during model training. Experimental results on the CIC-IDS-2017 dataset indicate that the TRBMA model achieves an accuracy of 98.66% in predicting malicious traffic types, with improvements in precision, recall, and F1-score compared to the baseline model. Furthermore, to address the challenge of low identification rates for malicious traffic types with small sample sizes in unbalanced datasets, this paper introduces TRBMA (BS-OSS), a variant of the TRBMA model that integrates Borderline SMOTE-OSS hybrid sampling. Experimental results demonstrate that this model effectively identifies malicious traffic types with small sample sizes, achieving an overall prediction accuracy of 99.88%, thereby significantly enhancing the performance of the network intrusion detection model.

PMID:40096461 | DOI:10.3390/s25051578

Sensors (Basel). 2025 Mar 4;25(5):1574. doi: 10.3390/s25051574.

ABSTRACT

Face recognition (FR) is a less intrusive biometrics technology with various applications, such as security, surveillance, and access control systems. FR remains challenging, especially when there is only a single image per person as a gallery dataset and when dealing with variations like pose, illumination, and occlusion. Deep learning techniques have shown promising results in recent years using VAE and GAN, with approaches such as patch-VAE, VAE-GAN for 3D Indoor Scene Synthesis, and hybrid VAE-GAN models. However, in Single Sample Per Person Face Recognition (SSPP FR), the challenge of learning robust and discriminative features that preserve the subject's identity persists. To address these issues, we propose a novel framework called AD-VAE, specifically for SSPP FR, using a combination of variational autoencoder (VAE) and Generative Adversarial Network (GAN) techniques. The proposed AD-VAE framework is designed to learn how to build representative identity-preserving prototypes from both controlled and wild datasets, effectively handling variations like pose, illumination, and occlusion. The method uses four networks: an encoder and decoder similar to VAE, a generator that receives the encoder output plus noise to generate an identity-preserving prototype, and a discriminator that operates as a multi-task network. AD-VAE outperforms all tested state-of-the-art face recognition techniques, demonstrating its robustness. The proposed framework achieves superior results on four controlled benchmark datasets-AR, E-YaleB, CAS-PEAL, and FERET-with recognition rates of 84.9%, 94.6%, 94.5%, and 96.0%, respectively, and achieves remarkable performance on the uncontrolled LFW dataset, with a recognition rate of 99.6%. The AD-VAE framework shows promising potential for future research and real-world applications.

PMID:40096455 | DOI:10.3390/s25051574

J Clin Med. 2025 Mar 3;14(5):1693. doi: 10.3390/jcm14051693.

ABSTRACT

Background: Patients suffering from idiopathic pulmonary fibrosis (IPF) may experience acute exacerbation (AE-IPF), which frequently results in acute respiratory failure (ARF) requiring hospitalization. Objective: This study aims to determine if survival has improved over the last decade in patients hospitalized for ARF consequent to AE-IPF, in view of the progress recently made in pharmacological and supportive treatment strategies. Methods: This was an observational retrospective single-center study. The data of 14 patients admitted to an Intermediate Respiratory Care Unit (IRCU) between 1 January 2004 and 31 December 2013 (group A) were compared with those of 26 patients admitted between 1 January 2014 and 31 December 2023 (group B). This study's primary endpoint was survival following IRCU admission. Results: Survival time was significantly longer in the second group of patients compared to the first one [median survival time: 134 (31-257) vs. 25.5 (20-50) days; p < 0.001]. Group B patients also had a lower IRCU mortality rate (6/26 vs. 10/14; p = 0.003) and a significantly shorter stay in the IRCU [6 (1-60) vs. 14 (1-43) days; p = 0.039]. Conclusions: Innovative pharmacologic treatments and supportive therapeutic strategies are able to prolong survival and reduce the risk of in-hospital mortality in patients with AE-IPF hospitalized for ARF.

