Front Pharmacol. 2025 Jan 8;15:1462193. doi: 10.3389/fphar.2024.1462193. eCollection 2024.

ABSTRACT

INTRODUCTION: Tuberculosis (TB) poses a significant threat to global health, with millions of new infections and approximately one million deaths annually. Various modeling efforts have emerged, offering tailored data-driven and physiologically-based solutions for novel and historical compounds. However, this diverse modeling panorama may lack consistency, limiting result comparability. Drug-specific models are often tied to commercial software and developed on various platforms and languages, potentially hindering access and complicating the comparison of different compounds.

METHODS: This work introduces stormTB: SimulaTOr of a muRine Minimal-pbpk model for anti-TB drugs. It is a web-based interface for our minimal physiologically based pharmacokinetic (mPBPK) platform, designed to simulate custom treatment scenarios for tuberculosis in murine models. The app facilitates visual comparisons of pharmacokinetic profiles, aiding in assessing drug-dose combinations.

RESULTS: The mPBPK model, supporting 11 anti-TB drugs, offers a unified perspective, overcoming the potential inconsistencies arising from diverse modeling efforts. The app, publicly accessible, provides a user-friendly environment for researchers to conduct what-if analyses and contribute to collective TB eradication efforts. The tool generates comprehensive visualizations of drug concentration profiles and pharmacokinetic/pharmacodynamic indices for TB-relevant tissues, empowering researchers in the quest for more effective TB treatments. stormTB is freely available at the link: https://apps.cosbi.eu/stormTB.

PMID:39845781 | PMC:PMC11750688 | DOI:10.3389/fphar.2024.1462193

Front Plant Sci. 2025 Jan 8;15:1446383. doi: 10.3389/fpls.2024.1446383. eCollection 2024.

ABSTRACT

INTRODUCTION: Rice samples exposed to the space environment have generated diverse phenotypic variations. Miniature-inverted-repeat transposable elements (MITEs), often found adjacent to genes, play a significant role in regulating the plant genome. Herein, the contribution of MITEs in regulating space-mutagenic phenotypes was explored.

METHODS: The space-mutagenic phenotype changes in the F3 to F5 generations of three space-mutagenic lines from the rice varieties Dongnong423 (DN423) and Dongnong (DN416) were meticulously traced. Rice leaves samples at the heading stage from three space-mutagenic lines were subjected to high coverage whole-genome bisulfite sequencing and whole-genome sequencing. These analyses were conducted to investigate the effects of MITEs related epigenetic and genetic variations on space-mutagenic phenotypes.

RESULTS AND DISCUSSION: Studies have indicated that MITEs within gene regulatory regions might contribute to the formation and differentiation of space-mutagenic phenotypes. The space environment has been shown to induce the transposable elements insertion polymorphisms of MITEs (MITEs-TIPs), with a notable preference for insertion near genes involved in stress response and phenotype regulation. The space-induced MITEs-TIPs contributed to the formation of space-mutagenic phenotype by modulating the expression of gene near the insertion site. This study underscored the pivotal role of MITEs in modulating plant phenotypic variation induced by the space environment, as well as the transgenerational stability of these phenotypic variants.

PMID:39845491 | PMC:PMC11751223 | DOI:10.3389/fpls.2024.1446383

Front Plant Sci. 2025 Jan 8;15:1457713. doi: 10.3389/fpls.2024.1457713. eCollection 2024.

NO ABSTRACT

PMID:39845489 | PMC:PMC11750989 | DOI:10.3389/fpls.2024.1457713

Microb Biotechnol. 2025 Jan;18(1):e70068. doi: 10.1111/1751-7915.70068.

NO ABSTRACT

PMID:39844583 | DOI:10.1111/1751-7915.70068

BMC Bioinformatics. 2025 Jan 22;26(1):26. doi: 10.1186/s12859-024-06026-8.

ABSTRACT

BACKGROUND: Interpretability is a topical question in recommender systems, especially in healthcare applications. An interpretable classifier quantifies the importance of each input feature for the predicted item-user association in a non-ambiguous fashion.

