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摘要： Background: Human voltage-dependent anion channel 1 (hVDAC1), a major mitochondrial outer membrane porin, plays a central role in cellular energy metabolism and apoptosis. Its overexpression in multiple cancer types and its involvement in neurodegeneration make it a compelling therapeutic target. Despite this relevance, marine metabolites have not been systematically evaluated as hVDAC1 modulators. Methods: A curated library of 79 marine-associated microalgal and microbial metabolites was assembled from PubChem with documented marine origins. Virtual screening was performed against hVDAC1 (PDB: 2JK4, 2.3 A) using AutoDock Vina, followed by quantum chemical characterization at the B3LYP/6–311++G(d,p)/PCM level in Gaussian 16 and 100-nanosecond molecular dynamics simulations in Desmond. Structural descriptor correlation analysis (Pearson r) was applied to contextualize scoring trends. Results: Anthraquinone Green G Base (-8.7 kcal/mol) and Platencin A1 (-8.6 kcal/mol) emerged as top candidates from 79 screened compounds (mean score: -6.66 ± 1.48 kcal/mol). Anthraquinone Green G Base interacts via hydrophobic and pi-alkyl contacts with Pro8, Tyr10, Lys99, and Leu128, while Platencin A1 forms hydrogen bonds with Lys227, Thr251, and Thr261. Molecular dynamics simulations confirmed stable binding over 100 ns (ligand RMSD 1.35 A and 1.68 A, respectively). Heavy atom count correlated significantly with binding affinity (r = -0.62), validating size-complementarity with the hVDAC1 channel lumen. ADMET profiling indicated favorable drug-like

摘要： Sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) are cardio- and kidney-protective, yet their uptake in clinical practice has been suboptimal. The association between pharmacists embedded in primary care clinics and prescribing rates of SGLT2i and GLP-1RA is unknown.

关键词： slanted vector field   hyperbolicity   complex hypersurface  

摘要： In this paper, we develop the techniques of slanted vector fields, especially the techniques of partial slanted vector fields, to apply them to Wronskian-type holomorphic n-jet differentials on the n-dimensional complex hypersurface in the projective space constructed by Cramer’s rule, to prove the hyperbolicity of generic n-dimensional complex hypersurfaces of degree greater than or equal to 49n^(2) in the projective space.

关键词： Androgen receptor   Castration-resistance   Chromatin looping   LRH-1   Prostate cancer  

摘要： The androgen receptor (AR) signaling axis is regarded as the key driver of prostate cancer (PCa). Besides acting as a well-characterized transactivator of diverse targets, accumulating evidence suggests that AR can also function as a transrepressor. However, AR-repressed targets and their significance in PCa and castration-resistant PCa (CRPC) remain poorly understood. Among multiple mechanisms, intratumoral androgen biosynthesis is regarded as an important factor responsible for persistent AR signaling in CRPC. Previously, we characterized that the nuclear receptor LRH-1 (NR5A2) plays a key role in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of multiple key steroidogenic enzymes. However, the transcriptional control of LRH-1 in PCa is still undefined. In this study, we show that androgen-activated AR could suppress, whereas antiandrogen-suppressed AR could up-regulate the LRH-1 expression in PCa cells. Furthermore, our genomics analysis showed that the transcriptional repression of NR5A2 by ligand-activated AR was mediated through the induction of a distinct androgen-dependent chromatin looping formed within the topologically associated domain of NR5A2 via direct binding of AR to the regulatory elements of NR5A2. Our present study demonstrates the significance of decreased androgen levels in androgen-deprivation therapy, resulting in the relief or up-regulation of LRH-1 toward intratumoral androgen biosynthesis in CRPC.

关键词： PMM1   Obesity   Adipose thermogenesis   Inosine   Adenosine receptor   PKA  

摘要： Phosphomannomutase 1 (PMM1) is an evolutionarily conserved metabolic enzyme classically linked to mannose metabolism, but its physiological role in adipose tissue remains unknown. This study aimed to define the function of PMM1 in thermogenic regulation and systemic metabolism.

关键词： inflammation   inter-individual variability   n-of-1   nutrition   oxidative stress   personalized   vitamin C  

摘要： Personalized antioxidant supplementation is promoted to optimize redox balance and inflammation profile.

关键词： Fab-based antibody-drug conjugates   Butelase-1 ligation   Site-specific conjugation   Protein engineering   HER2-positive breast cancer  

摘要： Antibody-drug conjugates (ADCs) are constrained by limited tumor penetration of IgG formats and heterogeneity from stochastic conjugation. We addressed these challenges by engineering a compact trastuzumab Fab-based ADC with site-specific installation of DM1 using the peptide ligase butelase-1 and by extending serum persistence via genetic fusion of an albumin-binding domain (ABD). Butelase-1 ligation proceeded rapidly under mild conditions to afford a homogeneous product with a defined drug-to-antibody ratio. The conjugate selectively killed HER2-positive cells in vitro while sparing HER2-negative controls. ABD fusion increased serum albumin binding and improved in vivo exposure;the resulting T-Fab-ABD(H + L)-DM1 produced superior tumor growth inhibition in HER2-positive xenografts compared with its non-ABD analogue. The ADC showed no significant body weight loss or organ damage in mice, indicating good tolerability. These findings validate a modular strategy combining a Fab scaffold, enzymatic site-specific conjugation, and ABD-mediated half-life extension to generate potent, homogeneous ADCs and nominate T-Fab-ABD(H + L)-DM1 as a promising candidate for HER2-positive cancer therapy.

关键词： SRSF6   Serine-arginine rich splicing factor 6   RNA-binding protein   Tandem RRM   Backbone assignment   15N-relaxation  

摘要： The human serine-arginine rich splicing factor 6 (SRSF6) is part of the SR-protein family consisting of 12 members and is involved in (alternative-) splicing regulation. It is composed of an N-terminal RRM domain, followed by a pseudo-RRM and a C-terminal serine/arginine-rich disordered domain. Despite extensive studies on the functions of SRSF6, its determinants for specific RNA-recognition have remained unresolved due to a lack of high-resolution structures based on unambiguous boundaries of individual domains and the involved disordered regions. We here provide the first near-complete NMR backbone and sidechain assignments of human SRFS6 RRM1 and backbone assignments of the pseudo-RRM2 (ΨRRM2), as well as the tandem RRM. The derivable carbon secondary chemical shifts were used to define secondary structure elements as well as exact domain boundaries, showcasing a canonical β₁α₁β₂β₃α₂β₄-fold for either RRM. Consequently, we defined the inter-domain linker with a length of 37 residues. Furthermore, ¹⁵N-relaxation data measured for the single and tandem RRMs indicate that the two RRMs tumble as one entity. However, the minor chemical shift differences between the respective constructs suggest a merely transient interaction with no defined interface between the two RRMs. Lastly, we show that AlphaFold3 models are majorly supported by our solution NMR data, but there are subtle inconsistencies with regard to the formation of the β₄-strand. In sum, our initial work underlines the role of NMR for visualizing crucial functional details of biology and sets the critical basis for future high-resolution structures of and residue-resolved determinants of specific RNA-recognition by the splicing regulator SRSF6.

关键词： pregnancy   preeclampsia   placental growth factor   vascular endothelial growth factor receptor-1   sFlt-1/PlGF ratio  

摘要： The ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) over placental growth factor (PlGF) increases before clinical onset in women with suspected preeclampsia (PE). We aimed to estimate its value in asymptomatic patients.