PMID:40095670 | DOI:10.3390/jcm14051693

J Epidemiol Glob Health. 2025 Mar 17;15(1):44. doi: 10.1007/s44197-025-00377-y.

ABSTRACT

BACKGROUND: Advances in the understanding of idiopathic pulmonary fibrosis (IPF) and international cooperation have led to the publication and subsequent updates of international practice guidelines. The impact of these guidelines, especially significant updates occurring after 2011, on IPF epidemiology and clinical practices remains relatively unexplored.

METHODS: This retrospective nationwide population-based study utilized the Whole-Population Datafiles (WPD) of Taiwan's National Health Insurance Research Database that contained basic demographics, complete claim data, and causes of death for all insured persons. We refined the code-based definition to identify IPF cases from the WPD between 2011 and 2019. Independent validation confirmed the high accuracy of this definition. We analyzed the annual standardized rates of IPF incidence, prevalence, overall and IPF-specific all-cause mortality. Additionally, we examined trends in the prescription of selected medications and the proportions of patients with respiratory failure receiving invasive (IMV) and non-invasive (NIV) mechanical ventilation.

RESULTS: We included 4359 incident cases of IPF. From 2011 to 2019, the annual standardized incidence rates increased from 1.66 (95% confidence interval [CI], 1.36-1.97) to 11.35 (95% CI, 10.65-12.04) per 100,000 standard population, and the annual standardized prevalence rates increased from 1.98 (95% CI, 1.65-2.31) to 27.25 (95% CI, 26.17-28.33) per 100,000 standard population. The standardized IPF-specific all-cause mortality and respiratory failure rates remained stable. Male and older patients received IPF diagnoses more frequently, and experienced higher mortality rates, compared to their female and younger counterparts. Most deaths were attributed to respiratory causes, without significant seasonal variation. Changing trends in the management of IPF mirrored with the evolving guideline recommendations, and showed diminishing roles of immunosuppressants, growing usage of antifibrotics, and NIV usage surpassing IMV.

CONCLUSIONS: Our findings reflected the longitudinal impact of the recently evolving guideline recommendations on IPF epidemiology and real-world management.

PMID:40095261 | DOI:10.1007/s44197-025-00377-y

J Clin Med. 2025 Feb 24;14(5):1496. doi: 10.3390/jcm14051496.

ABSTRACT

Telomeropathies, or telomere biology disorders (TBDs), are syndromes that can cause a number of medical conditions, including interstitial lung disease (ILD), bone marrow failure, liver fibrosis, and other diseases. They occur due to genetic mutations to the telomerase complex enzymes that result in premature shortening of telomeres, the caps on the ends of cellular DNA that protect chromosome length during cell division, leading to early cell senescence and death. Idiopathic pulmonary fibrosis (IPF) is the most common manifestation of the telomere biology disorders, although it has been described in other interstitial lung diseases as well, such as rheumatoid arthritis-associated ILD and chronic hypersensitivity pneumonitis. Telomere-related mutations can be inherited or can occur sporadically. Identifying these patients and offering genetic counseling is important because telomerapathies have been associated with poorer outcomes including death, lung transplantation, hospitalization, and FVC decline. Additionally, treatment with immunosuppressants has been shown to be associated with worse outcomes. Currently, there is no specific treatment for TBD except to transplant the organ that is failing, although there are a number of promising treatment strategies currently under investigation. Shortened telomere length is routinely discovered in patients undergoing lung transplantation for IPF. Testing to detect early TBD in patients with suggestive signs or symptoms can allow for more comprehensive treatment and multidisciplinary care pre- and post-transplant. Patients with TBD undergoing lung transplantation have been reported to have both pulmonary and extrapulmonary complications at a higher frequency than other lung transplant recipients, such as graft-specific complications, increased infections, and complications related to immunosuppressive therapy.

PMID:40095034 | DOI:10.3390/jcm14051496

Aging (Albany NY). 2025 Mar 12;17. doi: 10.18632/aging.206220. Online ahead of print.

