Integrated transcriptomic and metabolomic analysis of intestinal responses of Litopenaeus vannamei under acute freshwater stress.

Screening of purine nucleoside analogues against intracellular Toxoplasma gondii.

Recent developments in Haspin kinase inhibitors: Structure, synthesis and activities.

Efforts to improve the effectiveness of existing interventions for antimicrobial-resistant infections include identifying new ways to overcome resistance to licensed antibiotics using adjuvants or deploying antibiotics in novel combinations. Although antibiotics targeting the bacterial cell wall (e.g., β-lactams) and folate metabolism (e.g., trimethoprim-sulfamethoxazole [TMP-SMX]) remain cornerstones of modern healthcare, resistance to both classes poses an ongoing therapeutic challenge. We recently demonstrated that purine nucleosides can act as potent antibiotic adjuvants, restoring β-lactam susceptibility in methicillin-resistant Staphylococcus aureus (MRSA). Here, we show that guanosine significantly reduces intracellular thymidine levels in MRSA and potentiates the activity of antifolate antibiotics (TMP-SMX), as well as the pyrimidine antimetabolites 5-fluorouracil and 5-fluorouridine. Incorporation of oxacillin into guanosine-antifolate or guanosine-pyrimidine analog combinations further enhanced killing of both planktonic and biofilm-associated MRSA. Thymidine depletion was accompanied by elevated intracellular reactive oxygen species and dissipation of membrane potential, providing mechanistic insight into the bactericidal effects of these combinations. Together, these findings demonstrate that guanosine expands MRSA susceptibility beyond β-lactams to include additional clinically relevant antimicrobial drug classes commonly used to treat bacterial infections.

Purine derivatives as potential agents against Chagas disease: Ex vivo, in vitro, in silico evaluation, and identification of targets in Trypanosoma cruzi.

Grape seed proanthocyanidin extract suppresses bladder cancer by dual blockade of IMPDH1/2-mediated purine and pyrimidine nucleotide biosynthesis.

The rational design of fluorescent organic molecules is central to the development of advanced linear and nonlinear photonic materials. Purine-based compounds have emerged as promise candidates for several photonics applications due to their structural similarity to biological nucleobases synthetic versatility and favorable photophysical properties. However, their optical characterization typically generates large and complex data sets that are difficult to interpret, particularly when multiple compounds are analyzed simultaneously. Here, we apply principal component analysis (PCA) to a series of purine derivatives to systematically investigate the relationships between molecular descriptors and photophysical performance. The PCA model applied in the optical properties of the set captures 76.8% of the total variance within the first two principal components, enabling clear clustering of molecules according to their electronic structure. Importantly, by applying PCA directly to one- and two-photon absorption spectra, we achieve effective spectral deconvolution with 91.87% and 94.51%, respectively, isolating contributions associated with intensity, spectral shifts, and bandwidth. The robustness of this approach is validated through accurate spectral reconstruction. To extend the analysis toward predictive modeling, multiple linear regression (MLR) was employed to correlate PCA-derived features from one-photon absorption data with the transition dipole moment (μ01). The proposed PCA-MLR framework effectively captures the intrinsic relationships within the spectra of the studied group, minimizing the need for extensive experimental trials. The resulting model exhibits excellent predictive performance (R2 = 0.9728) and accurately estimating the μ01 = 7.07D of an external validation molecule with a deviation of approximately 2.5%. Overall, this PCA-MLR framework provides a powerful and efficient strategy for interpreting complex photophysical data sets and accelerating the design and optimization of organic molecules for linear and nonlinear photonic applications.

Uncovering metabolic reprogramming in ovarian and cervical cancers with multi-omics.

Low-Dose Vemurafenib Plus Rituximab in Front-Line and Relapsed or Refractory Hairy Cell Leukemia: The Scripps Regimen.

