Plant Genome. 2025 Mar;18(1):e70004. doi: 10.1002/tpg2.70004.

ABSTRACT

Fusarium wilt (FW) significantly affects the growth and development of chickpea (Cicer arietinum L.), leading to substantial economic losses. FW resistance is a quantitative trait that is controlled by multiple genomic regions. In this study, a meta-analysis was conducted on 32 quantitative trait loci (QTLs) associated with FW resistance, leading to the identification of seven meta-QTL (MQTL) regions distributed across CaLG2, CaLG4, CaLG5, and CaLG6 of the chickpea linkage groups. The integrated analysis revealed several candidate genes potentially important for FW resistance, including genes associated with sensing (e.g., LRR-RLK), signaling (e.g., mitogen-activated protein kinase [MAPK1]), and transcription regulation (e.g., NAC, WRKY, and bZIP). Subsequently, a marker-assisted backcrossing (MABC) trial was executed leveraging the MQTL outcomes to introgress FW resistance from an FW-resistant chickpea cultivar (Ana) into a superior high-yielding Kabuli cultivar (Hashem). The breeding process was extended over 5 years (2018-2023) and resulted in the development of BC3F2 genotypes. Consequently, 12 genotypes carrying homozygous resistance alleles were chosen, with three genotypes showing genetic backgrounds matching 90%-96% of the recurrent parent. The findings of this study have significant implications for upcoming programs, encompassing fine-mapping, marker-assisted breeding, and genetic engineering, consequently contributing to the effective control of FW and the improved production of chickpea.

PMID:40050693 | DOI:10.1002/tpg2.70004

Nat Immunol. 2025 Mar 6. doi: 10.1038/s41590-025-02105-x. Online ahead of print.

ABSTRACT

Tissue-resident memory T (TRM) cells are a specialized T cell population that reside in tissues and provide a rapid protective response upon activation. Here, we showed that human and mouse CD4+ TRM cells existed in a poised state and stored messenger RNAs encoding proinflammatory cytokines without protein production. At steady state, cytokine mRNA translation in TRM cells was suppressed by the integrated stress response (ISR) pathway. Upon activation, the central ISR regulator, eIF2α, was dephosphorylated and stored cytokine mRNA was translated for immediate cytokine production. Genetic or pharmacological activation of the ISR-eIF2α pathway reduced cytokine production and ameliorated autoimmune kidney disease in mice. Consistent with these results, the ISR pathway in CD4+ TRM cells was downregulated in patients with immune-mediated diseases of the kidney and the intestine compared to healthy controls. Our results indicated that stored cytokine mRNA and translational regulation in CD4+ TRM cells facilitate rapid cytokine production during local immune response.

PMID:40050432 | DOI:10.1038/s41590-025-02105-x

Nat Commun. 2025 Mar 6;16(1):2256. doi: 10.1038/s41467-025-57430-4.

ABSTRACT

Functional proteomics provides critical insights into cancer mechanisms, facilitating the discovery of novel biomarkers and therapeutic targets. We have developed a comprehensive cancer functional proteomics resource using reverse phase protein arrays, incorporating data from nearly 8000 patient samples from The Cancer Genome Atlas and approximately 900 samples from the Cancer Cell Line Encyclopedia. Our dataset includes a curated panel of nearly 500 high-quality antibodies, covering all major cancer hallmark pathways. To enhance the accessibility and analytic power of this resource, we introduce DrBioRight 2.0 ( https://drbioright.org ), an intuitive bioinformatic platform powered by state-of-the-art large language models. DrBioRight enables researchers to explore protein-centric cancer omics data, perform advanced analyses, visualize results, and engage in interactive discussions using natural language. By streamlining complex proteogenomic analyses, this tool accelerates the translation of large-scale functional proteomics data into meaningful biomedical insights.

PMID:40050282 | DOI:10.1038/s41467-025-57430-4

Metab Eng. 2025 Mar 4:S1096-7176(25)00031-X. doi: 10.1016/j.ymben.2025.03.001. Online ahead of print.