ABSTRACT

The dynamic nature of epigenetic modifications has been leveraged to construct epigenetic clocks that accurately predict an individual's age based on DNA methylation levels. Here we explore whether the accumulation of epimutations, which can be quantified by Shannon's entropy, changes reproducibly with age. Using targeted bisulfite sequencing, we analyzed the associations between age, entropy, and methylation levels in human buccal swab samples. We find that epigenetic clocks based on the entropy of methylation states predict chronological age with similar accuracy as common approaches that are based on methylation levels of individual cytosines. Our approach suggests that across many genomic loci, methylation entropy changes reproducibly with age.

PMID:40096548 | DOI:10.18632/aging.206220

Plant Cell. 2025 Mar 17:koaf055. doi: 10.1093/plcell/koaf055. Online ahead of print.

ABSTRACT

Photosystem (PS) II assembly requires auxiliary factors, including Psb28. Although the absence of Psb28 in cyanobacteria has little effect on PSII assembly, we show here that the Chlamydomonas (Chlamydomonas reinhardtii) psb28 null mutant is severely impaired in PSII assembly, showing drastically reduced PSII supercomplexes, dimers and monomers, while overaccumulating early PSII assembly intermediates reaction center II (RCII), CP43mod and D1mod. The mutant had less PSI and more cytochrome b6f complex, its thylakoids were organized mainly as monolayers and it had a distorted chloroplast morphology. Complexome profiling of the psb28 mutant revealed that THYLAKOID ENRICHED FRACTION 5 (TEF5), the homolog of Arabidopsis (Arabidopsis thaliana) PHOTOSYSTEM B PROTEIN 33 (PSB33)/LIGHT HARVESTING-LIKE 8 (LIL8), co-migrated particularly with RCII. TEF5 also interacted with PSI. A Chlamydomonas tef5 null mutant was severely impaired in PSII assembly and overaccumulated RCII and CP43mod. RC47 was not detectable in the light-grown tef5 mutant. Our data suggest a possible role for TEF5 in RCII photoprotection or maturation. Both the psb28 and tef5 mutants exhibited decreased synthesis of CP47 and PsbH, suggesting negative feedback regulation possibly exerted by the accumulation of RCII and/or CP43mod in both mutants. The strong effects of missing auxiliary factors on PSII assembly in Chlamydomonas suggest a more effective protein quality control system in this alga than in land plants and cyanobacteria.

PMID:40096524 | DOI:10.1093/plcell/koaf055

Elife. 2025 Mar 17;14:RP103877. doi: 10.7554/eLife.103877.

ABSTRACT

The Gillespie algorithm is commonly used to simulate and analyze complex chemical reaction networks. Here, we leverage recent breakthroughs in deep learning to develop a fully differentiable variant of the Gillespie algorithm. The differentiable Gillespie algorithm (DGA) approximates discontinuous operations in the exact Gillespie algorithm using smooth functions, allowing for the calculation of gradients using backpropagation. The DGA can be used to quickly and accurately learn kinetic parameters using gradient descent and design biochemical networks with desired properties. As an illustration, we apply the DGA to study stochastic models of gene promoters. We show that the DGA can be used to: (1) successfully learn kinetic parameters from experimental measurements of mRNA expression levels from two distinct Escherichia coli promoters and (2) design nonequilibrium promoter architectures with desired input-output relationships. These examples illustrate the utility of the DGA for analyzing stochastic chemical kinetics, including a wide variety of problems of interest to synthetic and systems biology.

PMID:40095799 | DOI:10.7554/eLife.103877

Plant Biol (Stuttg). 2025 Mar 17. doi: 10.1111/plb.70012. Online ahead of print.

