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Characterization of membrane structures regulating primary ciliogenesis by quantitative isotropic ultrastructure imaging
Abstract The trafficking, docking, and fusion of membrane vesicles at the mother centriole (MC) are important for primary cilium construction. Here, we determined the three-dimensional (3D) membrane ultrastructures, and associated proteins, involved in this primary cilium assembly mechanism upstream of axoneme growth. Our work suggests that the enlargement of small vesicles docked to the MC is a key trigger for ciliogenesis progression, a process requiring the MC distal appendage protein CEP164. These vesicles appear to fuse to form tubular C-shaped intermediates and an unprecedented toroidal membrane intermediate. The formation of these previously uncharacterized tubular membrane ciliogenesis intermediates is orchestrated by the membrane trafficking regulators EHD1 and RAB8, and is associated with the IFT-B complex protein IFT88. Remarkably, we show that EHD1, through its membrane tubulation function, regulates ciliogenesis progression by directly promoting CP110/CEP97 removal from the MC cap. The establishment of these tubular membrane structures is also associated with the recruitment of the ciliary gate transition zone proteins. Together, these findings redefine the architectural framework of early ciliogenesis and underscore the utility of isotropic ultrastructural imaging combined with quantitative 3D analysis for elucidating mechanisms of membrane trafficking and organelle biogenesis.
Pharmacological treatments and clinical events in newly diagnosed heart failure patients stratified by ejection fraction in Japan
Abstract There is a limited understanding of the uptake of pharmacological treatments and incidence of clinical events in newly diagnosed heart failure (HF) patients, stratified by left-ventricular ejection fraction (LVEF) in contemporary clinical settings in Japan. A retrospective cohort study was conducted using a nationwide Japanese hospital database to evaluate the patterns of HF medications and clinical events in adult patients with a first confirmed HF diagnosis from January 1, 2020–July 31, 2023 (n = 16,001). Fine-Gray sub-distribution hazard models were applied to assess factors associated with HF medication initiations and clinical events. Overall, 5473 (34.2%), 3053 (19.1%), and 7475 (46.7%) patients with HF with reduced ejection fraction, mildly reduced ejection fraction (HFmrEF), and preserved ejection fraction (HFpEF) were included, respectively. Within the first 6 months, prescription rates of HF medications were: angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, or angiotensin receptor blocker-neprilysin inhibitor (65.6%), beta-blockers (57.6%), mineralocorticoid antagonists (55.7%), and sodium-glucose cotransporter-2 inhibitors (33.2%), with the lowest rates in HFpEF patients. The increase in prescription rates between 6 and 12 months was modest across all medication classes. One-year incidence rates per 100 person-years (95% confidence interval) of in-hospital all-cause mortality and in-hospital cardiovascular death were 23.0 (22.1–24.0) and 16.6 (15.8–17.4), respectively. HFmrEF and HFpEF were associated with lower hazards of treatment initiation for most HF medications, whereas the risks of in-hospital all-cause mortality and in-hospital cardiovascular death did not differ significantly across all LVEF subtypes. The findings underscore the suboptimal uptake of pharmacological treatments, despite the poor prognosis of newly diagnosed HF patients. The disparities in initiations of recommended treatments reaffirm the importance of properly implementing evidence-based therapies within each LVEF subtype.
Intrinsic DNA codes govern distinct modes of nucleosome-transcription factor interactions
The effect of voluntary environmental regulation on corporate financialization in China
Spatial architecture of autism pathogenesis reveals mosaic structural disarray during early development
Spatiotemporal evolution and driving mechanisms of ecological quality in shanxi province based on XGBoost-SHAP
Operando identification of anion effect on lithium nucleation and growth via in situ transmission electron microscopy
Natural variation in antimicrobial activity and composition of the secreted metabolomes of the model moss Ceratodon purpureus
Abstract Bryophytes have recently emerged as potentially promising producers of bioactive metabolites with multiple applications in biomedicine and biotechnology. Our previous studies have established that the model moss Ceratodon purpureus produces novel compounds with potent antimicrobial activities against Gram-positive bacteria. Here, we conducted a comparative analysis of metabolites produced by four different natural isolates of C. purpureus and observed considerable variation in the composition of antibacterial compounds. Next, we partially purified bioactive compounds from extracellular exudates produced by the two model C. purpureus lines, GG1 and R40. Untargeted metabolomic analysis revealed that GG1 isolate secreted a much more diverse set of metabolome components, including various amines, fatty acids, lactones, quinones and terpenoids, in comparison to the R40 isolate. However, the relative percentages of nitrogen-, phosphorus- and sulfur-containing compounds were notably similar in both metabolomes. Importantly, our analysis predicted the presence of several classes of potentially bioactive metabolites in metabolomes of both moss isolates. Taken together, our experiments provided an important evidence that extracellular metabolomes of the model moss Ceratodon purpureus are characterized by a remarkable intraspecific variability in the secretion, composition and abundance of different extracellular compounds.