ABSTRACT

The utilization of microorganisms to transform biomass into biofuels and biochemicals presents a viable and competitive alternative to conventional petroleum refining processes. Halomonas species are salt-tolerant and alkaliphilic, endowed with various beneficial properties rendering them as contamination resistant platforms for industrial biotechnology, facilitating the commercial-scale production of valuable bioproducts. Here we summarized the metabolic and genomic engineering approaches, as well as the biochemical products synthesized by Halomonas. Methods were presented for expanding substrates utilization in Halomonas to enhance its capabilities as a robust workhorse for bioproducts. In addition, we briefly reviewed the Next Generation Industrial Biotechnology (NGIB) based on Halomonas for open and continuous fermentation. In particular, we proposed the industrial attempts from Halomonas chassis and the rising prospects and essential strategies to enable the successful development of Halomonas as microbial NGIB manufacturing platforms.

PMID:40049362 | DOI:10.1016/j.ymben.2025.03.001

Food Chem. 2025 Mar 1;478:143663. doi: 10.1016/j.foodchem.2025.143663. Online ahead of print.

ABSTRACT

Southern Thailand sweet pickled mango (MBC) is a famous delicacy and economically important for the local communities. This study aimed to elucidate important metabolites related to MBC deterioration at 4 °C (STR4) and 30 °C (STR30). The results show that deterioration of MBCs was linked to increased levels of ethyl acetate, isopropyl alcohol, trans-β-ocimene, isopentyl acetate, 2-phenethyl acetate, glucose, and fructose, along with a decrease in sucrose. Moreover, isopentyl acetate, ethyl acetate, and 2-phenethyl acetate were significantly higher in STR4 compared to STR30 with log 2[fold change (FC)] 3.2, 2.0, and 1.0, respectively. Meanwhile, STR4 had a lower sucrose level (log [FC] -1.4) than STR30. It was postulated that a longer storage time of STR4 than STR30 affects sucrose hydrolysis. Due to the abundance of volatile metabolites in deteriorated MBC, applying odor/flavor absorber film on MBC packaging might help prolong its shelf life.

PMID:40049138 | DOI:10.1016/j.foodchem.2025.143663

Lancet HIV. 2025 Mar;12(3):e191-e200. doi: 10.1016/S2352-3018(24)00344-8.

ABSTRACT

BACKGROUND: Long-acting cabotegravir and long-acting rilpivirine constitute a completely intramuscular antiretroviral therapy (ART) regimen for adults with HIV. We aimed to assess the safety, antiviral activity, and pharmacokinetics of oral cabotegravir and rilpivirine followed by a combination of long-acting cabotegravir and long-acting rilpivirine in virologically suppressed adolescents with HIV.

METHODS: The IMPAACT 2017/MOCHA study is a phase 1/2, multicentre, open-label, non-comparative, dose-finding trial being conducted at 18 sites across Botswana, South Africa, Thailand, Uganda, and the USA. In cohort 2 of this study, adolescents (aged 12-18 years; weight ≥35 kg) with HIV and no serious comorbidities who were receiving stable combination ART with confirmed virological suppression and had either previously enrolled in the first cohort or had not previously participated in the study were eligible for inclusion. Participants stopped their background combination ART and received oral cabotegravir 30 mg once daily and oral rilpivirine 25 mg once daily orally for 4-6 weeks, followed by long-acting injectable cabotegravir 600 mg (3 mL) and long-acting injectable rilpivirine 900 mg (3 mL) intramuscularly at weeks 4 and 8, and every 8 weeks thereafter. The primary outcome was safety, including all adverse events, at week 24. Primary safety outcome measures were summarised as frequencies, percentages, and exact Clopper-Pearson 95% CIs in the evaluable analysis population, which included participants who were treated exclusively with the regimen and either completed all scheduled treatments or experienced severe adverse events, permanently discontinued the treatment, or died, whichever occurred first; and in the all-treated analysis population, which included all participants who received at least one dose of any study product. This study is registered with ClinicalTrials.gov (NCT3497676) and is ongoing.