RESULTS: We introduce the novel Joint Embedding Learning-classifier for improved Interpretability (JELI). By combining the training of a structured collaborative-filtering classifier and an embedding learning task, JELI predicts new user-item associations based on jointly learned item and user embeddings while providing feature-wise importance scores. Therefore, JELI flexibly allows the introduction of priors on the connections between users, items, and features. In particular, JELI simultaneously (a) learns feature, item, and user embeddings; (b) predicts new item-user associations; (c) provides importance scores for each feature. Moreover, JELI instantiates a generic approach to training recommender systems by encoding generic graph-regularization constraints.

CONCLUSIONS: First, we show that the joint training approach yields a gain in the predictive power of the downstream classifier. Second, JELI can recover feature-association dependencies. Finally, JELI induces a restriction in the number of parameters compared to baselines in synthetic and drug-repurposing data sets.

PMID:39844056 | DOI:10.1186/s12859-024-06026-8

Acta Endocrinol (Buchar). 2024 Apr-Jun;20(2):249-255. doi: 10.4183/aeb.2024.249. Epub 2025 Jan 18.

ABSTRACT

INTRODUCTION: Diabetes mellitus, a chronic metabolic disorder stemming from pancreatic dysfunction, is surging in India, notably among those aged 60 and above. The escalating disease prevalence in this demographic necessitates heightened medication use, escalating the risk of Adverse Drug Reactions (ADRs). This underscores the vital role of ADR monitoring to curtail potential harm.

METHOD: A 12-month cross-sectional, prospective, observational study engaged 200 participants from the geriatric Outpatient Department (OPD). Diabetic patients in the geriatric OPD, willing to participate, underwent face-to-face evaluations using a structured questionnaire focused on adverse reactions to anti-diabetic medications. The study also included a Knowledge, Attitude, and Practice (KAP) assessment.

RESULTS: Of the 200 patients, 57% were male, 43% female. Thirteen participants (7 male, 6 female) reported ADR encounters during therapy, predominantly categorized as mild in causality and severity. KAP assessments unveiled a robust understanding of ADRs, primarily shaped by physicians and reinforced by pharmacists. Anticipation of ADR occurrence was noted in 70% of respondents, linked to non-compliance and lifestyle factors.

CONCLUSION: Educating caregivers about the critical importance of monitoring medication adherence among the elderly is imperative. Cultivating an attitude of reporting even minor ADRs to appropriate authorities is essential for harm prevention.

PMID:39845748 | PMC:PMC11750232 | DOI:10.4183/aeb.2024.249

Clin Transl Sci. 2025 Jan;18(1):e70134. doi: 10.1111/cts.70134.

ABSTRACT

The Timor-Leste Pharmacovigilance (PV) became an associate member of the WHO Programme for International Drug Monitoring in 2019; however, the adverse drug reaction (ADR) reporting rate remains low, with only nine reports per 1342 million inhabitants over 5 years. This study aimed to evaluate the knowledge, attitude, practice, and barriers related to ADRs, pharmacovigilance, and ADR reporting among healthcare professionals (HCPs) in Timor-Leste. A cross-sectional survey with a validated, self-administered questionnaire was conducted among 600 HCPs, including clinical doctors, nurses, and pharmacy employees from one national referral and five referral hospitals. Of the 461 HCPs who responded (76.8% response rate), 98 were clinical doctors (21.3%), 311 nurses (67.4%), and 52 pharmacy employees (11.3%). The knowledge score on ADRs was 3.81 ± 0.36 out of 8, with clinical doctors, nurses, and pharmacy employees scoring 4.49 ± 0.51, 3.47 ± 0.24, and 4.56 ± 0.26, respectively. On pharmacovigilance and ADR reporting, the score was 3.00 ± 0.16 out of 8, with clinical doctors, nurses, and pharmacy employees scoring 3.36 ± 0.26, 2.81 ± 0.08, and 3.50 ± 0.24, respectively. All scores referred to the number of correctly answered questions. Positive attitudes were observed, with 53.4% agreeing that ADR reporting is crucial for drug safety, although only 22.0% reported observed ADRs. Key barriers included unavailability of reporting forms (81.0%), insufficient financial support (71.9%), and lack of reporting by colleagues (71.4%). These findings highlight the need for increased awareness, training, and resources to improve ADR reporting in Timor-Leste.