Annealing of skyrmion lattice in van der Waals magnet via field modulation
Evaluating pXRF accuracy for predicting soil fertility: effects of moisture and soil properties
Regional sex differences in human cortical anatomy vary in their morphometric bases and overlap with sex chromosomal and gonadal influences
Abstract Humans show reproducible sex differences in regional cortical volume (CV), but it remains unclear how these relate to the two biologically dissociable determinants of CV – surface area (SA) and cortical thickness (CT) – or to potentially causal sex chromosomal and gonadal effects. Here, we analyze neuroimaging data in two independent human cohorts ( N = 1754) to identify and interrelate highly reproducible sex differences in regional CV, SA and CT – as well as their alignment with distinct functional networks and histomolecular signatures. Integrating neuroimaging data from clinical cohorts with sex chromosome aneuploidy and isolated gonadotropin-releasing hormone deficiency (N = 313) establishes that regions of sex-biased cortical anatomy are enriched for congruent effects of X-chromosome dosage (e.g., primary sensory and insular cortices) and gonadal hormones (e.g., dorsal parietal regions and angular gyrus). This work refines maps of sex-biased human cortical organization and helps to narrow hypotheses regarding their potential genetic and endocrine causes.
Prior acute ozone injury modulates inflammatory responses to subsequent repetitive ozone exposures in mice
Single-atom substitution redirects KatG reactivity from cofactor biogenesis to stereoselective sulfoxidation
Abstract Protein-derived cofactors rely on precisely positioned heteroatoms to direct redox chemistry, yet isolating their individual contributions remains challenging. The indole N–H of tryptophan plays a central yet elusive role in biogenesis and function of the Met–Tyr–Trp (MYW) cofactor in catalase-peroxidase (KatG). Here, we use genetic code expansion to replace cofactor-forming Trp105 with thiotryptophan (S-Trp), enabling a single-heteroatom (N → S) substitution. Instead of forming the MYW crosslink, KatG bearing S-Trp105 undergoes site-specific monooxygenation to yield a chiral sulfoxide. HPLC-MS, circular dichroism, and FT-IR spectroscopy identify selective oxygen insertion at the sulfur, establishing enantioselective formation of an ( S )-configured sulfoxide. A 2.22 Å cryo-EM structure visualizes the oxidized S-Trp105, revealing the S = O moiety orienting toward the iron and confirming the absence of crosslinking. The S-atom oxygenation is heme-dependent and proceeds via a two-electron oxygen-atom transfer, contrasting with the radical-mediated one-electron chemistry of native tryptophan. This redirection suppresses catalase activity by perturbing cofactor formation. These results show that a single-atom substitution reroutes the distal heme site from radical crosslinking to stereoselective sulfoxidation, uncovering a monooxygenase-like capability within KatG. This work highlights using noncanonical amino acids to achieve atomic-level control over reaction pathways and to interrogate cofactor biogenesis with unprecedented precision.
Integrated metabolomics and antioxidant activity assessment of Sphagneticola trilobata (L.) Pruski
Abstract Sphagneticola trilobata (L.) Pruski (Asteraceae), formerly known as Wedelia trilobata , is a widely distributed ornamental plant utilized in traditional medicine for various ailments. This study aims to provide the first comprehensive comparative analysis of the metabolomic profiles of Sphagneticola trilobata flowerheads and leaves to elucidate the chemical basis for their differential antioxidant capacities. Ultra-high-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry was employed in both positive and negative ionization modes. The resulting datasets were subjected to multivariate chemometric analyses, including Principal Component Analysis and Orthogonal Partial Least Squares Analysis. Antioxidant potential was assessed using in vitro DPPH, FRAP, and ABTS assays. A total of 86 metabolites were tentatively annotated, spanning classes of terpenoids, flavonoids, phenolic acids, lipids, and amino acids. Notably, 18 of these compounds were observed in this plant for the first time. Chemometric analysis revealed distinct metabolic variances: flowerheads were enriched with flavonoids and phenolic acids, whereas leaves were characterized by a predominance of sesquiterpenoids and diterpenoids. Biological assays demonstrated that flowerheads possess significantly higher antioxidant activity compared to leaves. Moreover, correlation analysis identified key biomarkers responsible for this activity, including 3’,4’,7-trihydroxy-flavanone hexoside, luteolin, myricetin hexoside, and 4,5-dicaffeoyl-quinic acid. The study establishes that the superior antioxidant potential of Sphagneticola trilobata flowerheads is driven by their high flavonoid and phenolic acid content, distinguishing them from the terpenoid-rich leaves. These findings validate the utility of metabolomics in identifying bioactive markers and suggest the flowerheads as a promising source of natural antioxidants for pharmaceutical or cosmeceutical applications.
