Front Plant Sci. 2025 Feb 13;15:1474906. doi: 10.3389/fpls.2024.1474906. eCollection 2024.

ABSTRACT

Mung bean seeds are very important in agricultural production and food processing, but due to their variety and similar appearance, traditional classification methods are challenging, to address this problem this study proposes a deep learning-based approach. In this study, based on the deep learning model MobileNetV2, a DMS block is proposed for mung bean seeds, and by introducing the ECA block and Mish activation function, a high-precision network model, i.e., HPMobileNet, is proposed, which is explored to be applied in the field of image recognition for the fast and accurate classification of different varieties of mung bean seeds. In this study, eight different varieties of mung bean seeds were collected and a total of 34,890 images were obtained by threshold segmentation and image enhancement techniques. HPMobileNet was used as the main network model, and by training and fine-tuning on a large-scale mung bean seed image dataset, efficient feature extraction classification and recognition capabilities were achieved. The experimental results show that HPMobileNet exhibits excellent performance in the mung bean seed grain classification task, with the accuracy improving from 87.40% to 94.01% on the test set, and compared with other classical network models, the results show that HPMobileNet achieves the best results. In addition, this study analyzes the impact of the learning rate dynamic adjustment strategy on the model and explores the potential for further optimization and application in the future. Therefore, this study provides a useful reference and empirical basis for the development of mung bean seed classification and smart agriculture technology.

PMID:40017618 | PMC:PMC11865048 | DOI:10.3389/fpls.2024.1474906

Chem Biomed Imaging. 2025 Jan 17;3(2):85-94. doi: 10.1021/cbmi.4c00065. eCollection 2025 Feb 24.

ABSTRACT

Disease-recapitulating animal models are valuable tools in preclinical development for the study of compounds. In the case of fibrotic pulmonary diseases such as idiopathic pulmonary fibrosis (IPF), the bleomycin model of lung injury in the mouse is widely used. To evaluate bleomycin-induced changes in the lung, we employed a quantitative, multimodal approach. Using in vivo microcomputed tomography (μCT), we demonstrated radiographic changes associated with disease progression in aeration levels of the lung parenchyma. There exists an unmet need for a quantitative, high-resolution imaging probe to detect pulmonary fibrosis, particularly that can differentiate between inflammatory and fibrotic components of the disease. Matrix remodeling and overexpression of extracellular matrix (ECM) proteins such as collagen and fibronectin are hallmarks of organ fibrosis. A splice variant of fibronectin containing extra domain A (FnEDA) is of particular interest in fibrosis due to its high level of expression in diseased tissue, which is confirmed here using immunohistochemistry (IHC) in mouse and human lungs. An antibody against FnEDA was evaluated for use as an imaging tool, particularly by using in vivo single-photon emission computed tomography (SPECT) and ex vivo near-infrared (NIR) fluorescence imaging. These data were further corroborated with histological tissue staining and fibrosis quantitation based on a Modified Ashcroft (MA) score and a digital image analysis of whole slide lung tissue sections. The fusion of these different approaches represents a robust integrated workflow combining anatomical and molecular imaging technologies to enable the visualization and quantitation of disease activity and treatment response with an inhibitor of the TGFβ signaling pathway.

PMID:40018646 | PMC:PMC11863149 | DOI:10.1021/cbmi.4c00065

J Integr Neurosci. 2025 Feb 19;24(2):36279. doi: 10.31083/JIN36279.

NO ABSTRACT

PMID:40018783 | DOI:10.31083/JIN36279

Chem Biomed Imaging. 2024 Dec 19;3(2):111-122. doi: 10.1021/cbmi.4c00077. eCollection 2025 Feb 24.