Genes in many bacteria are rich in purine nucleotides (A and G), but the origin of this preference is unclear. Here, using a large-scale reporter assay in Bacillus subtilis, we show that this purine bias is critical for gene expression. It prevents premature transcription termination in species that exhibit runaway transcription, in which RNA polymerases outpace ribosomes, leaving nascent mRNA exposed to the termination factor Rho. This vulnerability is resolved by a divergence between Rho's heightened target specificity and coding-strand nucleotide content. Selective pressure to avoid Rho appears to drive strong gene purine bias across species that exhibit runaway transcription, except in lineages that have lost Rho. This purine requirement underlies codon usage biases, promotes suppression of pyrimidine-rich antisense transcripts and can suppress expression of engineered constructs. Our results suggest that avoidance of premature transcription termination imposes major constraints on nucleotide content during genome evolution and adaptation of foreign genes.

Translational arrest and antioxidant collapse: Physiological and molecular ecotoxicity of perchlorate stress in Saccharina japonica gametophytes revealed by integrated multiomics.

Graphene oxide (GO) as typical 2D nanomaterials (NMs) have various applications, but their long-term neurological effects, particularly under health conditions like obesity, are unknown. This study investigated the chronic neurotoxicity of GO in zebrafish, both alone and in combination with high-fat diet (HFD)-induced obesity. Zebrafish were exposed to 0.01 or 0.1 mg/L GO for up to 3 months to establish a chronic exposure regimen. Subsequently, the co-exposure group was treated with HFD and 0.1 mg/L GO for 3 months. Our results showed that chronic exposure to GO induced subtle alterations in locomotor behavior, and HFD + GO co-exposure resulted in neurobehavioral impairment similar to HFD alone. Histopathological analysis revealed significant brain damage particularly in the HFD + GO co-exposure group. RNA-sequencing data revealed that co-exposure uniquely perturbed the inositol phosphate metabolism pathway, as well as 13 gene ontology terms related to metabolic processes, including phosphatidylinositol, glycerophospholipid, glycerolipid, and purine nucleotide metabolism. We further verified that the co-exposure upregulated the protein levels of HIF-1α, LDHA, and caspase-3, as well as key genes involved in glycolysis. This study demonstrates that chronic low-dose GO exposure can induce neurobehavioral changes and neuropathology in zebrafish, and HFD-induced obesity exacerbated HIF-1-mediated metabolic pathway changes, suggesting a combined or additive effect on specific neuropathological and molecular endpoints. These findings highlight the importance of considering underlying metabolic conditions, such as obesity, for the assessment of environmental health risks of NMs.

Uncoupling Protein 1 (UCP1) is a defining feature of brown fat and facilitates the specialized ability of the tissue to generate heat in the process of non-shivering thermogenesis. The protein is activated by fatty acids, which overcome its inhibition by purine nucleotides, to catalyze proton leak across the mitochondrial inner membrane, uncoupling nutrient oxidation from ATP production to release energy as heat. Thermogenesis through this process contributes to thermoregulation in many mammals and can promote nutrient turnover in humans to support metabolic health. UCP1 is a member of the mitochondrial carrier family of solute exchangers. For many years, its underlying mechanisms of activity and regulation have remained unclear. However, recent cryo-EM structures of UCP1 have clarified details on nucleotide inhibition and, with advances in our understanding of the mitochondrial carrier transport mechanism, provided important molecular constraints to rationalize how the protein may operate. Here, we review the molecular nature of UCP1, re-evaluating past structure-function relations in this structural context. Key carrier features and putative novel bonding that likely support state changes in the protein and proton leak activity are highlighted, as well as new hypotheses to explain subtleties in purine nucleotide binding discrimination.

