A total of 320 nursery pigs (DNA 241 × 600; initially 5.4 ± 0.52 kg) were used to evaluate the effect of dietary S-abscisic acid (S-ABA) supplementation on the growth performance and antioxidant status of pigs. Pigs were weaned at approximately 18 d of age and assigned to pens in generalized randomized block design with sex and weight category as blocking factors. Pigs were fed a common phase 1 diet for 7 d postweaning. On d 7 post-weaning, pen of pigs (6.4 ± 0.57 kg) within sex × weight blocks were randomly allotted to 1 of 4 dietary treatments. Treatments included a conventional nursery diet (Control) and 3 diets which used the Control formulation with increasing S-ABA (0.5, 1.0 and 5.0 mg/kg). Treatments were provided during phases 2 (d 0 to 14) and 3 (d 14 to 35). Growth performance was measured weekly. Additionally, 32 pigs on d 0 and 2 pigs per pen on d 14 and 35 were bled to assess the erythrocytes' total glutathione (GSH + GSSG), reduced glutathione (GSH), oxidized to reduced glutathione ratio (GSSG:GSH), and serum total antioxidant capacity (TAC), superoxide dismutase (SOD), and thiobarbituric acid reactive substances (TBARS). At the termination of the trial, 2 pigs in each pen were euthanized and duodenal, jejunal, and ileal mucosa were collected to measure GSH + GSSG, GSH and GSSG:GSH. No interactive effects between S-ABA and sex on growth performance were observed. Additionally, increasing S-ABA did not influence growth performance. There were also no interactions between S-ABA and collection day on antioxidant parameters. Erythrocyte GSH + GSSG tended to increase (linear, P = 0.056) with increasing S-ABA in the diet on d 14, while GSH tended to increase (linear, P = 0.096) at d 14 and increased up to 1 mg/kg S-ABA (quadratic, P = 0.100) on d 35 with little increase thereafter. The d 35 GSSG:GSH ratio decreased (quadratic, P = 0.022) with increasing S-ABA in the diet. Serum TAC, SOD and TBARS were not influenced by S-ABA in the diet. Similarly, dietary S-ABA had no effect on GSH + GSSG, GSH and GSSG:GSH in the intestinal mucosa. In conclusion, supplementation of S-ABA in the diet reduced the erythrocyte GSSG:GSH ratio without negative effects on growth performance.
Graphene can support spin transport over long distances, yet achieving large electrical spin signals remains challenging because spin injection and detection are highly sensitive to disorder at tunnel-barrier interfaces. Here we demonstrate that suppressing such interfacial disorder enables high-fidelity spin injection and detection in graphene. We fabricate van der Waals graphene spin valves by exfoliating and assembling constituent two-dimensional crystals inside an inert glovebox, combined with contamination-suppressing lamination and thorough post-transfer cleaning to realize atomically flat hexagonal boron nitride tunnel barriers. Our four-terminal nonlocal devices exhibit exceptionally large spin polarizations approaching 90 percent and nonlocal spin signals up to 1.6 kΩ. The high tunnel-barrier quality enables robust spin detection down to nanoampere excitation currents and gate-tunable magnetoresistance exceeding 80 percent. Spin precession measurements reveal Elliott-Yafet-type relaxation with nearly isotropic spin dynamics. These results establish interface-controlled van der Waals fabrication as an effective route to high-signal spin transport in graphene.
Vascular bypasses that connect branches of the superficial temporal artery (STA) to cerebral arteries are a recognised treatment option for carefully selected cases involving various cerebral vascular conditions. Among the different microsurgical techniques, one common method is the direct STA-middle cerebral artery (MCA) bypass. This study aimed to evaluate blood flow parameters in the STA and its branches in healthy volunteers. The study involved ultrasound measurements on a group of 157 adult volunteers without vascular disease. The male-to-female ratio was 1.01. Additionally, cardiovascular risk factors within the population were assessed. Blood flow parameters-peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MnV), and minute flow-were obtained. Statistical analysis of the acquired values was performed, and the relation charts have been created. The STA diameters ranged from 0.7 to 2.3 mm, with minute flow rates from 3 to over 100 mL/min. The sex ratio for each vessel size was approximately 1.15, favoring males (P value <0.001). Significantly higher flow values in right STA were observed in men (P value =0.01). Gender differences for left STA were borderline statistically significant (P value =0.051). Neither vessel diameter nor flow rate was influenced by age or cerebrovascular risk factors. No significant difference was observed between sides of the head, though individual cases showed notable left-right asymmetries. Both artery size and blood flow volume increased gradually with higher body weight and overall growth in both female and male groups. There was no strong correlation between the diameters and flow rates of the terminal branches and the trunk of the temporal artery (R value <0.57). Assessing the vessel intended as a graft donor directly is essential in all revascularisation procedures. Comparing patient-specific features to population references can aid in forecasting the success of bypass blood flow. Ultrasound measurement might provide a good compromise between precision and ease of access.