ABSTRACT

The COVID-19 pandemic has underscored the importance of in-depth research into the proteins encoded by coronaviruses (CoV), particularly the highly conserved nonstructural CoV proteins (nsp). Among these, the nsp13 helicase of severe pathogenic MERS-CoV, SARS-CoV-2, and SARS-CoV is one of the most preserved CoV nsp. Utilizing single-molecule FRET, we discovered that MERS-CoV nsp13 unwinds DNA in distinct steps of about 9 bp when ATP is employed. If a different nucleotide is introduced, these steps diminish to 3-4 bp. Dwell-time analysis revealed 3-4 concealed steps within each unwinding process, which suggests the hydrolysis of 3-4 dTTP. Combining our observations with previous studies, we propose an unwinding model of CoV nsp13 helicase. This model suggests that the elongated and adaptable 1B-stalk of nsp13 may enable the 1B remnants to engage with the unwound single-stranded DNA, even as the helicase core domain has advanced over 3-4 bp, thereby inducing accumulated strain on the nsp13-DNA complex. Our findings provide a foundational framework for determining the unwinding mechanism of this unique helicase family.

PMID:40018651 | PMC:PMC11863148 | DOI:10.1021/cbmi.4c00077

Front Mol Neurosci. 2025 Feb 13;18:1544971. doi: 10.3389/fnmol.2025.1544971. eCollection 2025.

ABSTRACT

INTRODUCTION: Growing recognition of microglia's role in neurodegenerative disorders has accentuated the need to characterize microglia profiles and their influence on pathogenesis. To understand changes observed in the microglial profile during the progression of synucleinopathies, microglial gene expression and DNA methylation were examined in the mThy1-α-synuclein mouse model.

METHODS: Disease progression was determined using behavioral tests evaluating locomotor deficits before DNA and RNA extraction at 7 and 10 months from isolated microglia for enzymatic methyl-sequencing and RNA-sequencing.

RESULTS: Pathway analysis of these changes at 7 months indicates a pro-inflammatory profile and changes in terms related to synaptic maintenance. Expression and methylation at both 7 and 10 months included terms regarding mitochondrial and metabolic stress. While behavior symptoms progressed at 10 months, we see many previously activated pathways being inhibited in microglia at a later stage, with only 8 of 53 shared pathways predicted to be directionally concordant. Despite the difference in pathway directionality, 21 of the 22 genes that were differentially expressed and annotated to differentially methylated regions at both 7 and 10 months had conserved directionality changes.

DISCUSSION: These results highlight a critical period in disease progression, during which the microglia respond to α-synuclein, suggesting a transition in the role of microglia from the early to late stages of the disease.

PMID:40018011 | PMC:PMC11865073 | DOI:10.3389/fnmol.2025.1544971

Front Oral Health. 2025 Feb 13;6:1543667. doi: 10.3389/froh.2025.1543667. eCollection 2025.

ABSTRACT

INTRODUCTION: Derivatives from Saccharomyces cerevisiae yeast including yeast extracts and yeast cell walls are sustainable sources of valuable nutrients, including dietary fibers and proteins. Previous studies have shown that certain components from these yeast derivatives can inhibit the growth of harmful intestinal bacteria and promote the growth of beneficial bacteria. However, the effects of yeast derivatives on oral health have not yet been investigated.

METHODS: An in vitro oral biofilm model was employed to examine the impacts of yeast derivatives on the oral microbiota and their potential benefits for maintaining oral homeostasis. The model incorporated dental plaque donor material from both healthy and periodontitis diagnosed individuals. Biofilm formation, density, and microbial composition were quantified. Additionally, the production of short-chain fatty acids in the biofilm supernatants was measured.

RESULTS: Yeast extracts had only minor effects on oral biofilm formation. In contrast, yeast cell wall derivatives, which are rich in polysaccharides such as beta-glucans and mannans, significantly reduced the density of the oral biofilms in vitro. This reduction in biofilm density was associated with an overall shift in the bacterial community composition, including an increase in beneficial bacteria and a decrease in the abundance of Tannerella forsythia, an important species involved in bacterial coaggregation and the development and maturation of the oral biofilm. Furthermore, the yeast cell wall derivatives decreased the production of short-chain fatty acids, including acetic and butyric acid. These findings were consistent across both healthy and periodontitis microbiomes.