ABSTRACT

Iron (Fe) is essential for plants and humans, with over 2 billion people suffering deficiency disorders because most plant foods, including cereals, are low in Fe. Durum wheat, a staple crop in Mediterranean regions, is facing increased droughts, which reduce plant yield and ability to acquire and use Fe. Therefore, understanding mechanisms underlying Fe acquisition and accumulation in durum wheat under drought is essential for both agronomic and nutritional purposes. Here, a durum wheat (Triticum turgidum subsp. durum) genotype with a purple grain pericarp was grown hydroponically under adequate (80 μM) or limited (10 μM) Fe, with or without water stress (induced with 10% PEG 6000) for 6 days. Fe accumulation decreased under Fe deficiency and drought, with the highest phytosiderophore (PS) release in Fe-deficient plants. Interestingly, despite adequate Fe availability, drought inhibited Fe accumulation in roots. This response was accompanied by increased release of PS from roots, although the increase was less than that observed with single or combined Fe deficiency. Both TdIRT1 and TdYS15 were upregulated by Fe deficiency but downregulated by drought and the combined stress. Drought stress and Fe deficiency led to increased ABA production, being 250-fold higher with respect to controls. TdIRT1 downregulation in plants exposed to the combined stress suggests a trade-off between water and Fe stress responses. Our findings demonstrate that the response to combined stress differs from, and is rarely additive to, the response to a single stressor, reinforcing the complexity of plant adaptation to combined environmental stresses.

PMID:40095748 | DOI:10.1111/plb.70012

FASEB J. 2025 Mar 31;39(6):e70419. doi: 10.1096/fj.202401661RRR.

ABSTRACT

Zinc finger-containing ubiquitin peptidase 1 (ZUP1) is a protein characterized by four N-terminal zinc finger domains and a C-terminal deubiquitinase (DUB) domain. While it is associated with the DNA damage response, the role of ZUP1 in innate immunity remains unclear. Here, we identify ZUP1 as a crucial component of the mitochondrial antiviral signaling (MAVS) complex, essential for host antiviral defense. We show that viral infection significantly upregulates ZUP1 expression, and mice lacking ZUP1 exhibit impaired type I interferon (IFN) production and increased susceptibility to viral infection, as evidenced by higher mortality rates. This underscores the protective role of ZUP1 in host immunity. Mechanistically, ZUP1 binds to MAVS through its C-terminal domain independently of DUB activity. Instead, ZUP1 utilizes its zinc finger domains, particularly the third zinc finger, to directly bind viral RNA. This interaction enhances the association of ZUP1 with MAVS and promotes its aggregation on mitochondria during viral infection. ZUP1 also interacts with TBK1 and NEMO within the MAVS complex, facilitating IRF3 activation and type I IFN production. These findings establish ZUP1 as a zinc finger-containing regulator that amplifies MAVS-dependent antiviral immunity, linking viral RNA recognition to downstream signaling and highlighting potential targets for therapeutic intervention against viral infections.

PMID:40095368 | DOI:10.1096/fj.202401661RRR

Planta. 2025 Mar 17;261(4):92. doi: 10.1007/s00425-025-04666-5.

ABSTRACT

Big data and network biology infer functional coupling between genes. In combination with machine learning, network biology can dramatically accelerate the pace of gene discovery using modern transcriptomics approaches and be validated via genome editing technology for improving crops to stresses. Unlike other living things, plants are sessile and frequently face various environmental challenges due to climate change. The cumulative effects of combined stresses can significantly influence both plant growth and yields. In navigating the complexities of climate change, ensuring the nourishment of our growing population hinges on implementing precise agricultural systems. Conventional breeding methods have been commonly employed; however, their efficacy has been impeded by limitations in terms of time, cost, and infrastructure. Cutting-edge tools focussing on big data are being championed to usher in a new era in stress biology, aiming to cultivate crops that exhibit enhanced resilience to multifactorial stresses. Transcriptomics, combined with network biology and machine learning, is proving to be a powerful approach for identifying potential genes to target for gene editing, specifically to enhance stress tolerance. The integration of transcriptomic data with genome editing can yield significant benefits, such as gaining insights into gene function by modifying or manipulating of specific genes in the target plant. This review provides valuable insights into the use of transcriptomics platforms and the application of biological network analysis and machine learning in the discovery of novel genes, thereby enhancing the understanding of plant responses to combined or sequential stress. The transcriptomics as a forefront omics platform and how it is employed through biological networks and machine learning that lead to novel gene discoveries for producing multi-stress-tolerant crops, limitations, and future directions have also been discussed.