FINDINGS: Between July 26, 2021, and Aug 27, 2022, 44 (80·0%) of 55 adolescents who participated in cohort 1 and 100 (87·0%) of 115 screened study-naive adolescents were enrolled in cohort 2. 74 (51·4%) participants were female and 70 (48·6%) were male. Overall, 15 (10·8% [95% CI 6·2-17·2]) of all 139 participants in the evaluable analysis population had at least one adverse event of grade 3 or above by week 24. Among 142 participants who received at least one injection, 43 (30%) experienced at least one injection site reaction (ISR). All 106 ISRs were either grade 1 (98 [92·5%]) or grade 2 (eight [7·5%]), and 97 (91·5%) resolved within 7 days. No participant experienced a drug-related serious adverse event or prematurely discontinued treatment due to a drug-related adverse event.

INTERPRETATION: Long-acting injectable cabotegravir and long-acting injectable rilpivirine, administered to adolescents at recommended adult dosages every 8 weeks, showed no unanticipated safety concerns in the 24 weeks following administration.

FUNDING: National Institutes of Health, ViiV Healthcare, and Johnson & Johnson.

PMID:40049924 | DOI:10.1016/S2352-3018(24)00344-8

J Nucl Med. 2025 Mar 6:jnumed.124.268872. doi: 10.2967/jnumed.124.268872. Online ahead of print.

ABSTRACT

A first-in-human phase I clinical study aimed to assess the safety profile, radiation dosimetry, and biodistribution of a potential cardiac PET myocardial perfusion imaging tracer, [18F]SYN2 (18F-labeled acridine derivative), in healthy subjects. Methods: [18F]SYN2 intravenous administration with PET imaging was performed on healthy volunteers, and sequential whole-body imaging was performed over 4 h. Blood and urine samples were collected for up to 240 min. Safety follow-up visits took place at 2, 5, and 14 d after the administration. Results: Ten subjects (8 women and 2 men) completed all study procedures. The mean age was 38.1 ± 8.8 y, and the mean body mass index was 22.7 ± 3.0 kg/m2 The mean administered dose of radioactivity was 258 MBq (range, 246-272 MBq). There were no drug-related adverse events, and the tracer was well tolerated in all subjects. The mean whole-body effective radiation dose for [18F]SYN2 was 0.0195 mSv/MBq. The tracer was rapidly taken up by the myocardial wall and cleared from plasma, leading to good image quality within minutes of tracer injection. Conclusion: On the basis of the safety profile, radiation dosimetry, and biodistribution of [18F]SYN2, it appears to be a promising agent for clinical PET myocardial perfusion imaging and to warrant further clinical studies.

PMID:40049745 | DOI:10.2967/jnumed.124.268872

Biomaterials. 2025 Mar 3;320:123237. doi: 10.1016/j.biomaterials.2025.123237. Online ahead of print.

ABSTRACT

Acute kidney injury (AKI) is a major cause of mortality in hospitalized patients, yet effective therapeutic interventions remain underdeveloped. To address this critical need, we have employed tetrahedral framework nucleic acid (tFNA) as a carrier to self-assemble a complex incorporating G-quadruplex and hemin (G4/Hemin). This novel formulation exhibits uniform particle size, targeted delivery, and significant therapeutic efficacy for AKI. In a chemotherapy-induced AKI model, G4/Hemin-tFNA preferentially accumulated in the renal tubules, significantly mitigating drug-induced renal tubular injury. In healthy mice, G4/Hemin-tFNA was rapidly cleared from circulation due to efficient renal filtration. Safety evaluations conducted over a continuous 30-day period indicated minimal side effects associated with G4/Hemin-tFNA administration. Mechanistic studies elucidated three primary molecular mechanisms through which G4/Hemin-tFNA exerts its therapeutic effects in AKI: 1) Enhanced Renal Targeting. G4/Hemin-tFNA facilitates effective renal targeting and protection during blood circulation, leading to significant accumulation of drug within the kidneys. 2) Reactive Oxygen Species (ROS) Clearance. The complex exhibits peroxidase-like activity, enabling the rapid clearance of ROS at the site of AKI lesions, thereby inhibiting the oxidative stress progression. 3) Activation of heme oxygenase-1 (HO-1). G4/Hemin-tFNA selectively activates HO-1, enhancing the concentration of anti-inflammatory factors at inflamed sites and promoting an anti-inflammatory microenvironment. Collectively, these findings demonstrate that G4/Hemin-tFNA is a safe and effective therapeutic agent for AKI. By activating HO-1 and clearing ROS, G4/Hemin-tFNA inhibits disease progression, offering a promising approach for the development of future AKI therapies.