CONCLUSION: This study has demonstrated the potential of yeast cell wall derivatives to positively impact oral health by significantly reducing biofilm density, modulating the oral microbial composition, and decreasing the production of short-chain fatty acids. The observed effects highlight the promising applications of these yeast-based compounds as an approach to managing oral diseases. Further research is needed to fully elucidate the mechanisms of action and explore the clinical potential of yeast cell wall derivatives in promoting and maintaining oral health.

PMID:40017617 | PMC:PMC11865069 | DOI:10.3389/froh.2025.1543667

J Indian Soc Periodontol. 2024 Jul-Aug;28(4):494-498. doi: 10.4103/jisp.jisp_147_23. Epub 2025 Jan 6.

ABSTRACT

Drug-induced gingival enlargement often occurs due to patient's lack of awareness about the side effects of prescribed medications. This case report details an unusual instance of massive drug-induced gingival overgrowth in a 50-year-old female, successfully managed through a multidisciplinary approach, including surgical intervention and prosthetic rehabilitation. The surgical treatment involved multiple extractions and the excision of excessive tissue. Both arches healed completely after surgery, and the patient underwent prosthetic rehabilitation, with no signs of recurrence. Effective management of such cases relies on patient counseling and appropriate drug substitution. Increasing awareness about the side effects of certain medications and the connection between systemic and oral health is crucial to prevent such cases of gingival enlargement.

PMID:40018719 | PMC:PMC11864326 | DOI:10.4103/jisp.jisp_147_23

Malawi Med J. 2024 Oct 16;36(3):163-169. doi: 10.4314/mmj.v36i3.2. eCollection 2024 Oct.

ABSTRACT

BACKGROUND: Spontaneous reporting of adverse drug reaction (ADRs) is low in Malawi. We assessed the impact of training intervention on knowledge, attitudes, and practices of health care professionals (HCPs) in pharmacovigilance (PV).

METHODS: We employed a mixed-methods study design. A questionnaire was administered among HCPs who were trained in PV, followed by face-face interviews. We further extracted individual case safety reports which were submitted to the local databasewithin a period of six months prior and after the PV training. Quantitative data was analyzed using STATA 14.1. Paired t-test was used to assess the differences in PV knowledge among HCPs before and after the training. For qualitative data, we manually derived key themes from the participant's responses.

RESULTS: Overall, the mean knowledge score was significantly improved across all the participants from a mean of 56% (95% CI 53% to 58%) to 66% (95% CI 64% to 69%) after the training, p< 0.001. There was a 2.8-fold increase in the number of participants who were able to detect an ADR after the training and a 1.8-fold increase in the percentage of reporting the detected ADRs after the training. Participants expressed preference of a paper-based reporting system to other reporting tools. However, they outlined several challenges to the system which discourages HCPs from reporting ADRs, such as lack of feedback, unavailability of reporting forms and delay to transmit data to the national centre.

CONCLUSION: The survey found that in-service training for HCPs improves KAP of PV and reporting rates of ADRs. We recommend widening of the training and introducing PV courses in undergraduate programs for health care workers in Malawi.

PMID:40018398 | PMC:PMC11862858 | DOI:10.4314/mmj.v36i3.2

Eur J Med Res. 2025 Feb 27;30(1):143. doi: 10.1186/s40001-025-02406-9.

ABSTRACT

BACKGROUND: Overactive bladder (OAB) syndrome has a significant impact on quality of life, and vibegron has emerged as a therapeutic option. This study aims to evaluate the safety profile of vibegron in a disproportionality analysis by analyzing adverse event (AE) reports from the Food and Drug Administration Adverse Event Reporting System (FAERS) database.