PMID:40095140 | DOI:10.1007/s00425-025-04666-5

Front Pharmacol. 2025 Feb 28;16:1449062. doi: 10.3389/fphar.2025.1449062. eCollection 2025.

ABSTRACT

BACKGROUND: Anti-hypertensive drugs have been reported to demonstrate anti-inflammatory and anti-angiogenic effects. This study aims to investigate the association between anti-hypertensive drugs and the prognosis of colorectal cancer (CRC) patients.

METHODS: Clinical data of 1134 CRC patients with hypertensions and the prescription of anti-hypertensive drugs who had undergone curative surgery in our hospital between 2005 and 2015 were retrieved. Their survival data and immune cell population in circulatory blood were compared among different types of anti-hypertensive drugs and overall CRC patients.

RESULTS: The 5-year overall survival for the antihypertensives-treated patients (65.2%) was higher than the CRC patients in Hong Kong (58.2%). Hydrochlorothiazide (HCTZ) group showed the best prognosis (79.1%) among different antihypertensive drug, particularly for advance stage or elderly patients, which are poor prognostic factors for overall CRC patients, demonstrated an obviously improved prognosis upon HCTZ treatment. Moreover, our data showed the recurrence rate was significantly lower for HCTZ group (18.3%) compared to non-HCTZ group (26.8%) and the reported rate (31%) of CRC patients in Hong Kong. Finally, patients with a lower pre-operative basophil level showed better overall and disease-free survival following HCTZ treatment.

CONCLUSION: This study demonstrated the association of HCTZ treatment with a better prognosis of CRC patients.

PMID:40093321 | PMC:PMC11906466 | DOI:10.3389/fphar.2025.1449062

medRxiv [Preprint]. 2025 Mar 4:2025.02.28.25323099. doi: 10.1101/2025.02.28.25323099.

ABSTRACT

Psychiatric disorders and symptoms are associated with differences in pain perception and sensitivity. These differences can have important implications in treating spinal degenerative disease (SDD) and chronic low-back pain (CLBP). Leveraging data from the UK Biobank (UKB) and the All of Us Research Program (AoU), we investigated the effects linking psychiatric disorders (alcohol use disorder, anxiety, attention deficit hyperactivity disorder, bipolar disorder, cannabis use disorder, depression, opioid use disorder, posttraumatic stress disorder, and schizophrenia) to SDD and CLBP. We applied multi-nominal regression models, polygenic risk scoring (PRS), and one-sample Mendelian randomization (MR) to triangulate the effects underlying the associations observed. We also performed gene ontology and drug-repurposing analyses to dissect the biology shared among mental illnesses, SDD, and CLBP. Comparing individuals affected only by SDD (UKB N=37,745, AoU N=3,477), those affected only by CLBP (UKB N=15,496, AoU N=23,325), and those affected by both conditions (UKB N=11,463, AoU N= 13,451) to controls (UKB N=337,362, AoU N= 117,162), observational and genetically informed analyses highlighted that the strongest effects across the three case groups were observed for alcohol use disorder, anxiety, depression, and posttraumatic stress disorder. Additionally, schizophrenia and its PRS appeared to have an inverse relationship with CLBP, SDD, and their comorbidity. One-sample MR highlighted a potential direct effect of internalizing disorders on the outcomes investigated that was particularly strong on SDD. Our drug-repurposing analyses identified histone deacetylase inhibitors as targeting molecular pathways shared among psychiatric disorders, SDD, and CLBP. In conclusion, these findings support that the comorbidity among psychiatric disorders, SDD, and CLBP is due to the contribution of direct effects and shared biology linking these health outcomes. These pleiotropic mechanisms together with sociocultural factors play a key role in shaping the SDD-CLBP comorbidity patterns observed across the psychopathology spectrum.