PMID:40049024 | DOI:10.1016/j.biomaterials.2025.123237

Langmuir. 2025 Mar 6. doi: 10.1021/acs.langmuir.4c04840. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa (P. aeruginosa) is a pathogen commonly associated with lung infections in cystic fibrosis (CF) patients, often developing a mucoid phenotype that overproduces alginate, a major component of the biofilm's extracellular polymeric substances (EPS) matrix, increasing tolerance to antibiotics. Past studies have shown that low-frequency ultrasound (LFU) increases the antibiotic susceptibility of P. aeruginosa in biofilms, but its effects on mucoid strains are unknown. In this study, we assessed the combined application of LFU and antibiotics on P. aeruginosa FRD1, a mucoid strain, and compared it to nonmucoid P. aeruginosa PAO1 biofilms. The mucoid biofilm exhibited greater stiffness, thickness, and density, with polysaccharides (likely alginate) comprising over 70% of the EPS matrix. Although LFU application led to a 50% increase in biofilm creep compliance, no synergistic effect was observed with tobramycin. However, the same LFU treatment significantly improved ciprofloxacin susceptibility. We implemented a one-dimensional model that estimated a 25-fold increase in the diffusion coefficient for ciprofloxacin following LFU, though higher intensities were needed to induce comparable effects in diffusivity and mechanical properties compared to the nonmucoid biofilm. The model also suggested that tobramycin likely sorbed to alginate, hindering diffusion to the biofilm interior, thereby reducing its inactivation efficiency. Our findings suggest that LFU can impact antibiotic diffusion through the biofilm and mechanical properties but not necessarily overcome antibiotic interactions with the EPS matrix. Additionally, variations in EPS matrix composition may require different LFU intensities for effective outcomes. These results may have significant implications for potential clinical applications, especially for CF patients.

PMID:40048555 | DOI:10.1021/acs.langmuir.4c04840

PLoS One. 2025 Mar 6;20(3):e0319037. doi: 10.1371/journal.pone.0319037. eCollection 2025.

ABSTRACT

Clozapine has superior efficacy to other antipsychotics, especially in patients with treatment-resistant schizophrenia. However, its pharmacokinetics and pharmacodynamics vary largely among patients. We aimed to evaluate the clinical and genetic factors associated with the pharmacokinetics and pharmacodynamics of clozapine in patients with schizophrenia. Blood samples for clozapine pharmacokinetic assessment were collected from patients with schizophrenia at weeks 2 (visit 2), 8 (visit 3), and 18 (visit 4) from the initiation of clozapine treatment. The Positive and Negative Syndrome Scale (PANSS) score was assessed at baseline (visit 1) and visits 3 and 4. Linear mixed models were used to identify the clinical and genetic variables associated with the clozapine concentration and total PANSS score. A total of 45 patients were included in the pharmacogenomic analysis. Owing to the small sample size, we categorized concomitant medications into four groups. However, individual drugs may have different effects on clozapine concentration. Clozapine concentration was significantly associated with smoking status and cumulative clozapine dose. Clozapine concentration was significantly associated with five single nucleotide polymorphisms (SNPs) in three genes (rs28371726 and rs202102799 in CYP2D6, rs4148323 and rs34946978 in UGT1A1, and rs2011404 in UGT1A4). Furthermore, follow-up time, body mass index, and total bilirubin levels were significantly associated with the total PANSS scores. The PANSS score was significantly associated with four SNPs in two genes (rs7787082 and rs10248420 in ABCB1 and rs2133251840 and rs762502 in DRD4). This study suggests potential clinical and genetic predictors of clozapine concentration and psychiatric symptoms in patients with schizophrenia treated with clozapine. With further investigations in diverse populations, our findings may provide important information on variables to be considered in individualized clozapine treatment.

PMID:40048458 | DOI:10.1371/journal.pone.0319037

ACS Appl Mater Interfaces. 2025 Mar 6. doi: 10.1021/acsami.4c22848. Online ahead of print.