METHODS: We conducted a retrospective analysis of the FAERS database from January 2021 to September 2023. After duplicate removal and thorough screening, 1137 vibegron-related AE reports were identified. We analyzed these reports for demographic and clinical characteristics, signal detection at the system organ class (SOC) level, and specific AEs.

RESULTS: Females comprised a higher percentage (67.72%) of AE reports compared to males. The elderly population (age > 64 years) accounted for 15.84% of the cases. The majority (95.69%) of the reports originated from the USA. Signal detection revealed significant findings across 19 organ systems with notable SOCs, including renal and urinary disorders (ROR = 7.72, 95%CI 6.83-8.72), gastrointestinal disorders (ROR = 1.38, 95%CI 1.21-1.58), and respiratory, thoracic, and mediastinal disorders (ROR = 1.21, 95%CI 1.01-1.45). In addition, several unexpected AEs were identified, such as dry mouth, hot flush, constipation, and increased blood pressure.

CONCLUSIONS: This study provides comprehensive insights into vibegron's safety profile, revealing both known and unexpected AEs. The findings highlight the need for careful patient selection and monitoring, especially among females and the elderly. The results advocate for ongoing pharmacovigilance and further research to ensure vibegron's safe and effective use in OAB treatment.

PMID:40016845 | DOI:10.1186/s40001-025-02406-9

Sci Rep. 2025 Feb 27;15(1):7035. doi: 10.1038/s41598-024-83555-5.

ABSTRACT

The relationship between ischemic stroke (IS) and pyroptosis centers on the inflammatory response elicited by cerebral tissue damage during an ischemic stroke event. However, an in-depth mechanistic understanding of their connection remains limited. This study aims to comprehensively analyze the gene expression patterns of pyroptosis-related differentially expressed genes (PRDEGs) by employing integrated IS datasets and machine learning techniques. The primary objective was to develop classification models to identify crucial PRDEGs integral to the ischemic stroke process. Leveraging three distinct machine learning algorithms (LASSO, Random Forest, and Support Vector Machine), models were developed to differentiate between the Control and the IS patient samples. Through this approach, a core set of 10 PRDEGs consistently emerged as significant across all three machine learning models. Subsequent analysis of these genes yielded significant insights into their functional relevance and potential therapeutic approaches. In conclusion, this investigation underscores the pivotal role of pyroptosis pathways in ischemic stroke and identifies pertinent targets for therapeutic development and drug repurposing.

PMID:40016488 | DOI:10.1038/s41598-024-83555-5

Sci Rep. 2025 Feb 28;15(1):7109. doi: 10.1038/s41598-025-91096-8.

ABSTRACT

Computational approaches complement traditional in-vitro or in-vivo assays, significantly accelerating the drug discovery process by increasing the probability of identifying promising lead compounds. In this study, the apoptotic compounds were assessed for antimycobacterial activity and immunomodulatory potential in infected THP-1 macrophage cells. The antimycobacterial activity of the apoptotic compounds was evaluated using the minimum inhibitory concentration (MIC) assay. The immunomodulatory potential of the apoptotic compounds was determined on mycobacterial-infected THP-1 and non-infected THP-1 macrophage cells. The potential binding dynamics of the compounds against InhA were predicted using molecular docking, molecular dynamics, and MM-GBSA binding free energies. The in-vitro MIC assay showed that cepharanthine (CEP) had the highest antimycobacterial activity against Mycobacterium smegmatis mc2155 and Mycobacterium tuberculosis H37Rv, with MICs of 3.1 and 1.5 µg/mL, respectively, followed by CP-31398 dihydrochloride hydrate (DIH) (MICs = 6.2 and 3.1 µg/mL, respectively), marinopyrrole A (MAR) (MICs = 25 and 12.5 µg/mL, respectively), and nutlin-3a (NUT) (MICs = 50 and 25 µg/mL, respectively). MICs for the rest of the drugs were > 200 µg/mL against both M. smegmatis mc2155 and M. tuberculosis H37Rv. Furthermore, the growth of M. smegmatis mc2155 in infected THP-1 macrophage cells treated with DIH, CEP, carboxyatractyloside potassium salt (CAR), and NUT was inhibited by the mentioned drugs. Cytokine profiling showed that DIH optimally regulated the secretion of IL-1β and TNF-α which potentially enhanced the clearance of the intracellular pathogen. Molecular dynamics simulations showed that NUT, MAR, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), and BV02 strongly bind to InhA. However, 17-AAG and BV02 did not show significant activity in-vitro. This study highlights the importance of probing already existing chemical scaffolds as a starting point for discovery of therapeutic agents against M. tuberculosis H37Rv using both pathogen and host directed approaches. The integration of molecular dynamics simulations provides valuable insights into potential scaffold modifications to enhance the affinity.