PMID:39844473 | DOI:10.1111/cts.70134

BMC Immunol. 2025 Jan 23;26(1):4. doi: 10.1186/s12865-025-00682-y.

ABSTRACT

Vanishing bile duct syndrome (VBDS) is a serious drug induced liver injury characterized by chronic cholestasis and loss of intrahepatic bile ducts. VBDS has been reported also following checkpoint inhibitor treatment. We compared CD3 + , CD4 + , CD8 + , CD20 + , CD57 + , PD-1 + and PD-L1 + lymphocyte infiltrates in liver biopsies of patients that encountered VBDS (n = 2) or hepatotoxicity (n = 3) after pembrolizumab (n = 4) or nivolumab (n = 1) treatment with samples from normal liver (n = 10), non-alcohol steatohepatitis (NASH, n = 10), primary biliary cholangitis (PBC, n = 10) or pembrolizumab-treated patients without adverse events (n = 2). Notably, none of the cancer patients had primary nor metastatic liver tumors. We also studied direct growth effects of pembrolizumab on primary human intrahepatic biliary epithelial cells (HIBEpiC) in vitro. Liver sections of all checkpoint inhibitor- treated patients exhibited significantly higher CD3 + infiltration than normal livers, and significantly higher PD-L1 + , CD4 + and CD8 + infiltration, than other groups. PD-1 + infiltration was significantly increased in livers of patients with severe hepatic adverse event. CD57 + infiltration was similar in normal livers, NASH- and PBC groups, but highly increased in the checkpoint inhibitor-treated patients. Immune cell infiltrates were similar between NASH and normal livers. PBC samples had significantly higher CD3 + , CD4 + , CD8 + and CD20 + infiltrates than normal livers. HIBEpiC express PD-L1 but pembrolizumab did not affect their viability in vitro. Our findings suggest that VBDS is not due to direct cytotoxicity of checkpoint inhibitors and that the immunological attack against livers induced by these drugs is different from other cholestatic liver conditions.Biological insight: Checkpoint inhibitors upregulate PD-1 and PD-L1, as well as cytotoxic CD57 + cells in the non-cancerous liver tissues and this may be associated with checkpoint inhibitor-induced hepatotoxicity.

PMID:39844069 | DOI:10.1186/s12865-025-00682-y

Funding Opportunity PAR-25-378 from the NIH Guide for Grants and Contracts. The purpose of this notice of funding opportunity (NOFO) is to support research on interventions to improve health in Native American (NA) populations. This includes 1) etiologic research, where there is a significant gap in knowledge, that will directly inform intervention development or adaptations, 2) research that develops, adapts, or tests the efficacy or effectiveness of health promotion and disease prevention interventions, 3) research that tests culturally informed treatment or recovery interventions and 4) where a sufficient body of knowledge on intervention efficacy exists, research on dissemination and implementation that develops and tests strategies to overcome barriers to the adoption, integration, scale-up, and sustainability of effective interventions. Existing data suggest that significant acute and chronic disease inequities exist for NA populations. Concurrently, NA populations experience unique sociopolitical, historical, and environmental stressors and risks that may exacerbate health conditions and/or impact the effectiveness of existing solutions to address the conditions. They also possess unique strengths and resiliencies that can mitigate stressors or inform intervention strategies. Through this initiative, intervention and related research is sought to build upon community knowledge, resources, and resilience to test science-based, culturally appropriate solutions to reduce morbidity and mortality through identification and remediation of precursors to diseases and disorders and through culturally informed treatment. Interventions should be designed with a consideration for sustainability within the communities where they are tested, and have the flexibility to be readily adapted, disseminated, and scaled up to other communities where culturally appropriate. For the purposes of this NOFO, NA includes the following populations: Alaska Natives, American Indians (whose ancestral lands fall at least partially within the U.S. main land).