Spatial cellular order underlies locally-confined mechanisms of immune resistance in oropharyngeal cancer
Abstract Oropharyngeal squamous cell carcinomas (OPSCCs) frequently result from oncogenic human papilloma virus (HPV) infections (HPV-OPSCC). The mechanisms underlying effective immune escape, despite abundant viral antigens, are incompletely understood. Here, we performed single-cell spatial gene expression profiling of HPV-OPSCC to characterize cellular organization and mechanisms of immune resistance. We describe distinct tumor-parenchymal immune foci that differ in cytokine expression, spatial location, immune cell infiltration and cancer cell states. Furthermore, immune foci display profound differences related to co-inhibitory receptor signaling and immunosuppressive myeloid cells, suggesting that different tumor-parenchymal regions may be dominated by distinct, locally-confined mechanisms of immunosuppression. Additionally, senescent-like HPV-OPSCC cells lacking HPV transcripts (HPVoff) are evident across the tumor parenchyma and able to evade HPV-specific T cell-mediated immunity in vitro. HPVoff cells are enriched within hypoxic regions and near IFN-γ producing T cells suggesting that both hypoxia and IFN-γ signaling can promote the HPVoff phenotype. In conclusion, our findings highlight a complex cellular interplay underlying heterogeneous cancer cell states, spatial immune cell organization, and diverse mechanisms of immune escape.
Disease-related complications and risk factors in hemoglobin H disease in a Thai multicenter registry
Molecular pharmacodynamics of amoxicillin-clavulanic acid for urinary tract infections caused by Escherichia coli
Abstract Amoxicillin-clavulanic acid (AMX-CLV) is a widely used oral β-lactam/β-lactamase inhibitor combination against Escherichia coli . Clinical success is largely confined to urinary tract infections. The mechanistic basis for this site-specific efficacy remains unclear. Using a hollow-fibre infection model to replicate human plasma and urinary pharmacokinetics, we show that plasma-like exposures rapidly select for pre-existing resistant subpopulations; whereas, urinary exposures produce sustained bactericidal activity without resistance emergence. Genomic and transcriptomic analyses following plasma drug exposure reveal that treatment selectively enriches pre-existing resistant lineages already harbouring oxidative-stress-associated mutations that activate the SOS response and drive IS-mediated amplification of blaTEM-1 , leading to β-lactamase hyperproduction and treatment failure. In contrast, the high urinary concentrations of clavulanic acid exert direct antibacterial activity, eradicating these subpopulations. Our findings demonstrate that local pharmacokinetic environments fundamentally shape evolutionary trajectories under β-lactam/β-lactamase inhibitor therapy, explaining the restricted efficacy of AMX-CLV and revealing a dynamic interplay between stress responses, genome plasticity, and drug partitioning that governs treatment outcome.
The OEGMA-based hydrogel is active against all species of the ESKAPE pathogens, Streptococcus mutans and the pathogenic yeast Candida albicans
Abstract Wound dressings serve as a crucial first barrier against microbial contamination, particularly in severe wounds requiring rapid antimicrobial protection. Building on our previously established hydrogel system based on copolymers of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) and 2-(dimethylamino)ethyl methacrylate (DMAEMA) crosslinked during quaternization with 1,6-dibromohexane, we extend the biological evaluation of this material to a broader spectrum of clinically relevant pathogens. The hydrogel was assessed against the complete multidrug resistant ESKAPE group, the Gram-positive bacterium Streptococcus mutans , and the opportunistic yeast Candida albicans . Pronounced contact-mediated antimicrobial activity was observed against all tested organisms, resulting in a significant reduction of microbial viability. In detail, C. albicans and P. aeruginosa viability was reduced to 30.25% and 25.34%, respectively, whereas all other strains exhibited < 5% residual viability compared to untreated controls. A. baumannii and K. quasipneumoniae retained 4.32% and 2.73% viable cells, while absolute eradication was achieved for E. faecalis VRE , S. aureus and S. mutans . Importantly, the material retained excellent biocompatibility, showing no adverse effects on mammalian skin fibroblasts or human blood cells. The combination of broad-spectrum antimicrobial efficacy, biological compatibility, and a robust yet simple fabrication approach highlights the potential of this hydrogel as a promising candidate for wound dressing applications, including emergency wound care in critical injury settings.