PMID:40016256 | DOI:10.1038/s41598-025-91096-8

NPJ Genom Med. 2025 Feb 27;10(1):13. doi: 10.1038/s41525-025-00474-8.

ABSTRACT

Advances in genomic technologies have revolutionized the diagnosis of rare genetic diseases, leading to the emergence of precision therapies. However, there remains significant effort ahead to ensure the promise of precision medicine translates to improved outcomes. Here, we discuss the challenges in advancing precision child health and highlight how international collaborations such as the International Precision Child Health Partnership, which embed research into clinical care, can maximize benefits for children globally.

PMID:40016282 | DOI:10.1038/s41525-025-00474-8

Neuromolecular Med. 2025 Feb 27;27(1):18. doi: 10.1007/s12017-025-08840-6.

ABSTRACT

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic form of stroke. It is caused by a cysteine-altering variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of Notch3. NOTCH3 pathogenic variants in EGFr 1-6 are associated with high disease severity, whereas those in EGFr 7-34 are associated with late stroke onset and increased survival. However, whether and how the position of the NOTCH3 variant directly affects the disease severity remains unclear. In this study, we aimed to generate human-induced pluripotent stem cells (hiPSCs) from patients with CADASIL with EGFr 1-6 and 7-34 pathogenic variants to evaluate whether the NOTCH3 position affects the cell phenotype and protein profile of the generated hiPSCs lines. Six hiPSCs lines were generated: two from patients with CADASIL with EGFr 1-6 pathogenic variants, two from patients with EGFr 7-34 variants, and two from controls. Notch3 aggregation and protein profiles were tested in the established six hiPSCs lines. Cell analysis revealed that the NOTCH3 variants did not limit the cell reprogramming efficiency. However, EGFr 1-6 variant position was associated with increased accumulation of Notch3 protein in pluripotent stem cells and proteomic changes related with cytoplasmic reorganization mechanisms. In conclusion, our analysis of hiPSCs derived from patients with CADASIL support the clinical association between the NOTCH3 variant position and severity of CADASIL.

PMID:40016442 | DOI:10.1007/s12017-025-08840-6

Chem Biol Interact. 2025 Feb 25:111448. doi: 10.1016/j.cbi.2025.111448. Online ahead of print.