Postmenopausal osteoporosis (PMOP) elevates fracture risk. Zoledronic acid effectively reduces fractures, but individual bone mineral density (BMD) responses vary. Systematic evidence on independent site-specific predictors of BMD changes across femoral neck, total hip, and lumbar spine remains scarce. This study aimed to identify independent factors associated with 12-month BMD changes at the femoral neck (ΔFNBMD), total hip (ΔTHBMD), and lumbar spine (ΔLSBMD) in PMOP patients (T-score ≤ - 2.5) following initial zoledronic acid treatment. A single-center retrospective cohort of 145 PMOP patients (BMD T-score ≤-2.5) was analyzed. Baseline BMD, bone turnover markers (β-cross-linked C-terminal telopeptide of type I collagen [β-CTX-I], N-terminal propeptide of type I procollagen [PINP]), blood biochemistry, and body mass index (BMI) were assessed. BMD was reassessed at the 12-month follow-up. Multiple regression and logistic models identified predictors of ΔFNBMD, ΔTHBMD, and ΔLSBMD. Receiver operating characteristic (ROC) analysis evaluated predictive performance. ΔFNBMD correlated independently with baseline β-CTX-I (β = 0.031, P = 0.017). ΔTHBMD was associated with β-CTX-I (β = 0.036, P < 0.001) and BMI (β = 0.001, P = 0.027). ΔLSBMD linked to PINP (β = 0.000, P = 0.009), serum iron (β = 0.003, P = 0.023), and chloride (β=-0.005, P = 0.023). Logistic regression showed higher baseline PINP increased the odds of effective FNBMD improvement (odds ratio [OR] = 1.042 per 1 ng/mL increase, 95% confidence interval [CI]: 1.018-1.067, P < 0.001), while β-CTX-I (OR = 1.003, P = 0.008) and BMI (OR = 1.156, P = 0.023) influenced THBMD response. ROC analysis confirmed PINP as a robust predictor for FNBMD efficacy (area under the curve [AUC] = 0.724, P < 0.001), and β-CTX-I (AUC = 0.669, P = 0.004) and BMI (AUC = 0.637, P = 0.021) as clinically actionable predictors for THBMD efficacy. Zoledronic acid-induced BMD changes in PMOP exhibit site-specific associations with distinct biomarkers and clinical parameters. These findings provide preliminary evidence for tailoring treatment based on baseline metabolic and anthropometric profiles, though larger prospective studies are required to validate these markers for clinical application.
Pulmonary arterial hypertension (PAH) and congenital heart disease (CHD), particularly in pretricuspid shunts or Eisenmenger syndrome, are associated with significant mortality and limited therapeutic options. A 35-year-old woman presented with hypoxemia and right heart strain at 12 weeks' gestation. Echocardiography and right heart catheterization revealed severe PAH and a large secundum atrial septal defect (ASD). Following pregnancy termination and gradual initiation of triple pulmonary vasodilator therapy, her PAH improved significantly over 8 years. She underwent fenestrated ASD closure with significant improvement in functional status. This case illustrates a "treat-and-repair" strategy in PAH in CHD (PAH-CHD) and highlights how medical therapy can convert a previously inoperable patient into a procedural candidate. Combined pulmonary vasodilator therapy can improve PAH and make ASD closure in PAH-CHD feasible. A "treat-and-repair" strategy requires multidisciplinary care.