ABSTRACT

In the past decades, conjugated polyelectrolytes (CPEs) have become prominent in sensing applications due to their unique properties, including strong and tunable light absorption, high sensitivity, water solubility, and biocompatibility. Inspired by mammalian olfactory and gustatory systems, CPE-based sensor arrays have made significant strides in discriminating structurally similar analytes and complex mixtures for various applications. This review consolidates recent advancements in CPE-based sensor arrays, highlighting rational design, controllable fabrication, and effective data processing methods. It covers the fundamentals of CPE fluorescence sensing, emphasizing design strategies for sensor array units and data processing techniques. The broad applicability of CPE-based sensor arrays is demonstrated across diverse domains, including environmental monitoring (e.g., detecting metal ions and explosives), medical diagnostics (e.g., sensing disease markers and analyzing biological samples), and food safety (e.g., assessing the freshness, quality, and source of food products). Further, challenges and future directions in the field are discussed to inspire further research and development in this area.

PMID:40048404 | DOI:10.1021/acsami.4c22848

IEEE Trans Pattern Anal Mach Intell. 2025 Mar 6;PP. doi: 10.1109/TPAMI.2025.3548148. Online ahead of print.

ABSTRACT

Single Image Reflection Removal (SIRR) is a canonical blind source separation problem and refers to the issue of separating a reflection-contaminated image into a transmission and a reflection image. The core challenge lies in minimizing the commonalities among different sources. Existing deep learning approaches either neglect the significance of feature interactions or rely on heuristically designed architectures. In this paper, we propose a novel Deep Exclusion unfolding Network (DExNet), a lightweight, interpretable, and effective network architecture for SIRR. DExNet is principally constructed by unfolding and parameterizing a simple iterative Sparse and Auxiliary Feature Update (i-SAFU) algorithm, which is specifically designed to solve a new model-based SIRR optimization formulation incorporating a general exclusion prior. This general exclusion prior enables the unfolded SAFU module to inherently identify and penalize commonalities between the transmission and reflection features, ensuring more accurate separation. The principled design of DExNet not only enhances its interpretability but also significantly improves its performance. Comprehensive experiments on four benchmark datasets demonstrate that DExNet achieves state-of-the-art visual and quantitative results while utilizing only approximately 8% of the parameters required by leading methods.

PMID:40048344 | DOI:10.1109/TPAMI.2025.3548148

IEEE Trans Pattern Anal Mach Intell. 2025 Mar 6;PP. doi: 10.1109/TPAMI.2025.3548729. Online ahead of print.

ABSTRACT

Foundation models have emerged as critical components in a variety of artificial intelligence applications, and showcase significant success in natural language processing and several other domains. Meanwhile, the field of graph machine learning is witnessing a paradigm transition from shallow methods to more sophisticated deep learning approaches. The capabilities of foundation models in generalization and adaptation motivate graph machine learning researchers to discuss the potential of developing a new graph learning paradigm. This paradigm envisions models that are pre-trained on extensive graph data and can be adapted for various graph tasks. Despite this burgeoning interest, there is a noticeable lack of clear definitions and systematic analyses pertaining to this new domain. To this end, this article introduces the concept of Graph Foundation Models (GFMs), and offers an exhaustive explanation of their key characteristics and underlying technologies. We proceed to classify the existing work related to GFMs into three distinct categories, based on their dependence on graph neural networks and large language models. In addition to providing a thorough review of the current state of GFMs, this article also outlooks potential avenues for future research in this rapidly evolving domain.

PMID:40048343 | DOI:10.1109/TPAMI.2025.3548729

IEEE J Biomed Health Inform. 2025 Mar 6;PP. doi: 10.1109/JBHI.2025.3547315. Online ahead of print.