ABSTRACT

A comprehensive understanding of isoniazid (INH)-mediated hepatotoxic effects is essential for developing strategies to predict and prevent severe liver toxicity in tuberculosis treatment. In this study, we used multi-omics profiling in vitro to investigate the toxic effects of INH, revealing significant involvement of endoplasmic reticulum (ER) stress, mitochondrial impairment, redox imbalance, and altered metabolism. Additional analysis using transcriptomics data from repeated time-course INH treatments on human-specific hepatic microtissues revealed that cellular responses to ER stress and oxidative stress happened prior to disturbances in mitochondrial complexes. Mechanistic validation studies using time-lapse measurements of cytosolic and mitochondrial reactive oxygen species (ROS) revealed that INH initially triggered cytosolic ROS increasement and Nrf2 signaling pathway activation before mitochondrial ROS accumulation. Molecular imaging showed that INH subsequently disrupted mitochondrial function by impairing respiratory complexes I-IV and caused mitochondrial membrane proton leakage without affecting mitochondrial complex V, leading to mitochondrial depolarization and reduced ATP production. These disturbances enhanced mitochondrial fission and mitophagy. Our findings highlight the potential of inhibiting ER stress during early INH exposure to mitigate cytosolic and mitochondrial oxidative stress. We also revealed the critical role of Nrf2 signaling in protecting hepatocytes under INH-induced oxidative stress by maintaining redox homeostasis and enabling metabolic reprogramming through regulating antioxidant gene expression and cellular lipid abundance. Alternative antioxidant pathways, including selenocompound metabolism, HIF-1 signaling, and the pentose phosphate pathway-also responded to INH-induced oxidative stress. Collectively, our study emphasizes the importance of ER stress, redox imbalance, metabolic changes, and mitochondrial dysfunction that underlie INH-induced hepatotoxicity.

PMID:40015660 | DOI:10.1016/j.cbi.2025.111448

Intensive Care Med Exp. 2025 Feb 27;13(1):27. doi: 10.1186/s40635-025-00731-1.

ABSTRACT

BACKGROUND: Streptococcus pneumoniae, a primary cause of community-acquired pneumonia (CAP), is typically treated with β-lactams and macrolides or quinolones. Corticosteroids are now recommended as adjunctive therapy in severe CAP to improve outcomes. In this prospective randomized animal study, we evaluated the bactericidal efficacy of various antibiotic regimens combined with corticosteroids using a porcine pneumococcal pneumonia model.

RESULTS: In 30 White-Landrace female pigs, pneumonia was induced by intrabronchial inoculation of macrolide-resistant S. pneumoniae 19A isolate. Animals were randomized to receive saline, ceftriaxone (CRO) with levofloxacin (LVX), CRO with azithromycin (AZM), or combinations of these with methylprednisolone (MP). The primary outcome, S. pneumoniae concentrations in lung tissue after 48 h of treatment, showed that the CRO + LVX, CRO + AZM, CRO + LVX + MP, and CRO + AZM + MP groups were equally effective in reducing bacterial load. However, complete bacterial eradication from lung tissue was achieved only in the CRO + AZM + MP group. Secondary outcomes, including bacterial burden in tracheal aspirates and bronchoalveolar lavage (BAL) samples, showed similar bactericidal activity across all treatment groups. The CRO + AZM + MP group demonstrated the most controlled inflammatory response, achieving baseline levels of inflammation, while other groups exhibited elevated inflammatory markers.

CONCLUSIONS: Despite using a macrolide-resistant S. pneumoniae isolate, the combination of CRO, AZM, and MP achieves similar or even superior results compared to other antibiotic combinations. This regimen provides both bactericidal and immunomodulatory benefits, suggesting its effectiveness in treating macrolide-resistant S. pneumoniae pneumonia.

PMID:40016489 | DOI:10.1186/s40635-025-00731-1

Methods Mol Biol. 2025;2903:97-111. doi: 10.1007/978-1-0716-4410-2_9.

ABSTRACT

Rhinovirus primarily infects airway epithelial cells lining the conductive airways. Mucociliary-differentiated airway epithelial cell cultures, established from airway basal cells, are relevant in vitro model systems to examine the rhinovirus-stimulated innate immune responses and changes in barrier function. The airway epithelium in patients with chronic respiratory diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease often shows remodeling, such as goblet cell metaplasia, squamous metaplasia, and basal cell hyperplasia. Such changes profoundly affect the airway epithelial responses to rhinovirus infection. Previously, we have demonstrated that mucociliary-differentiated cell cultures, established from airway basal cells isolated from COPD patients, show goblet cell and basal cell hyperplasia similar to that observed in patients. These cultures also show a pro-inflammatory phenotype and abnormal innate immune responses to rhinovirus infection. We describe a culturing method that maintains these in vivo features.