Kidney transplant recipients present reduced physical function and a high prevalence of cardiometabolic complications, which increase cardiovascular risk and compromise long-term graft outcomes. Resistance training has demonstrated beneficial effects in this population; however, previous interventions have shown heterogeneity in load prescription and have not incorporated objective monitoring of movement velocity. Velocity-based resistance training (VBT) allows precise regulation of exercise intensity and fatigue, potentially improving the safety and individualization of exercise prescription in clinical populations. This study aims to evaluate the effects of a 12-week VBT program on renal function and metabolic health in kidney transplant recipients and to compare 2 different load-control strategies based on movement velocity. This pilot randomized controlled trial will include adult kidney transplant recipients with stable graft function. Participants will be randomly assigned (1:1) to either a maximal velocity group, in which sets will be terminated at a 20% velocity loss threshold, or a constant submaximal velocity group, in which participants will perform repetitions at 50% of the participant's individual maximal velocity. Both groups will complete 3 supervised training sessions per week for 12 weeks with real-time velocity monitoring. Primary outcomes will include renal and metabolic health domains assessed through venous blood analysis. Serum creatinine will be the prespecified hierarchical primary renal end point, and high-density lipoprotein cholesterol will be the prespecified hierarchical primary metabolic end point. Estimated glomerular filtration rate will be calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Secondary outcomes will include blood pressure, body composition, muscular strength, metabolic syndrome criteria, and the force-velocity profile. Data will be analyzed using analysis of covariance and linear mixed-effects models following a predefined hierarchical inferential strategy. The study was initiated in September 2025. Participant recruitment and the intervention phase have been completed. All 14 participants completed the 12-week training program, and no participants were lost to follow-up. Preintervention and postintervention data collection has been completed according to the study protocol. The study database has been cleaned and locked, and statistical analyses are currently underway. Publication of the primary study results is anticipated in late 2026. This study introduces the implementation of VBT in kidney transplant recipients. The findings are expected to provide evidence on the feasibility and potential benefits of this approach and may support the integration of exercise professionals into multidisciplinary transplant care teams. ClinicalTrials.gov NCT07370727; https://clinicaltrials.gov/study/NCT07370727. DERR1-10.2196/94010.
Metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptor involved in synaptic transmission and neurological disorders. Group I mGlu receptors (mGlu1 and mGlu5) predominantly couple to Gq/11, whereas group II and III receptors primarily engage Gi/o. Although Gi/o-coupling mechanisms have been defined for several group II/III receptors, how group I receptors preferentially engage Gq/11 remains unclear. Here we report cryo-electron microscopy structures of active mGlu-G protein complexes (mGlu1-Gq, mGlu1-Gi, mGlu5-Gq, and mGlu5-Gi) bound to l-glutamate and positive allosteric modulators (PAMs), together with two additional activated-state structures of mGlu1. Comparative structural and biochemical analyses identify a group I-specific ICL2 insertion that promotes preferential Gq engagement. Each receptor dimer asymmetrically binds one G protein heterotrimer via an intracellular pocket engaging the Gα amino-terminal helix. PAM binding to one 7TM domain induces W6.50 rotation and TM6 outward movement, bringing the two 7TMs into closer. These findings provide a structural basis for preferential Gq/11 engagement and activation of group I mGlu receptors.
The mitochondrial control region (CR) is the largest non-coding region in the vertebrate mitogenome and contains essential elements for replication and transcription. Despite its functional relevance, its evolutionary dynamics remain poorly understood. Here, we analyzed 5,235 complete vertebrate CRs spanning 11 classes to investigate how conserved sequences blocks (CSBs) and Extended Termination-Associated sequences (ETAS) shaped CR evolution. We hypothesized that CR length is positively associated with repeat accumulation, with tetrapods exhibiting longer and more complex CRs than fishes, while core elements remain conserved. Our analyses revealed marked inter- and intra-class variability, with longer CRs in tetrapods (1,283.27 ± 489.6 bp) than in fishes (969.25 ± 239.5 bp). Duplication events were restricted to tetrapods, especially birds and reptiles. Nucleotide composition was heterogeneous among orders, and structural divergence of CSBs was inferred across lineages. Repetitive elements were present in ~43% of CRs, with their abundance strongly correlated with CR length. Importantly, longer CRs were associated with higher GC content and greater variation in copy number of ETAS and CSBs. These results demonstrate that mitogenome CR expansion in vertebrates is largely driven by repeat proliferation, whereas key motifs required for replication and transcription are retained. We further identify lineage-specific trends, including pronounced CR elongation in amphibians and reptiles, contrasted with progressive reduction and simplification in birds and mammals. Our study provides the first comprehensive comparative framework of vertebrate CR evolution, highlighting how repetitive elements, conserved motifs, and nucleotide composition jointly contribute to both functional regulation and lineage-specific diversification.