PMID:40093242 | PMC:PMC11908311 | DOI:10.1101/2025.02.28.25323099

Expert Opin Pharmacother. 2025 Mar 17. doi: 10.1080/14656566.2025.2480764. Online ahead of print.

ABSTRACT

INTRODUCTION: Pulmonary hypertension is a life-threatening condition characterized by elevated mean pulmonary arterial pressure and vascular resistance. Significant advances in diagnosis and treatment have been achieved over the 20th and 21st centuries, yet challenges remain in improving long-term outcomes.

AREAS COVERED: This review discusses the historical milestones in understanding and pharmacotherapy of the pulmonary arterial hypertension (PAH). A comprehensive literature search was conducted to explore the earliest reports of each approved medication for pulmonary hypertension, along with historical papers detailing the pathophysiological and diagnostic development. Additionally, the search aimed to identify novel therapeutic strategies, including repositioned drugs and emerging targets.

EXPERT OPINION: While current therapies, such as prostacyclin analogs and PDE5 inhibitors, improve functional capacity and hemodynamics, they face limitations, including costs, administration, and a predominantly vasodilatory approach. Additionally, the limitations of current clinical trial designs for rare diseases like pulmonary arterial hypertension hinder the evaluation of potentially effective drugs. These challenges underscore the urgent need for translational research to optimize trial methodologies, accelerating the development of new therapies. Innovative approaches, such as drug repositioning and the exploration of novel molecular targets, are critical to overcoming these barriers and ensuring timely, effective, and affordable treatment options for patients with PAH.

PMID:40091694 | DOI:10.1080/14656566.2025.2480764

Microbiol Spectr. 2025 Mar 17:e0331824. doi: 10.1128/spectrum.03318-24. Online ahead of print.

ABSTRACT

Fungal pathogens pose a serious threat to human health, with Candida and Aspergillus spp. representing some of the most significant opportunistic invaders. Aspergillus fumigatus causes aspergillosis, one of the most prevalent fungal diseases of humans. There is a limited number of drugs available to combat these infections, and antifungal drug resistance is on the rise. In this manuscript, we show 4-[4-(4-Piperidinyl) phenyl]-7-[4-(-(trifluoromethyl) phenyl]-2-naphthalenecarboxylic acid (PPTN), a highly specific antagonist of the human P2Y14 receptor, is a promising antifungal adjuvant against diverse fungal pathogens. PPTN interacts with caspofungin (CAS), ibrexafungerp, voriconazole (VOR), and amphotericin against A. fumigatus CAS- and VOR-resistant clinical isolates, and also CAS against Candida spp and Cryptococcus neoformans. The combination of PPTN and CAS increases cell death in A. fumigatus. In the model yeast Saccharomyces cerevisiae, heterozygous deletion of genes involved in chromatin remodeling results in PPTN hypersensitivity, and in A. fumigatus, PPTN can have increased fungicidal activity when combined with the histone deacetylase inhibitor trichostatin A and the DNA methyltransferase inhibitor 5-azacytidine. Finally, PPTN has reduced toxicity to human immortalized cell lineages and partially clears A. fumigatus conidia infection in A549 pulmonary epithelial cells. Our results indicate that PPTN is a novel adjuvant antifungal drug against fungal diseases caused by A. fumigatus and Candida spp.