Notice NOT-HS-25-015 from the NIH Guide for Grants and Contracts

Notice NOT-EY-25-006 from the NIH Guide for Grants and Contracts

Notice NOT-TW-25-001 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-DK-26-009 from the NIH Guide for Grants and Contracts. The New Investigator Gateway Award in T1D Research is designed to supporta robust pipeline of innovative projects and talented new investigators in T1D research. In addition to providing support for preliminary research, the Gateway program provides an opportunity for new Program Directors/Principal Investigators (PD/PIs) to pursue their studies within the intellectual environment of a select number of large, ongoing collaborative research programs. Embedding awardees within an established scientific framework in each of these consortia will provide unique opportunities for New andEarly Stage Investigators to increase their understanding of key questions in the field, to network, and to establish unique and potentially long-lasting collaborations that will propel their careers forward. Bringing New and Early Stage Investigators into existing collaborative research networks will also benefit the networks by providing new ideas and perspectives.

Notice NOT-HD-25-001 from the NIH Guide for Grants and Contracts

Biomed Pharmacother. 2025 Jan 21;183:117862. doi: 10.1016/j.biopha.2025.117862. Online ahead of print.

ABSTRACT

The strategy of drug repositioning has historically played a significant role in the identification of new treatments for Parkinson's disease. Still today, numerous clinical and preclinical studies are investigating drug classes, already marketed for the treatment of metabolic disorders, for their potential use in Parkinson's disease patients. While drug repurposing offers a promising, fast, and cost-effective path to new treatments, these drugs still require thorough preclinical evaluation to assess their efficacy, addressing the specific neurodegenerative mechanisms of the disease. This review explores the state-of-the-art approaches to drug repurposing for Parkinson's disease, highlighting particularly relevant aspects. Preclinical studies still predominantly rely on traditional neurotoxin-based animal models, which fail to effectively replicate disease progression and are characterized by significant variability in model severity and timing of drug treatment. Importantly, for almost all the drugs analyzed here, there is insufficient data regarding the mechanism of action responsible for the therapeutic effect. Regarding drug efficacy, these factors may obviously render results less reliable or comparable. Accordingly, future preclinical drug repurposing studies in the Parkinson's disease field should be carried out using next-generation animal models like α-synuclein-based models that, unfortunately, have to date been used mostly for studies of disease pathogenesis and only rarely in pharmacological studies.

PMID:39842271 | DOI:10.1016/j.biopha.2025.117862

Nature. 2025 Jan 22. doi: 10.1038/s41586-024-08468-9. Online ahead of print.

ABSTRACT

Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

PMID:39843750 | DOI:10.1038/s41586-024-08468-9

J Pharm Biomed Anal. 2025 Jan 20;256:116684. doi: 10.1016/j.jpba.2025.116684. Online ahead of print.

ABSTRACT

Alkaptonuria (AKU) is a rare autosomal-recessive disease which is characterized through black urine and ochronosis. It is caused by deficiency of the enzyme Homogentisate 1,2-dioxygenase in the Phenylalanine/Tyrosine degradation pathway which leads to the accumulation of Homogentisic acid (HGA). Urine was provided by AKU patients and healthy controls. Several different methods were developed in this study each with a specific goal. Firstly, a simple and inexpensive RP-UHPLC-UV method for routine monitoring of HGA as a key metabolite employing a Phenylhexyl stationary phase chemistry. Validation was performed in accordance to FDA guidelines and method selectivity was further evaluated via on-line high-resolution sampling 2D-LC-QToF-MS, coupling the Phenylhexyl phase in the first dimension with a C18 phase in the second dimension. Secondly, a targeted and accurate RP-UHPLC-MRM-QTRAP assay, providing quantitative analysis of the relevant pathway metabolites based on a Phenylhexyl stationary phase, and lastly an untargeted HILIC-UHPLC-QToF-MS/MS method with SWATH (sequential window acquisition of all theoretical mass spectra) acquisition employing a sulfobetaine-type HILIC-Z superficially porous particle column, with the aim of uncovering more details about the metabolic profile of this genetic disorder. By untargeted analysis 204 metabolites could be detected and annotated in positive and negative ESI mode in total. Two separate LC methods were employed, differing in their conditions depending on the ionization mode (20 mM ammonium formate as buffer additive adjusted to a pH = 3.5 with formic acid in ESI+ mode and 20 mM ammonium acetate adjusted to a pH = 7.5 with acetic acid in ESI- mode). By effectively combining the aforementioned methods, a comprehensive workflow was developed, allowing the effective analysis of both patient and control urine samples.