Recent data on 161Tb-labeled radiopharmaceuticals indicate a benefit in treatment efficacy due to the emission of high-energy Auger and conversion electrons in addition to β particles. We aimed to investigate differences in therapeutic potential of the gastrin-releasing peptide receptor (GRPR) antagonists RM2 (DOTA-Pip5-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) and AMTG (DOTA-Pip5-D-Phe6-Gln7-α-Me-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) radiolabeled with 161Tb and 177Lu in PC-3 tumor-bearing mice. We hypothesized that the superior in vivo stability of AMTG in combination with 161Tb would result in improved tumor control and overall survival as compared to RM2 and 177Lu counterparts. Treatment studies in PC-3 tumor-bearing Nu/J mice were initiated once tumor volume was ~ 100 mm3. 161Tb- and 177Lu-Labeling was completed at 90 °C within 10 min (1.0 M sodium acetate buffer, pH = 5.5, molar activity of ~ 50 MBq/nmol). Radiolabeled GRPR ligands were administered in treatment (PC-3 tumor-bearing, n = 6-7 per group) and toxicity (healthy animals, n = 3 per group) animals on day 0 and day 7 of the experiment (~ 15 MBq each). Treatment animals were sacrificed once tumor volume surpassed 1,500 mm3. Toxicity animals were sacrificed 45 d after injection and analyzed for complete blood count and metabolic panel. Animals were assigned to five groups (control, [177Lu]Lu-RM2, [177Lu]Lu-AMTG, [161Tb]Tb-RM2, [161Tb]Tb-AMTG). Each treatment group received a total activity amount of 26-31 MBq of the respective radiolabeled compound. All treatments resulted in improved tumor control and overall survival related to vehicle animals. [161Tb]Tb-AMTG had the longest median overall survival of 58.1 ± 5.4 d after initiation of treatment. No signs of long-term toxicity were observed during this study in any treatment group. The combination of Auger electrons with high in vivo stability of [161Tb]Tb-AMTG resulted in substantially improved tumor control and overall survival in PC-3 tumor-bearing mice, thus expanding the therapeutic potential of GRPR antagonists in GRPR-expressing malignancies.
Aptamers are single-stranded DNA or RNA molecules that specifically bind to a wide range of target molecules with high affinity, making them powerful tools for synthetic biology. Traditional aptamer selection via Systematic Evolution of Ligands by Exponential Enrichment (SELEX) is labor-intensive and prone to nonspecific binding. To address these issues, we developed the Bead-based One-Step aptamer Selection (BOSS) method. As proof of concept, we used this method to target Arabidopsis thaliana CONSTITUTIVE PHOTOMORPHOGENIC 1 (AtCOP1), a conserved E3 ubiquitin ligase central to photomorphogenesis. We expressed the N-terminal RING (Really Interesting New Gene) domain of AtCOP1, immobilized it on Ni-NTA beads, and incubated the beads with a random ssDNA library. After washing the beads with washing buffer and replacing the buffer five times, followed by high-throughput sequencing, we identified the high-affinity aptamer Lib1-9, with a Kd of 11.14 nM for AtCOP1-RING. Lib1-9 demonstrated species specificity, showing strong binding to AtCOP1, but not to other COP1 homologs. Truncation analysis revealed that the core variable region (△LR) of Lib1-9 retained near-full binding affinity (Kd = 1.679 nM) to AtCOP1, which is comparable to the values observed for thrombin-binding aptamers. When we delivered Cy5-labeled aptamers into the hypocotyl cells of transgenic YFP-NLS-AtCOP1/cop1-4 A. thaliana plants, both Cy5-Lib1-9 and Cy5-Lib2-11 colocalized with YFP-COP1. The BOSS method is an efficient platform for plant aptamer development, enabling the rapid generation of tools for synthetic biology applications such as COP1 biosensing and optogenetic control.
Heart failure is often a chronic, life-limiting illness associated with high symptom burden, frequent hospitalizations, and substantial suffering near the end of life. Although palliative care improves quality of life and is strongly recommended by clinical practice guidelines, fewer than 20% of people with heart failure receive it. We developed the Promoting Palliative Care for People with Heart Failure (P3HF) Clinical Decision Support (CDS) tool-an evidence-based, end-user informed tool integrating a validated prognostic-risk model, tiered functionality, and behavioral nudges in the electronic health record (EHR). This manuscript describes the development of the P3HF CDS and protocol for a clinical trial evaluating its effects. We will conduct a pragmatic randomized clinical trial at two large urban hospitals, within a single health system, using an embedded, convergent mixed-methods design to evaluate the P3HF CDS. Eligible patients are adults (≥ 18 years) hospitalized with heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥ 500 pg/mL, and receipt of intravenous diuretics within 24 h of admission. We will analyze data from the EHR and surveys and interviews with end-users (attending physicians, residents, fellows, advanced practice providers) of the CDS tool and palliative care clinicians to assess CDS usability, acceptability, appropriateness, feasibility (implementation outcomes), and efficacy in increasing inpatient palliative care (Primary clinical outcome) consultations. Secondary exploratory outcomes include increasing palliative care outpatient referrals, improved advance care planning documentation, higher hospice enrollment, and reductions in hospital length of stay and 30-day readmissions compared to usual care. The P3HF CDS is an evidence-based, theory and end-user informed tool designed to promote timely palliative care for people with heart failure. The P3HF trial will examine the acceptability and effects of the CDS in real-world clinical settings. NCT06933875 (https://clinicaltrials.gov/study/NCT06933875, Registration date: 2025-04-18).