IMPORTANCE: Invasive fungal infections have a high mortality rate, causing more deaths annually than tuberculosis or malaria. Aspergillus fumigatus is the main etiological agent of aspergillosis, one of the most prevalent and deadly fungal diseases. There are few therapeutic options for treating this disease, and treatment commonly fails due to host complications or the emergence of antifungal resistance. Drug repurposing, where existing drugs are deployed for other clinical indications, has increasingly been used in the process of drug discovery. Here, we show that 4-[4-(4-Piperidinyl) phenyl]-7-[4-(-(trifluoromethyl) phenyl]-2-naphthalenecarboxylic acid (PPTN), a highly specific antagonist of the human P2Y14 receptor, when combined with caspofungin (CAS), ibrexafungerp, voriconazole (VOR), and amphotericin can increase the fungicidal activity against not only A. fumigatus CAS- and VOR-resistant clinical isolates but also CAS against Candida spp.

PMID:40090930 | DOI:10.1128/spectrum.03318-24

medRxiv [Preprint]. 2025 Mar 5:2025.03.03.25323247. doi: 10.1101/2025.03.03.25323247.

ABSTRACT

African Americans (AAs) are underrepresented in pharmacogenomics which has led to a significant gap in knowledge. AAs are admixed and can inherit specific loci from either their African or European ancestor, known as local ancestry (LA). A previous study in AAs identified single nucleotide polymorphisms (SNPs) located in the CYP2C cluster that are associated with warfarin dose. However, LA was not considered in this study. An IWPC cohort (N=340) was used to determine the LA-adjusted association with warfarin dose. Ancestry-specific GWAS's were conducted with TRACTOR and ancestry tracts were meta-analyzed using METAL. We replicated top associations in the independent ACCOuNT cohort of AAs (N=309) and validated associations in a warfarin pharmacokinetic study in AAs. To elucidate functional roles of top associations, we performed short-read RNA-sequencing from AA hepatocytes carrying each genotype for expression of CYP2C9 and CYP2C19 . We identified 6 novel genome-wide significant SNPs (P<5E-8) in the CYP2C locus (lead SNP, rs7906871 (P=3.14E-8)). These associations were replicated (P≤2.76E-5) and validated with a pharmacokinetic association for S-Warfarin concentration in plasma (P=0.048). rs7906871 explains 6.0% of the variability in warfarin dose in AAs. Multivariate regression including rs7906871, previously associated SNPs, clinical and demographic factors explain 37% of dose variability, greater than previously reported studies in AAs. RNA-seq data in AA hepatocytes identified a significant alternate exon inclusion event between exons 6 and 7 in CYP2C19 for carriers of rs7906871. In conclusion, we have found and replicated a novel CYP2C variant associated with warfarin dose requirement and potential functional consequences to C YP2C19 .

PMID:40093246 | PMC:PMC11908343 | DOI:10.1101/2025.03.03.25323247

Infect Agent Cancer. 2025 Mar 17;20(1):18. doi: 10.1186/s13027-025-00647-1.

ABSTRACT

BACKGROUND: Despite the success of antiretroviral therapy in HIV treatment, cervical cancer remains a leading malignancy in HIV-infected women. Additionally, co-infection by HIV and HPV further accelerates cervical cancer development. There are limited studies on the role of host somatic variations in HIV infected and HIV-negative women with cervical cancer. Therefore, this study aimed to investigate and compare host somatic genetic variation in cervical biopsies obtained from HIV infected and HIV-negative women with cervical intraepithelial neoplasia 3 to understand the genomic landscape. The distribution of HPV types was also investigated between HIV infected and HIV-negative women.

METHODS: The project used an age-matched case-control study utilizing archived cervical biopsies from 88 women (44 HIV infected, 44 HIV-negative) attending Groote Schuur Hospital Cancer Clinic between 2020 and 2022. HPV infection and type were confirmed using the Anyplex™ II HPV28 Detection kit. Six hotspot regions in the four commonly mutated genes (TP53, PIK3CA, PTEN, and EGFR) in cervical cancer were genotyped using PCR and Sanger Sequencing. Variant pathogenicity was assessed using SIFT, Polyphen-2, and ClinVar tools.