ABSTRACT

One of the major challenges in drug development is maintaining acceptable levels of efficacy and safety throughout the various stages of clinical trials and successfully bringing the drug to market. However, clinical trials are time-consuming and expensive. While there are computational methods designed to predict the likelihood of a drug passing clinical trials and reaching the market, these methods heavily rely on manual feature engineering and cannot automatically learn drug molecular representations, resulting in relatively low model performance. In this study, we propose AGPred, an attention-based deep Graph Neural Network (GNN) designed to predict drug approval rates in clinical trials accurately. Unlike the few existing studies on drug approval prediction, which only use predicted targets of compounds, our novel approach employs a GNN module to extract high-potential features of compounds based on their molecular graphs. Additionally, a cross-attention-based fusion module is utilized to learn molecular fingerprint features, enhancing the model's representation of chemical structures. Meanwhile, AGPred integrates the physicochemical properties of drugs to provide a comprehensive description of the molecules. Experimental results indicate that AGPred outperforms four state-of-the-art models on both benchmark and independent datasets. The study also includes several ablation experiments and visual analyses to demonstrate the effectiveness of our method in predicting drug approval during clinical trials. The codes for AGPred are available at https://github.com/zhc940702/AGPred.

PMID:40048330 | DOI:10.1109/JBHI.2025.3547315

MMWR Morb Mortal Wkly Rep. 2025 Mar 6;74(7):109-115. doi: 10.15585/mmwr.mm7407a1.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a progressive lung disease characterized by scarring and worsening lung function, has a poor prognosis. A recent systematic review estimated that 21% of IPF deaths might be attributable to occupational exposures. To describe IPF mortality among U.S. residents aged ≥15 years who were ever employed, by industry and occupation, CDC conducted an exploratory analysis of 2020-2022 multiple cause-of-death data. During 2020-2022, a total of 67,843 (39,712 [59%] male and 28,131 [41%] female) decedents had IPF, suggesting that during this 3-year period, 8,340 IPF deaths in males and 5,908 deaths in females might have been associated with occupational exposures. By industry group, the highest proportionate mortality ratios among males were among those employed in utilities (1.15) and among females, were among those employed in public administration (1.12). By occupation group, the highest IPF mortality rates among males were among community and social services workers (1.23) and among females among farming, fishing, and forestry workers (1.24). Estimates of elevated IPF mortality among workers in specific industries and occupations warrant confirmation, control of known exposure-related risk factors, and continued surveillance to better understand the full range of occupational exposures that might increase risk for developing IPF.

PMID:40048397 | DOI:10.15585/mmwr.mm7407a1

Diabetes. 2025 Mar 6:db240655. doi: 10.2337/db24-0655. Online ahead of print.

ABSTRACT

Genome-wide association studies have identified SH2B3 as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single SH2B3 haplotype significantly associated with increased risk for human T1D. Fine mapping has demonstrated the most credible causative variant is the single nucleotide rs3184504*T polymorphism in SH2B3. To better characterize the role of SH2B3 in T1D, we used mouse modeling and found a T cellintrinsic role for SH2B3 regulating peripheral tolerance. SH2B3 deficiency had minimal effect on TCR signaling or proliferation across antigen doses, yet enhanced cell survival and cytokine signaling including common gamma chain-dependent and interferon-gamma receptor signaling. SH2B3 deficient naïve CD8+ T cells showed augmented STAT5-MYC and effector-related gene expression partially reversed with blocking autocrine IL-2 in culture. Using the RIP-mOVA model, we found CD8+ T cells lacking SH2B3 promoted early islet destruction and diabetes without requiring CD4+ T cell help. SH2B3-deficient cells demonstrated increased survival and reduced activation-induced cell death. Lastly, we created a spontaneous NOD.Sh2b3-/- mouse model and found markedly increased incidence and accelerated T1D across sexes. Collectively, these studies identify SH2B3 as a critical mediator of peripheral T cell tolerance limiting the T cell response to self-antigens.

PMID:40048557 | DOI:10.2337/db24-0655

Science. 2025 Mar 7;387(6738):eadn2623. doi: 10.1126/science.adn2623. Epub 2025 Mar 7.