Methyl-coenzyme M reductase (MCR) is the primary source of biogenic methane on Earth. In the active site of MCR, a nickel (Ni)-containing porphyrin (F430) must be in the Ni1+ oxidation state to initiate catalysis. The reductive activation of MCR, i.e., the reduction of F430 to its Ni1+ state, is an ATP-dependent process, but the underlying ATPase and its precise role remain unknown. Component A2 is an ATP-binding protein that associates with MCR but was reported to lack ATPase activity. Hence, it was proposed to function solely as an ATP-carrier protein. However, recent structural insights into the MCR activation complex suggest that component A2 may hydrolyze ATP to drive conformational changes required for enzyme activation. Here, we provide direct biochemical evidence that component A2 is a bona fide ATPase that hydrolyzes ATP under strictly anaerobic conditions and only upon interaction with MCR. Mutational analyses reveal that component A2 must be bound to ATP prior to association with MCR and that residues involved in ATP hydrolysis do not impact protein-protein interaction. The two nucleotide-binding domains of A2 act cooperatively but display asymmetric contributions to ATP hydrolysis and MCR engagement. In addition, a distinctive N-terminal zinc-binding motif (ZBM) is required for maximal ATPase activity but is dispensable for MCR binding. Phylogenetic analyses reveal that this ZBM distinguishes component A2 from related ATP-binding casette (ABC)-type ATPases. Together, these findings identify component A2 as a distinct class of remodeling ATPases that powers conformational changes underlying the reductive activation of MCR.
The calcium-sensing receptor (CaSR), a G protein-coupled receptor (GPCR), plays a critical role in kidney injury by promoting inflammation and apoptosis when activated. Whether Wulingsan (WLS), a traditional Chinese herbal formula used for kidney disorders, exerts its protective effects against acute kidney injury (AKI) via modulation of the CaSR pathway remains unclear. WLS's chemical profile was characterized by ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrometry (UHPLC-QE-MS). C57BL/6J mice were divided into Control, cisplatin (CP)-induced AKI, WLS (2.34/4.68/9.36 g/kg), and CaSR inhibitor NPS2143 (4.5 mg/kg) groups. Mice were pretreated with WLS/NPS2143 before CP injection (20 mg/kg, i. p.). Renal function, histopathology, inflammation, oxidative stress, and apoptosis were evaluated. Cisplatin-induced mouse renal tubular epithelial cells (mRTECs) were treated with WLS-containing serum (5%-10%) for in vitro validation. Molecular docking predicted the binding affinity of WLS components to CaSR. UHPLC-QE-MS identified 15 major WLS components, with 13 binding to CaSR (Polyporusterone E: binding energy of -10.4 kcal/mol). WLS pretreatment significantly improved renal function (reduced serum creatinine (SCr)/blood urea nitrogen (BUN)), attenuated tubular injury, suppressed inflammation (downregulated monocyte chemoattractant protein-1 (MCP-1)/tumor necrosis factor-α (TNF-α)/interleukin-1β (IL-1β)), alleviated oxidative stress (restored glutathione (GSH)/superoxide dismutase (SOD), reduced malondialdehyde (MDA)), and inhibited apoptosis (decreased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, modulated Bcl-2-associated X protein (Bax)/B-cell lymphoma-2 (Bcl-2) ratio, downregulated cleaved Caspase 3). Mechanistically, WLS inhibited renal CaSR/calmodulin-dependent protein kinase β (CaMKKβ)/adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway activation (reduced CaSR/CaMKKβ/p-AMPK expression). In vitro, WLS-containing serum reduced cisplatin-induced reactive oxygen species (ROS) production, intracellular Ca2+ overload, and apoptosis in mRTECs, effects reversed by the CaSR agonist cinacalcet. This study demonstrates that WLS protects against CP-induced kidney injury and inhibits apoptosis in renal tubular epithelial cells in association with the CaSR/CaMKKβ/AMPK pathway.