PMID:40016461 | DOI:10.1007/978-1-0716-4410-2_9

Transplant Proc. 2025 Feb 26:S0041-1345(25)00084-3. doi: 10.1016/j.transproceed.2025.01.007. Online ahead of print.

ABSTRACT

Genetic mutations are increasingly recognized as significant contributors to post-transplant complications. Common genetic conditions, such as short telomere syndrome (STS), lymphangioleiomyomatosis, cystic fibrosis (CF), and alpha-1 antitrypsin deficiency (AAT), have been documented to influence outcomes in lung transplant recipients. Here, we present a case of hereditary transthyretin (ATTR) cardiac amyloidosis leading to heart failure in a 71-year-old female, six years after undergoing a single-lung transplantation (LTx) for interstitial lung disease. This case report highlights the need for awareness of genetic predispositions, including rare conditions such as hereditary ATTR amyloidosis, among individuals being considered for solid organ transplantation.

PMID:40016044 | DOI:10.1016/j.transproceed.2025.01.007

J Biol Chem. 2025 Feb 25:108355. doi: 10.1016/j.jbc.2025.108355. Online ahead of print.

ABSTRACT

The 2-methylcitrate cycle (2-MCC) and the glyoxylate cycle are central metabolic pathways in Pseudomonas aeruginosa, enabling the organism to utilize organic acids such as propionate and acetate during infection. Here, we show that these cycles are linked through enzymatic redundancy, with isocitrate lyase (AceA) exhibiting secondary 2-methylisocitrate lyase (2-MICL) activity. Furthermore, we use a combination of structural analyses, enzyme kinetics, metabolomics, and targeted mutation of PrpBPa to demonstrate that whereas loss of PrpB function impairs growth on propionate, the promiscuous 2-MICL activity of AceA compensates for this by mitigating the accumulation of toxic 2-MCC intermediates. Our findings suggest that simultaneous inhibition of PrpB and AceA could present a robust antimicrobial strategy to target P. aeruginosa in propionate-rich environments, such as the cystic fibrosis airways. Our results emphasize the importance of understanding pathway interconnections in the development of novel antimicrobial agents.

PMID:40015638 | DOI:10.1016/j.jbc.2025.108355

Lancet Infect Dis. 2025 Feb 24:S1473-3099(24)00804-1. doi: 10.1016/S1473-3099(24)00804-1. Online ahead of print.

ABSTRACT

BACKGROUND: Sipavibart is an anti-spike monoclonal antibody that neutralises SARS-CoV-2 with exceptions, including Phe456Leu-containing variants (eg, KP.2* and KP.3*). This trial assessed sipavibart efficacy and safety for prevention of symptomatic COVID-19 in participants who are immunocompromised.

METHODS: In this ongoing, double-blind, international, phase 3 trial, we enrolled participants who were immunocompromised and aged 12 years or older at 197 hospitals, university health centres, and clinical trial units in 18 countries. Participants were randomly allocated 1:1 to a sipavibart group (intramuscular sipavibart 300 mg on days 1 and 181) or a comparator group (tixagevimab 300 mg-cilgavimab 300 mg on day 1 and placebo on day 181 or placebo on days 1 and 181), stratified by previous COVID-19 vaccination and infection status and use of tixagevimab-cilgavimab. The primary efficacy outcomes were symptomatic COVID-19 caused by any variant or symptomatic COVID-19 caused by non-Phe456Leu-containing variants within 181 days of dosing, assessed in the SARS-CoV-2-negative set, comprising all participants without a positive RT-PCR test for SARS-CoV-2 at baseline and who received at least one trial intervention dose. Safety outcomes for adverse events were assessed 90 days following the first dose and for serious adverse events throughout the study in the safety analysis set (ie, all participants who received at least one injection of sipavibart or comparator). This study is registered with ClinicalTrials.gov, NCT05648110.

