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Real-World Efficacy of IL-23 Inhibitors in Psoriasis Affecting High-Impact Areas: Indirect Comparison of Tildrakizumab 200 mg, Risankizumab, and Guselkumab—IL PSO (Italian Landscape Psoriasis)
No full textIntroductionPsoriasis involving special or high-impact areas (scalp, nails, palms/soles, genitalia) is associated with a disproportionate functional and psychological burden that is often underestimated by conventional severity scores and remains challenging to treat effectively. This study compared the real-world efficacy and safety of three interleukin (IL)-23p19 inhibitors-risankizumab, guselkumab, and tildrakizumab 200 mg-in patients with moderate-to-severe plaque psoriasis with involvement of high-impact sites.MethodsThis multicenter retrospective study included 670 patients treated for at least 52 weeks across 37 Italian dermatology centers. Patients received risankizumab (n = 254), guselkumab (n = 177), or tildrakizumab 200 mg (n = 239) according to approved regimens. Effectiveness was assessed using Psoriasis Area Severity Index (PASI) and site-specific Physician's Global Assessment (PGA) scores (scalp, nails, palms/soles, genitalia) at weeks 4, 16, 36, and 52. Safety was evaluated through reported adverse events.ResultsRisankizumab demonstrated the fastest and most pronounced reduction in PASI, achieving PASI90 and PASI100 responses in 89.6% and 82.1% of patients at week 52, respectively. Tildrakizumab 200 mg showed a slower onset but comparable long-term efficacy, particularly in nail and palmoplantar psoriasis. At week 52, complete nail clearance (fn-PGA = 0) was achieved in 90.0% of patients treated with risankizumab, 76.7% with tildrakizumab, and 66.7% with guselkumab. Palmoplantar and genital psoriasis showed near-complete resolution across all treatment groups by week 52. Scalp involvement improved markedly with all agents, with lower residual disease observed with risankizumab. All treatments were well tolerated, with infrequent and predominantly mild adverse events and no major safety concerns.ConclusionIn real-world clinical practice, IL-23p19 inhibitors provide high and sustained efficacy in psoriasis affecting high-impact sites. Risankizumab offers faster and deeper responses, while tildrakizumab 200 mg represents an effective long-term option, particularly in patients with higher BMI or more treatment-resistant disease. These findings support a personalized approach to biologic selection based on disease localization, patient characteristics, and therapeutic goals
Development of Novel Proline- and Pipecolic Acid-Based Allosteric Inhibitors of Dengue and Zika Virus NS2B/NS3 Protease
No full textIn this study, we report a novel series of proline- and pipecolic acid-based small molecules designed as allosteric inhibitors of the NS2B/NS3 serine proteases from dengue and Zika viruses, key targets in antiviral drug discovery. Results: Enzymatic studies revealed that S-proline derivatives bearing electron-withdrawing substituents on the aromatic ring, particularly that with a trifluoromethyl group in meta position (i.e., compound 3, IC50 = 5.0 μM), were the most potent against DENV NS2B/NS3, while nitro-substituted inhibitors were mostly effective only against the ZIKV protease. R-configured pipecolic acid-based derivatives were the only ones active against DENV NS2B/NS3, even if the mid-micromolar range; however, they demonstrated improved cellular efficacy since inhibitors 24 and 27 exhibiting strong activity in a DENV2 protease reporter gene assay (EC50 = 5.2 and 5.1 μM, respectively). All compounds showed no cytotoxicity (CC50 > 100 μM) and were selective for the viral protease over off-target serine proteases. Structure-based approaches were exploited to map the druggable allosteric site close to Asn152. Conclusions: Our findings led us to identify proline and pipecolic acid-based inhibitors as promising leads for the development of selective flaviviral NS2B/NS3 allosteric inhibitors
A 320-GHz Scalable Equivalent-Circuit Model With Dispersive NQS Effect for CMOS Transistors: From Theory to Experimental Validation
No full textIn this article, a scalable subterahertz equivalent circuit model for complementary metal–oxide–semiconductor (CMOS) transistors is proposed. At subterahertz frequencies, signal propagation exhibits extremely rapid dynamics, causing the nonquasi-static (NQS) effect to become pronounced. To address this challenge, a dispersive nonlinear resistance model based on carrier transport mechanisms was developed. This model integrated both carrier drift and diffusion effects, and further characterized the frequency dispersion phenomena associated with the NQS effect. Concurrently, a scalable gate capacitance model was established from the perspective of channel charge distribution. In addition, the scaling rules of parasitic parameters in the equivalent circuit model were presented. For model validation, 12 CMOS transistors with varying geometries were designed and fabricated in a partially depleted silicon-on-insulator (PDSOI) process. Subsequently, ultrawideband scattering (S -) parameter measurements were performed on these devices across the frequency range from 0.2 to 320 GHz. By comparing the model calculation results with the measured data, the maximum root-mean-square error of the model was 0.074. Furthermore, the proposed model was verified to have scaling capability across three geometric dimensions: gate length (L), single-finger gate width (Wf), and the number of gate fingers (Nf). This scalable model provides accurate modeling support for high-frequency circuit design