The recovery of voluntary movement after complete spinal cord injury (SCI) remains a formidable clinical challenge, as it necessitates both the reconstruction of disrupted spinal cord neural pathways and the restoration of the excitatory/inhibitory balance in sensorimotor neural circuits. To tackle this dual challenge, we transplanted a biomimetic spinal cord tissueoid (SCToid) into the injury cavity to structurally reestablish neural pathways, while concurrently applying tail nerve electrical stimulation (TNES) to functionally reactivate silent sensorimotor neural circuits. The results showed that combined SCToid transplantation and TNES promoted the regeneration of corticospinal tract and sensory afferent axons, which formed functional synapses with SCToid neurons. Moreover, monosynaptic tracer assays revealed direct innervation of lumbar spinal cord central pattern generator (CPG) interneurons by SCToid neurons; some CPG interneurons and sensory afferent axons also exhibited synaptic connectivity with motor neurons. Compared with the control group, transplantation of SCToids combined with TNES increased the ratio of excitatory/inhibitory synaptic terminals on the soma surfaces of CPG interneurons and motor neurons toward the pattern observed in normal spinal cords. This change ultimately enhanced the excitability of sensorimotor neural circuits and restored weight-bearing hindlimb walking. Collectively, these findings establish that reconstructing neural pathways and restoring the excitatory/inhibitory balance within CPG-regulated sensorimotor neural circuits are both necessary and sufficient to enable voluntary movement recovery. This synergistic mechanism establishes a robust theoretical framework for integrating biological and physical therapeutic strategies in SCI treatment, with specific implications for the combined application of transplantable engineered organoids and neurostimulation-based rehabilitation approaches.
Methyltransferase-like 13 (METTL13) is a member of the methyltransferase-like (METTL) family characterized by two conserved seven-beta-strand(7BS) catalytic domains. Current evidence identifies METTL13 primarily as a dual protein methyltransferase that modifies the translation elongation factor 1 A(eEF1A), including Lys55 dimethylation and N-terminal methylation. Through this best-established mechanism, METTL13 enhances eEF1A GTPase activity, reshapes translation elongation and codon-specific translational output, and promotes protein production in cells. In multiple cancer settings, METTL13 and the eEF1A-K55 methylation axis are associated with increased translational demand, tumor progression, and Ras-driven tumorigenesis. At the same time, accumulating studies indicate that METTL13 functions are strongly context dependent. Beyond its canonical eEF1A-centered role, METTL13 has been linked to additional regulatory programs, including the c-Cbl/SERCA2a axis, RNA-associated pathways, and disease-specific signaling networks, although these noncanonical mechanisms remain less well defined. Intriguingly, METTL13 may also exert protective or tumor-suppressive effects in selected contexts, such as ischemic heart failure, hereditary deafness, and clear cell renal cell carcinoma. In this narrative review, we summarize the structural and functional features of METTL13, its regulatory network, and current evidence for its roles in malignant and non-malignant diseases. By integrating structural features, molecular modification mechanisms, translational control, disease pathophysiology, and early clinical-translation evidence, this review reframes METTL13 as a context-dependent regulator of proteome adaptation and highlights unresolved mechanistic questions regarding substrate specificity, microenvironment-dependent functional outputs, and context-specific intervention strategies.
Physical, cognitive, and psychological conditions are associated with an increased risk of mortality, yet few studies have characterized terminal declines in these functional domains preceding death. In this multicohort study, we examined both separate and joint trajectories of physical, cognitive, and psychological functioning during the final decade of life and assessed the role of socioeconomic status (SES). We used data from three national cohort studies: the US Health and Retirement Study, the China Health and Retirement Longitudinal Study, and the Survey of Health, Ageing and Retirement in Europe. Physical, cognitive, and psychological functioning were assessed repeatedly using measures of activities of daily living, cognitive test performance, and depressive symptoms, respectively. Mortality information was obtained from proxy respondents or national death registries. Statistical analyses included linear mixed-effects models and group-based multi-trajectory models using a backward timescale. Among 79,305 participants (mean age 65.8 ± 10.3 years; 55.4% female), 12,135 (15.3%) died during the 10-year follow-up. Compared with survivors, decedents showed steeper and accelerated declines in physical (βdeath * time -0.354, 95% confidence interval [95% CI] -0.372 to -0.336) and cognitive (βdeath * time -0.077, 95% CI -0.092 to -0.063) functioning, and to a lesser extent in psychological functioning (βdeath * time -0.044, 95% CI -0.061 to -0.028). In joint trajectory analyses, decedents experienced varying degrees of decline in at least one functional domain, and rapid terminal decline in physical functioning was accompanied by low and worsening cognitive and psychological functioning. In addition, higher SES was associated with lower odds of membership in adverse co-decline patterns, particularly the trajectory characterized by rapidly declining physical functioning combined with low and worsening cognitive and psychological functioning (e.g., OR high SES 0.07, 95% CI 0.02 to 0.20). During the final decade of life, functional loss in physical and cognitive domains was more common than decline in psychological functioning. Higher SES was less likely to be associated with more unfavorable multidomain co-decline patterns.