RESULTS: The median age was 37 years (IQR: 34-41) for HIV infected women and 35 years (IQR:32- 43) for HIV-negative women. Significantly more HIV-negative women (51% vs. 12%) reported tobacco smoking (p < 0.0001), menstruation irregularities (74% vs. 35%; p = 0.005), and contraception usage (77% vs. 59%; p = 0.019), when compared to their HIV-infected counterparts. Common HPV types identified were HPV16 (n = 43/88, 49%), HPV35 (n = 12/88, 14%), and HPV58 (n = 10/88, 11%). A total of 232 genetic variants were reported. HIV infected women had a significantly higher (p = 0.0406) burden of pathogenic variants (31%) compared to the HIV-negative (15%). The spectrum of observed mutations included stop-gain, missense, synonymous, and intronic changes. Most of the stop gain mutations in TP53 and PIK3CA were reported among HIV infected women (n = 4/5), compared to HIV-negative women (n = 1/5). Damaging variants were more prevalent in women under 50 in both cohorts. We also report on rare HPV subtypes currently not included in the diagnostic HPV test kits in this cohort (HPV 82, 42, 43 and 53).

CONCLUSION: HIV-infection status and age appear to be risk factors for higher burden of pathogenic mutations in genes that predispose to cervical cancer. Mutation profiles in PIK3CA and TP53 genes could be biomarkers of cervical cancer progression but more studies are needed.

PMID:40091081 | DOI:10.1186/s13027-025-00647-1

mBio. 2025 Mar 17:e0036325. doi: 10.1128/mbio.00363-25. Online ahead of print.

ABSTRACT

The human pathogenic fungus Aspergillus fumigatus establishes dual biofilm interactions in the lungs with the pathogenic bacterium Pseudomonas aeruginosa. Screening of 21 A. fumigatus null mutants revealed seven mutants (two G protein-coupled receptors, three mitogen-activated protein kinase receptors, a Gα protein, and one histidine kinase receptor) with reduced biofilm formation, specifically in the presence of P. aeruginosa. Transcriptional profiling and metabolomics analysis of secondary metabolites produced by one of these mutants, ΔgpaB (gpaB encodes a Gα protein), showed GpaB controls the production of several important metabolites for the dual biofilm interaction, including pyripyropene A, a potent inhibitor of mammalian acyl-CoA cholesterol acyltransferase. Deletion of pyr2, encoding a non-reducing polyketide synthase essential for pyripyropene biosynthesis, showed reduced A. fumigatus Δpyr2-P. aeruginosa biofilm growth, altered macrophage responses, and attenuated mouse virulence in a chemotherapeutic murine model. We identified pyripyropene as a novel player in the ecology and pathogenic interactions of this important human fungal pathogen.IMPORTANCEAspergillus fumigatus and Pseudomonas aeruginosa are two important human pathogens. Both organisms establish biofilm interactions in patients affected with chronic lung pulmonary infections, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease. Colonization with A. fumigatus is associated with an increased risk of P. aeruginosa colonization in CF patients, and disease prognosis is poor when both pathogens are present. Here, we identified A. fumigatus genetic determinants important for the establishment of in vitro dual A. fumigatus-P. aeruginosa biofilm interactions. Among them, an A. fumigatus Gα protein GpaB is important for this interaction controlling the production of the secondary metabolite pyripyropene. We demonstrate that the lack of pyripyropene production decreases the dual biofilm interaction between the two species as well as the virulence of A. fumigatus in a chemotherapeutic murine model of aspergillosis. These results reveal a complete novel role for this secondary metabolite in the ecology and pathogenic interactions of this important human fungal pathogen.

PMID:40094363 | DOI:10.1128/mbio.00363-25