Biochemical fingerprinting of dried blood serum from chronic lymphocytic leukemia patients by Raman spectroscopy: Towards prognostic classification
No full textBiopriming-Induced Transcriptomic Memory Enhances Cadmium Tolerance in the Cd Hyperaccumulator Silene sendtneri
No full textSeed biopriming is increasingly recognized as a strategy capable of inducing molecular memory that enhances plant performance under heavy-metal stress. Here, we investigated how biopriming Silene sendtneri seeds with Paraburkholderia phytofirmans PsJN establishes a transcriptional state that predisposes seedlings for improved cadmium (Cd) tolerance. RNA-seq profiling revealed that primed seeds exhibited differential gene expression prior to Cd exposure, with strong upregulation of detoxification enzymes, antioxidant machinery, metal transporters, photosynthetic stabilizers, and osmoprotectant biosynthetic genes. Enrichment of gene ontology categories related to metal ion detoxification, redox homeostasis, phenylpropanoid metabolism, and cell wall organization indicated that biopriming imprints a preparatory transcriptional signature resembling early stress responses. Upon Cd exposure, primed plants displayed enhanced physiological performance, including preserved integrity, elevated antioxidant activity, particularly peroxidases in roots, higher osmolyte accumulation, stabilized micronutrient levels, and substantially increased Cd uptake and sequestration. These coordinated responses demonstrate that biopriming induces a sustained molecular memory that accelerates and strengthens downstream defense activation. These findings demonstrate that PGPR-based biopriming establishes a stable transcriptomic memory in seeds that enhances cadmium tolerance, metal sequestration, and stress resilience, highlighting its potential for improving hyperaccumulator performance in phytoremediation and stress adaptation strategies
ROLE OF CELLULAR SENESCENCE AND IMPAIRED INTRACELLULAR DEGRADATION PATHWAYS IN THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMUNARY DISEASE (COPD)
No full textCOPD is currently hypothesized to be a disease of accelerated lung aging as the cells of the lower airways of these patients show several features of cellular aging: for example shortening of telomeres and damage to DNA (deoxyribonucleic acid), cellular senescence, activation of Intracellular signalling pathway mediated by phosphatidyl-inositol-3-kinase and the mammalian target of rapamycin (PI3K-mTOR), autophagy impairments, mitochondrial disorders, stem cell depletion, microRNA profile impairment, immunosenescence, chronic inflammation (inflammaging), associated with a decrease in the expression of anti-aging molecules such as sirtuins (SIRTs).
Many of these processes are activated by oxidative stres
Redox Network Dysfunction: Integrating Ferroptosis and Cuproptosis Across Human Diseases
No full textOxidative stress (OS) is increasingly recognized as a dynamic disturbance of cellular redox networks rather than a simple imbalance between oxidants and antioxidants. In this context, ferroptosis and cuproptosis—two regulated and metal-dependent forms of cell death—emerge as key mechanisms linking OS to metabolic dysfunction, inflammation, and tissue injury. This review integrates findings from biochemical, lipidomic and metallomic studies to describe how lipid peroxidation (LPO), glutathione (GSH)–Glutathione Peroxidase 4 (GPX4) activity, ferritinophagy, copper-induced mitochondrial protein lipoylation, and altered communication between organelles generate distinct redox signatures across diseases. By examining cutaneous, metabolic, cardiovascular, infectious, neurodegenerative, and oncologic conditions, we outline the shared redox pathways that connect iron- and copper-dependent cell death to systemic inflammation, immune dysregulation, and chronic tissue damage. Common oxidative markers—such as oxidized phospholipids, lipid aldehydes including 4-Hydroxynonenal (4-HNE) and malondialdehyde (MDA), and systemic metal imbalance—are highlighted as potential indicators of disease severity and as emerging therapeutic targets. We also discuss innovative analytical tools, including redox lipidomics, metallomic profiling and artificial-intelligence (AI)-based classification approaches, which improve the characterization of redox vulnerability and may guide the development of precision redox therapies. Overall, ferroptosis and cuproptosis represent unifying mechanisms that connect OS to multisystem disease and provide new opportunities for diagnostic refinement and targeted antioxidant-based interventions