The initiation and resolution of acute inflammatory responses rely on highly orchestrated biochemical and cellular programs, in which a finely tuned repertoire of mediators regulates the dynamics, migration, and effector functions of immune cells in space and time. Persistent, incompletely resolved inflammatory reactions disrupt this delicate homeostatic equilibrium and foster the development of severe acute and chronic diseases. Central mediators that terminate inflammatory responses and actively transition them into resolution are therefore of paramount importance. These include not only specialized pro-resolving lipid mediators but also peptide and protein mediators, cytokines with context-dependent pro-resolving function, stromal and neuronal signals, as well as cell-intrinsic resolution mechanisms such as efferocytosis, metabolic reprogramming, and tissue-repair programs. Innate and adaptive immune cells integrate these signals and, as major sources and effectors of pro-resolving mediators, drive clearance of harmful stimuli and dying cells and foster tissue repair. Within this broader network of pro-resolving pathways, neuronal guidance proteins (NGPs) are increasingly recognized as critical regulators of immune cell positioning and function that act far beyond their classical roles in axon guidance and are now regarded as integral components of the active inflammation-resolution program. This chapter interrogates the fundamental biology of selected NGPs-including Netrin-1, repulsive guidance molecule A (RGM-A), Semaphorin 7A (Sema7A), Neogenin (Neo1), and Plexin C1 (PLXC1)-and delineates their dual roles within inflammatory and resolution programs, with particular emphasis on how these cues sculpt leukocyte trafficking, promote cellular clearance, and drive immune cell reprogramming along the temporal axis from the early phase of acute inflammation to the restoration of tissue homeostasis.
Treatment optimization through pharmacokinetic evaluation is needed to improve outcomes in tuberculous meningitis (TBM). Clinical assessment of drug penetration into the central nervous system (CNS) is limited to cerebrospinal fluid (CSF) sampling, which may not reflect drug exposures at the site-of-disease. We characterized the pharmacokinetics of antituberculosis drugs in CNS tissues using a rabbit model of TBM. Rabbits infected with Mycobacterium tuberculosis received human-equivalent doses of antituberculosis drugs after displaying signs of TBM. Blood was intensively sampled on day 1 and until euthanasia on day 3 when terminal plasma, CSF, and CNS tissues were collected. Total drug concentrations were quantified by LC-MS/MS and analyzed in NONMEM to estimate equilibration half-lives and CSF- and CNS tissue-to-plasma ratios. Across 5 experiments, 48 rabbits provided 600 plasma samples and 48 sets of terminal CSF/CNS tissue samples. Pyrazinamide and isoniazid showed high and consistent penetration, with CSF ratios of 0.98 and 0.85 and CNS tissue ratios ranging from 0.44 to 0.73 and 0.60-0.82, respectively. Linezolid demonstrated modest and uniform penetration (CSF ratio 0.39; CNS tissue ratios 0.15-0.44). Rifampicin showed the lowest overall penetration (CSF ratio 0.08; CNS tissue ratios 0.07-0.32). In contrast, the most lipophilic drugs, bedaquiline and rifabutin, showed low CSF ratios (0.01 and 0.42, respectively) compared with much higher CNS tissue ratios (1.11-6.34 and 1.23-6.78, respectively). CSF penetration in the rabbit TBM model closely mirrored reported human data, establishing its translational value. High relative CNS exposures of bedaquiline and rifabutin support their clinical evaluation for TBM treatment.