PMID:39842076 | DOI:10.1016/j.jpba.2025.116684

NPJ Antimicrob Resist. 2024 Feb 20;2(1):4. doi: 10.1038/s44259-024-00022-x.

ABSTRACT

Antimicrobial peptides (AMPs) are key components of innate immunity across all domains of life. Natural and synthetic AMPs are receiving renewed attention in efforts to combat the antimicrobial resistance (AMR) crisis and the loss of antibiotic efficacy. The gram-negative pathogen Pseudomonas aeruginosa is one of the most concerning infecting bacteria in AMR, particularly in people with cystic fibrosis (CF) where respiratory infections are difficult to eradicate and associated with increased morbidity and mortality. Cationic AMPs exploit the negatively charged lipopolysaccharides (LPS) on P. aeruginosa to bind and disrupt bacterial membrane(s), causing lethal damage. P. aeruginosa modifies its LPS to evade AMP killing. Free-LPS is also a component of CF sputum and feeds pro-inflammatory cycles. Glatiramer acetate (GA) is a random peptide co-polymer-of glycine, lysine, alanine, tyrosine-used as a drug in treatment of multiple sclerosis (MS); we have previously shown GA to be an AMP which synergises with tobramycin against CF P. aeruginosa, functioning via bacterial membrane disruption. Here, we demonstrate GA's direct binding and sequestration/neutralisation of P. aeruginosa LPS, in keeping with GA's ability to disrupt the outer membrane. At CF-relevant LPS concentrations, however, membrane disruption by GA was not strongly inhibited. Furthermore, exposure to GA did not result in increased Lipid A modification of LPS or in increased gene expression of systems involved in AMP sensing and LPS modification. Therefore, despite the electrostatic targeting of LPS by GA as part of its activity, P. aeruginosa does not demonstrate LPS modification in its defence.

PMID:39843948 | DOI:10.1038/s44259-024-00022-x

NPJ Antimicrob Resist. 2024 Nov 14;2(1):38. doi: 10.1038/s44259-024-00060-5.

ABSTRACT

Polymicrobial communities inhabit the cystic fibrosis (CF) airway, whereby microbial interactions can occur. One prominent CF pathogen is Mycobacterium abscessus, whose treatment is largely unsuccessful. This creates a need to discover novel antimicrobial agents to treat M. abscessus, however the methods used within antibiotic discovery are typically monomicrobial. This review will discuss this pathogen whilst considering the CF polymicrobial environment, to highlight future perspectives to improve M. abscessus drug discovery.

PMID:39843836 | DOI:10.1038/s44259-024-00060-5

NPJ Antimicrob Resist. 2024 Nov 5;2(1):34. doi: 10.1038/s44259-024-00054-3.

ABSTRACT

Mycobacterium abscessus complex (MABSC) comprises a group of environmental microorganisms, which are a concerning cause of opportunistic respiratory infections in patients with cystic fibrosis or bronchiectasis. Only 45.6% of MABSC treatments are successful, and therefore this is a need to discover new antimicrobials that can treat these pathogens. However, the transferability of outcomes to the clinic is flawed by an inability to accurately represent the lung environment within the laboratory. Herein, we apply two preestablished formulations of sputum media (ACFS and SCFM1) to MABSC antibiotic susceptibility testing. Using conventional broth microdilution, we have observed strain and antibiotic dependent alterations in antimicrobial sensitivity in each sputum media compared standard laboratory media (7H9), with an overall reduction in susceptibility within the physiologically relevant conditions. We provide a timely contribution to the field of M. abscessus antibiotic discovery by emphasising the need for improved physiological relevance.

PMID:39843503 | DOI:10.1038/s44259-024-00054-3