ABSTRACT

Millions of ribosomes are packed within mammalian cells, yet we lack tools to visualize them in toto and characterize their subcellular composition. In this study, we present ribosome expansion microscopy (RiboExM) to visualize individual ribosomes and an optogenetic proximity-labeling technique (ALIBi) to probe their composition. We generated a super-resolution ribosomal map, revealing subcellular translational hotspots and enrichment of 60S subunits near polysomes at the endoplasmic reticulum (ER). We found that Lsg1 tethers 60S to the ER and regulates translation of select proteins. Additionally, we discovered ribosome heterogeneity at mitochondria guiding translation of metabolism-related transcripts. Lastly, we visualized ribosomes in neurons, revealing a dynamic switch between monosomes and polysomes in neuronal translation. Together, these approaches enable exploration of ribosomal localization and composition at unprecedented resolution.

PMID:40048539 | DOI:10.1126/science.adn2623

Aging (Albany NY). 2025 Feb 28;17(2):607. doi: 10.18632/aging.206208. Epub 2025 Feb 28.

NO ABSTRACT

PMID:40048354 | DOI:10.18632/aging.206208

Proc Natl Acad Sci U S A. 2025 Mar 11;122(10):e2423767122. doi: 10.1073/pnas.2423767122. Epub 2025 Mar 6.

ABSTRACT

Recent physical binding screens suggest that protein-metabolite interactions are more extensive than previously recognized. To elucidate the functional relevance of these interactions, we developed a mass spectrometry-based screening method for higher throughput in vitro enzyme assays. By systematically quantifying the effects of 79 metabolites on the activity of 20 central Escherichia coli enzymes, we not only assess functional relevance but also gauge the depth of the current understanding of regulatory interactions within one of the best-characterized networks. Our identification of 50 inhibitors and 14 activators not only expands the range of known input signals but also uncovers novel regulatory logic. For instance, we observed that AMP inhibits malic enzyme to safeguard the cyclic operation of the tricarboxylic acid cycle, and erythrose-4-phosphate inhibits 6-phosphogluconate dehydrogenase to redirect flux from the pentose phosphate pathway into the Entner-Doudoroff pathway. Discrepancies between our standardized assays and existing database entries suggest that many previously reported interactions might occur only under specific, often nonphysiological conditions. Our dataset represents a systematically determined functional protein-metabolite interaction network, establishing a baseline for allosteric regulation in central metabolism. These results enhance our understanding of the regulatory logic governing metabolic processes and underscore its significance in cellular adaptation and growth.

PMID:40048276 | DOI:10.1073/pnas.2423767122

J Urol. 2025 Mar 6:101097JU0000000000004511. doi: 10.1097/JU.0000000000004511. Online ahead of print.

ABSTRACT

PURPOSE: Adults with low-grade intermediate risk non-muscle-invasive bladder cancer (LG-IR-NMIBC) commonly ask urologists how their routine/responsibilities will be affected by treatments, including the standard of care, transurethral resection of bladder tumor (TURBT). We asked patients in the ENVISION trial (NCT05243550) to compare TURBT to a non-surgical primary treatment (UGN-102 containing mitomycin) for acceptability and impact on their routine/responsibilities.

MATERIALS AND METHODS: ENVISION (NCT05243550) is a phase 3, single arm trial where UGN-102 was administered as six weekly intravesical instillations. Interviews with U.S. patients were conducted at enrollment (before instillations) and 3 months (primary trial endpoint). Transcripts were coded by three coders using the gold standard of content analysis to derive interview themes.

RESULTS: Forty-one U.S. patients from 31 sites were eligible, and 29/41 completed both interviews. Most participants were men (62%), White (83%), and age 65+ (69%). Three themes were derived: 1) Patients perceived that TURBT interfered more with their routine/responsibilities. 2) Urinary symptoms were perceived to be similar, but bleeding, catheter issues, and time to resuming sexual activity lasted longer with TURBT. For UGN-102, uncommon reports were internal itching and difficulty keeping gel in the bladder during instillations. 3) Patients would recommend UGN-102 to other patients because it was perceived to be less invasive, painful, and time-consuming than TURBT.

CONCLUSION: Patients perceived UGN-102 to be a favorable primary treatment alternative to traditional surgical resections for LG-IR-NMIBC. By focusing on the underexplored area of patient perceptions, this study provides key information urologists will need to conduct shared decision-making conversations.

PMID:40048558 | DOI:10.1097/JU.0000000000004511