Obstructive sleep apnea (OSA) is a prevalent yet underdiagnosed risk factor in atrial fibrillation (AF) patients and may influence AF burden. Systematic OSA screening and long-term non-invasive heart rhythm monitoring to follow up on AF remain challenging in clinical practice. This study aimed to validate the NOX-T3s polygraphy (PG) device for OSA screening, and to evaluate the feasibility of a structured OSA screening pathway combined with semi-continuous heart rhythm monitoring for mapping AF recurrences and burden. In the NOX-T3s validation study, NOX-T3s performance was evaluated in 30 AF patients undergoing PSG, with simultaneous and consecutive home NOX-T3s recordings. In the NOXFib-AF pilot study, the NOX-T3s was used for ambulatory OSA screening in another 30 AF patients, followed by 31 days of semi-continuous rhythm monitoring (every 9 min) via a smartwatch linked to the FibriCheck algorithm and twice-daily spot-checks via the FibriCheck smartphone application. Presence of AF was indicated as ≥1 AF measurement, with episodes defined as consecutive AF measurements terminated by a sinus rhythm measurement. Patients who screened OSA-positive were referred for PSG. Patient comfort with the devices was assessed via questionnaires. NOX-T3s demonstrated good diagnostic performance for detecting moderate-to-severe OSA (AUC 0.83 simultaneous; 0.80 home), with Apnea-Hypopnea Index (AHI) values comparable to PSG (simultaneous recording Δ0.5 (IQR:-4.2-3.3); p = 0.942; separate-night recordings Δ1.5 (IQR:-3.7-7.4); p = 0.306). An optimized AHI cut-off of 11.1 events/h improved NOX-T3s accuracy (0.85), with high sensitivity (92.9%) and specificity (75.0%). OSA screening was successful in the NOXFib-AF study in 97.1% of patients, identifying moderate-to-severe OSA in 79.3%. 91.3% underwent PSG, confirming OSA in 61.9%. Semi-continuous smartwatch-based rhythm monitoring was successful in 96.6%, 61.0% ± 11.5 was high-quality data, and there was high compliance and motivation. AF was detected in 64.3%, and the smartwatch detected 6.7 times more AF episodes compared to spot-check alone. Comfort was high for both NOX-T3s (32 out of 40 (IQR: 29-35) and rhythm monitoring [34 out of 40 (IQR: 29-37)]. NOX-T3s with an AHI cut-off ≥11.1 events/h is a reliable home screening tool for moderate-to-severe OSA. NOX-T3s-based OSA screening combined with semi-continuous FibriCheck-based rhythm monitoring has proven feasible and acceptable in AF patients.
Keloids are aggressive fibroproliferative disorders characterized by a sclerotic core and an actively invading margin, yet the cellular and molecular basis of this spatial heterogeneity remains poorly understood. The roles of immune-stromal crosstalk in driving peripheral invasion have not been systematically dissected. Paired infiltrating and hypercellular zones were collected from anterior chest keloids of four patients. Single-cell RNA sequencing was performed on 128,678 cells after rigorous quality control. Unbiased clustering, differential gene expression analysis, pseudotime trajectory reconstruction, and cell-cell interaction profiling were applied to compare the landscapes of cell composition, function, and differentiation/development trajectories between the two zones. The hypercellular zone was dominated by extracellular matrix-producing myofibroblasts, whereas the infiltrating zone was enriched in mononuclear phagocytes and endothelial cells, exhibiting a loose collagen architecture permissive for cellular invasion. Infiltrating zone fibroblasts adopted an immunomodulatory, inflammatory cancer-associated fibroblast-like phenotype, while macrophages displayed a type I interferon signature and immunoglobulin-mediated activation, indicating a chronic inflammatory state with features reminiscent of certain autoimmune conditions. Langerhans cells followed a three-stage developmental trajectory from a stress-responsive to a terminal NF-κB-driven effector state, orchestrating neutrophil and Th17 cell recruitment via chemokine and cytokine networks, with significant enrichment of the IL-17 signaling pathway. Endothelial cells at the margin underwent endothelial-to-mesenchymal transition, and Schwann cells exhibited phenotypic plasticity, mirroring aggressive tissue remodeling. In the context of this spatially resolved analysis, this study redefines the keloid margin as an immunology-dominated niche characterized by profound cellular and spatial heterogeneity that is associated with features that could drive peripheral invasion. These findings suggest a shift of the paradigm of keloid pathogenesis from a fibroblast-centric model to an immune-driven integrated landscape in this cohort and provide a theoretical foundation for keloid precision therapies and zone-specific biomarkers for treatment response and disease monitoring.