FINDINGS: Participants were screened from March 31 to Oct 27, 2023; 3349 participants (56·8% female) were randomly assigned: 1674 to the sipavibart group (five no first dose; 1669 sipavibart) and 1675 to the comparator group (nine no first dose; 1105 tixagevimab-cilgavimab and 561 placebo). Within 181 days of dosing, 122 (7·4%) of 1649 participants in the sipavibart group and 178 (10·9%) of 1631 participants in the comparator group had symptomatic COVID-19 due to any variant (relative risk reduction [RRR] 34·9% [97·5% CI 15·0 to 50·1]; p=0·0006), 54 (3·3%) participants in the sipavibart group and 90 (5·5%) participants in the comparator group had symptomatic COVID-19 due to non-Phe456Leu-containing variants (RRR 42·9% [95% CI 19·9 to 59·3]; p=0·0012), and 47 (2·9%) participants in the sipavibart group and 64 (3·9%) participants in the comparator group had symptomatic COVID-19 due to Phe456Leu-containing variants (30·4% [-1·8 to 52·5]). Adverse events occurred in 833 (49·9%) of 1671 participants in the sipavibart group and 857 (51·5%) of 1663 participants in the comparator group within 3 months of the first dose. One COVID-19-related death occurred in the comparator group. Serious adverse events considered related to trial intervention occurred in two (0·1%) of 1671 participants in the sipavibart group and seven (0·4%) of 1663 participants in the comparator group (none fatal). No serious cardiovascular or thrombotic events were considered to be related to sipavibart.

INTERPRETATION: The primary analysis showed efficacy and safety of sipavibart in preventing symptomatic COVID-19 in participants who are immunocompromised when susceptible (ie, non-Phe456Leu-containing) variants dominated, although no efficacy was shown against resistant (ie, Phe456Leu-containing) variants that dominate as of November, 2024.

FUNDING: AstraZeneca.

PMID:40015292 | DOI:10.1016/S1473-3099(24)00804-1

J Cannabis Res. 2025 Feb 27;7(1):13. doi: 10.1186/s42238-025-00268-w.

ABSTRACT

BACKGROUND: Cannabis sativa L. with a rich history of traditional medicinal use, has garnered significant attention in contemporary research for its potential therapeutic applications in various human diseases, including pain, inflammation, cancer, and osteoarthritis. However, the specific molecular targets and mechanisms underlying the synergistic effects of its diverse phytochemical constituents remain elusive. Understanding these mechanisms is crucial for developing targeted, effective cannabis-based therapies.

METHODS: To investigate the molecular targets and pathways involved in the synergistic effects of cannabis compounds, we utilized DRIFT, a deep learning model that leverages attention-based neural networks to predict compound-target interactions. We considered both whole plant extracts and specific plant-based formulations. Predicted targets were then mapped to the Reactome pathway database to identify the biological processes affected. To facilitate the prediction of molecular targets and associated pathways for any user-specified cannabis formulation, we developed CANDI (Cannabis-derived compound Analysis and Network Discovery Interface), a web-based server. This platform offers a user-friendly interface for researchers and drug developers to explore the therapeutic potential of cannabis compounds.

RESULTS: Our analysis using DRIFT and CANDI successfully identified numerous molecular targets of cannabis compounds, many of which are involved in pathways relevant to pain, inflammation, cancer, and other diseases. The CANDI server enables researchers to predict the molecular targets and affected pathways for any specific cannabis formulation, providing valuable insights for developing targeted therapies.

CONCLUSIONS: By combining computational approaches with knowledge of traditional cannabis use, we have developed the CANDI server, a tool that allows us to harness the therapeutic potential of cannabis compounds for the effective treatment of various disorders. By bridging traditional pharmaceutical development with cannabis-based medicine, we propose a novel approach for botanical-based treatment modalities.

PMID:40016810 | DOI:10.1186/s42238-025-00268-w