Triple negative breast cancer (TNBC) accounts for 15% of breast cancers, exhibiting high proliferation and resistance to conventional treatments, highlighting the need for innovative therapies. Purine derivatives are recognised for their anticancer potential, making them valuable candidates for drug development. In the present study, we sought to uncover the anticancer potential of novel 6-cycloalkylaminoadenine compounds and elucidate their mechanism of action. A versatile synthetic pathway was developed to prepare two series of new 6-cycloalkylaminoadenines that combine the adenine scaffold with morpholino and N-methylpiperazine units. The method starts with the preparation of imidazole-based amidrazone precursors, which were obtained from 5-amino-4-cyanoformimidoylimidazoles and 4-aminomorpholine or 4-methylaminopiperazine. The reaction of these amidrazone precursors with triethyl orthoformate under reflux gave the target 6-cycloalkylaminoadenines. The compounds' cytotoxicity on the TNBC cell line MDA-MB-231 was assessed, with the best IC50 values around 60-70 μM. The most promising compound, 3.2a, inhibits the migratory and invasive capacities of TNBC cells and promotes actin cytoskeleton reorganisation. Additionally, this compound induces caspase-3 activation, which promotes DNA fragmentation and ultimately leads to cell death. Molecular docking studies with key proteins involved in major signalling pathways associated with cancer progression further revealed that compound 3.2a has a higher affinity for CDK1. Altogether, our findings provide preliminary evidence supporting the potential of 6-cycloalkylaminoadenines in TNBC treatment.

Alpha-ketoglutarate accelerates granulocyte-monocyte progenitor differentiation and atherosclerotic plaque inflammation via oxoglutarate receptor 1.

Interactions of rumen-protected histidine and dietary starch in low-protein diets with adequate lysine and methionine: Effects on lactational performance and nitrogen utilization in dairy cows.

Classic Hairy Cell Leukemia (cHCL) and related conditions are rare, indolent B-cell malignancies characterized by distinctive morphological, immunophenotypic, and molecular features. Over the past decade, major advances in understanding the pathophysiology and molecular underpinnings have reshaped diagnostic and therapeutic approaches. This review synthesizes current knowledge on the cellular origins and signaling pathways that drive cHCL and Hairy Cell Variant (HCL-v)/splenic B-cell lymphoma/leukemia (SBLPN) and other molecular aberrations in disease pathogenesis. We discuss evolving diagnostic modalities, including flow cytometry, immunohistochemistry, and next-generation sequencing, that enhance diagnostic precision and disease monitoring. Additionally, we examine established and emerging therapeutic strategies-from purine nucleoside analogs (PNA) to targeted inhibitors and immunotherapies-that have significantly improved patient outcomes while highlighting challenges such as relapse and treatment resistance. By integrating insights from molecular biology and clinical practice, this review aims to provide a comprehensive understanding of cHCL and related disorders.

We investigated whether destroying malignant cells and the associated tumor microenvironment (TME) by focal gene therapy would broaden immune checkpoint inhibitor (ICI) effectiveness. We show that ICI antitumor activity against syngeneic (murine) triple-negative breast cancer (TNBC) was augmented when a therapeutic transgene (purine nucleoside phosphorylase, referred to here as E. coli PNP) was used to cleave fludarabine (2-fluoro-arabinofuranosyl adenine) to the anticancer purine base, 2-fluoroadenine (F-Ade). We also established strong repression of anatomically distant, non-PNP-expressing tumors being treated by the same strategy. TNBC cytoreduction was associated with decreased intratumoral PD1+ Tregs, increased granzyme B+ NK cells, elevated MKI67+ T8 cells, and rapid immune clearance. Because F-Ade works by a mechanism that destroys quiescent neoplastic and supporting cells in the microenvironment, and since resistance to ICIs depends upon an intact TME, tumor killing by this approach offers a means to sensitize refractory malignancies to immune ablation and points to broad applicability against numerous cancer subtypes.

Multi-omics profiling identifies inosine as a key metabolite associated with embryonic arrest in hydrosalpinx-associated infertility

Red Clover Isoflavones plus Urea for Partial Soybean Meal Substitution: Implications for Productivity and Nitrogen Utilization in Holstein cows.