Anna M.

1,24,25-trihydroxyvitamin D3 (1,24,25(OH)3D3), a primary catabolite of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), exhibits biological activity including antitumor effects but has less calcemic activity than 1,25(OH)2D3. In the present work, we investigated the biological and genomic effects of 1,24,25(OH)3D3 in human primary epidermal keratinocytes (HPEKp), which are not only essential for vitamin D3 photoproduction and activation but also serve as a direct target for 1,25(OH)2D3 via its nuclear receptor, the VDR. Although 1,24,25(OH)3D3 is a metabolite of the CYP24A1-catalyzed deactivation pathway, it showed comparable antiproliferative and VDR-nuclear translocation efficiency to 1,25(OH)2D3. Transcriptomic profiling revealed a substantial overlap in differentially expressed genes (DEGs) between both secosteroids, with up to 70% similarity, but also highlighted distinct gene regulation patterns, some specific for 1,24,25(OH)3D3 and others for 1,25(OH)2D3. Functional enrichment analyses confirmed shared modulation of immune signaling, keratinocyte differentiation, and GPCR-related (G protein-coupled receptor) pathways, with unique activation of processes such as gastrulation and cornified envelope formation by 1,24,25(OH)3D3. Moreover, both compounds preserved normal expression patterns of several genes associated with development of head and neck squamous cell carcinoma, confirming their anti-cancer potential. Considering its broad biological activity and the lower calcemic effect of 1,24,25(OH)3D3 compared to 1,25(OH)2D3, it appears to be a potential candidate for further clinical studies. It should be noted that both 1,25(OH)2D3 and 1,24,25(OH)3D3 were used at a supraphysiological concentration of 100 nM to ensure detectable effects in vitro; therefore, our results require further confirmation, including in vivo studies.

Dilute methane (CH4) emissions from dairy barns (<500 ppm) are a challenging agricultural greenhouse-gas source to abate via biofiltration because its poor solubility makes gas–liquid mass transfer a primary limitation in biotrickling filters (BTFs). Here, we evaluated lab-scale BTFs for treating dairy-relevant CH4 concentrations and tested two enhancement strategies: (1) aerosolised nutrient delivery to improve liquid distribution and (2) reduced liquid addition rates to increase gas–liquid mass-transfer efficiency. Liquid-fed BTFs and aerosol-fed BTFs (ABTFs) packed with scoria or glass beads were compared. Aerosolised nutrients reduced the elimination capacity (EC) compared to biotrickling delivery. Switching from liquid to aerosol decreased an initial EC of ~30 g m−3 h−1 by 35% at 2500 ppm CH4, and the original EC was not recoverable. Slower liquid addition consistently improved CH4 removal for both delivery techniques. In a glass bead ABTF at 2500 ppm CH4, the EC increased from 5.5 to 12.4 g m−3 h−1 when the liquid coalescence rate decreased from 0.79 to 0.006 cm h−1. In a scoria ABTF, a 1.5-fold increase in EC was observed as the rate decreased from 2.36 to 0.15 cm h−1. Below a threshold liquid addition rate in the scoria BTF, the EC dropped ~33%, likely due to uneven wetting or high pH conditions. Therefore, optimising liquid delivery can significantly enhance BTF performance for agricultural CH4 mitigation.

Background/Objectives: Personal values shape appraisal of stress and life satisfaction. We examined the relationship between perceived stress and life satisfaction among uniformed personnel in outpatient mental health care, and the role of a personal values hierarchy in this context. Methods: Cross-sectional study of 183 uniformed personnel (34 females, 149 males, age 30–66 years, M = 44.72, SD = 5.84) diagnosed with bodily distress disorder or post-traumatic stress disorder at a mental health clinic. Participants completed standardized questionnaires assessing perceived stress, satisfaction with life, coping styles, and personal values. For the Personal Value List, each value not selected by a participant was coded as 0 to avoid missing data; scores regarding symbols of happiness were not used. Reliability was evaluated via repeated measurement; two parts of a key instrument showed test–retest correlations of approximately 0.78 and 0.76. For assessing statistical significance, the bootstrap method was used (1000 resamples). Analyses were conducted in jamovi 2.3.28 using snowLatent (latent profile analysis) and medmod 1.1.0 (moderation analysis). Results: Perceived stress was negatively associated with satisfaction with life (B = −0.36, 95% CI [−0.48; −0.24], p < 0.001). Latent profile analysis extracted two personal values hierarchy profiles (AIC = 4237; BIC = 4587). Profile membership was not a significant predictor of satisfaction with life (p = 0.595) and did not moderate the relationship between perceived stress and satisfaction with life (p = 0.907). Distraction seeking was significantly higher in profile 1 (p = 0.010). Conclusions: In treated uniformed personnel, higher perceived stress is linked to lower life satisfaction. The personal values hierarchy did not moderate this relationship and was not associated with satisfaction with life; however, the personal values hierarchy was related to coping, specifically distraction seeking.

Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressin...

Background and ObjectivesAlthough diabetes mellitus (DM) is a well-established determinant of dementia risk, most studies have evaluated type 2 DM (T2DM) or any DM. The influence of type 1 DM (T1DM) on dementia risk remains unclear. We evaluated ...

Results of the phase 2 POLAR trial show that biomarker-guided treatment in patients with metastatic pancreatic cancer based on homologous repair deficiency leads to encouraging clinical response rates in immune cell-infiltrated tumors.

Factor XII (FXII) is a central mediator at the intersection of coagulation, fibrinolysis, inflammation, and immunity. It is activated upon contact with negatively charged surfaces, triggering the intrinsic coagulation pathway and driving thrombus formation and stabilization. Beyond clotting, FXII contributes to activation of the kallikrein–kinin system, generation of bradykinin, and modulation of inflammatory and immune responses. Congenital FXII deficiency does not increase bleeding risk, highlighting its unique role and making FXII inhibition an attractive strategy for anticoagulation and immune modulation with a potentially superior safety profile. Preclinical studies provide compelling evidence for this concept. In models of ischemic stroke and traumatic brain injury, FXII blockade significantly reduced infarct volume, improved neurological outcomes, and attenuated neuroinflammation without increasing hemorrhage. Similarly, in extracorporeal circulation and vascular stent implantation, FXII inhibition prevented thrombus formation and reduced fibrin deposition, achieving effects comparable to heparin but with markedly lower bleeding risk. Several classes of FXII inhibitors are currently in development, including antisense oligonucleotides, peptides, recombinant proteins, and monoclonal antibodies. Among them, Ixodes ricinus contact phase inhibitor (Ir-CPI) and recombinant human albumin-fused Infestin-4 (rHA-Infestin-4) have demonstrated strong antithrombotic efficacy in animal models. Most notably, garadacimab, a monoclonal anti-FXIIa antibody, has completed phase 3 trials and received regulatory approval for hereditary angioedema (HAE) prophylaxis, where it markedly reduces attack frequency with a favorable safety profile. This review summarizes current knowledge on FXII biology and evaluates its translational potential as a novel target for anticoagulant and anti-inflammatory therapies.

Synovial sarcoma (SyS) is a common type of soft tissue sarcoma, characterized by slow growth, high rates of metastasis, and diverse clinical symptoms. This malignancy is defined by the presence of the SS18-SSX fusion protein and the corresponding SS18-SSX program that promotes the core oncogenic pathways and a wide spectrum of tumor cell phenotypes. In this study, we used single-cell RNA sequencing to explore SyS diversity, highlighting four molecular subtypes. The mesenchymal NKD2+ SyS is characterized by the increased BMP signaling in tumor cells and the most severe immune escape and chemoresistance profile. The poorly differentiated HOXD11+ SyS displays the highest expression of the core oncogenic program and the likely suppression of the immune response through CXCL and MIF signaling. The fibroblast-like DCN+ SyS demonstrates high levels of mesenchymal differentiation, a surprising drop in the SS18-SSX program expression, and the angiogenesis-oriented cell-cell interactions. The biphasic EPCAM+ SyS has the highest levels of differentiation and lowest levels of the core oncogenic program. Our data complements the traditional classification of SyS and suggests that the monophasic mesenchymal SyS might consist of two molecular subtypes.