Search Results (253)

MDM4 (Murine Double Minute 4), also known as MDMX, is a crucial negative regulator of the tumor suppressor p53. MDM4 heterodimerizes with MDM2 to enhance MDM2-mediated ubiquitination and degradation of p53, thereby promoting tumorigenesis. Beyond its canonical role in inhibiting p53 activity, recent studies have revealed diverse p53-independent functions. MDM4 interacts with various proteins, including p73, E2F1, casein kinase 1α, PPARα, and TRIM21 to regulate cell cycle progression, β-catenin-mediated pre-leukemic progression, and ferroptosis independent of p53. In addition, MDM4 functions independently of both p53 and MDM2 by interacting with proteins, such as SMAD family members 3/4, retinoblastoma protein (pRB), p21, Nbs1 (also known as Nibrin), mTOR complex 1 (mTORC1), and the Polycomb Repressive Complexes (PRCs) complex, to control cell proliferation and survival, as well as protein degradation, double-strand break (DSB) repair, and replication fork progression. Intriguingly, multiple studies suggest that MDM4 exhibits oncogenic activity independent of p53; however, other reports highlight a potential tumor-suppressive role for MDM4 in the absence of p53. Thus, MDM4’s functions extend well beyond the canonical p53–MDM2 axis. A deeper understanding of MDM4 biology may facilitate the development of novel targeted therapies for various cancers. Full article

Chlorogenic acid (CGA), which is ubiquitous in diverse botanical sources, demonstrates considerable anticancer potential through modulation of multiple targets or signaling pathways, thereby posing substantial challenges for mechanistic elucidation and target identification. Based on the proteolysis targeting chimera (PROTAC) technology’s ability to induce targeted protein degradation via ubiquitin-proteasome pathway recruitment, we synthesized a panel of CGA-PROTACs. These compounds incorporated the natural product CGA as the target-binding ligand, conjugated to pomalidomide (an E3 ligase-recruiting moiety) via various synthetic linkers. The findings indicated that compound A7, linked with an alkane linker, exhibited a notable anti-proliferative effect on 4T1 and A375 cells in vitro. The IC₅₀ value of A7 on A375 cells reached 69.70 μM, which is 2.2 times better than the effect of the precursor compound CGA (IC₅₀ = 148.80 μM). Mouse double minute 4 (MDM4) was confirmed as a potential target of compound A7 through a combination of proteomics, Western blot analysis and molecular dynamics simulation. CGA-PROTAC A7 treatment led to a dose-dependent reduction in MDM4 protein levels while significantly upregulating p53 and p21 protein expression, and thus inhibited proliferation, induced G2/M phase cell cycle arrest, and markedly enhanced apoptosis in melanoma A375 cells. This study successfully applied an effective strategy for target identification and medication discovery of natural compounds. In addition, CGA-PROTAC A7 was synthesized in one step with an overall yield of 45.96%, providing a feasible route for synthesis and establishing a basis for the combination of natural product polyphenols with PROTAC technology. Full article

While pricing policy has emerged as a critical demand-side lever for decarbonizing mobility, its bidirectional effects on modal shift remain unexplored. Dynamic pricing in high-speed rail (HSR) creates a double-edged environmental outcome: advance discounts attract passengers from aviation, yet last-minute premiums may reverse these gains. Using 2.4 million price observations from Madrid–Barcelona (2019), we introduce a carbon leakage framework that quantifies this phenomenon within a multi-source validated framework. Our analysis reveals a structural tension: while early-bird pricing attracts 274,431 annual passengers from aviation—saving 23,650 tonnes CO₂/year—last-minute scarcity premiums systematically drive passengers back to air travel. Multi-source calibrated elasticity ($\epsilon =-0.95$, validated through triangulation across CNMC corridor data, meta-analytic evidence, and recent empirical studies within the range $[-1.91,-0.75]$) shows that 22.3% of last-minute tickets exceed the EUR 120 aviation threshold, creating 1511 tonnes CO₂ leakage annually (6.4% offset of gross savings). Critically, this leakage ratio is shown to be structurally independent of elasticity specification, being determined by the price distribution shape rather than demand parameters. Scenario analysis suggests that under static assumptions, price caps at EUR 110–120 would eliminate leakage while preserving an estimated 94% of operator revenue, though general equilibrium effects remain unmodeled. These findings identify illustrative scenario thresholds for carbon-aware revenue management, demonstrating that demand-side decarbonization requires not only attracting passengers to sustainable modes but also preventing their reversal to high-carbon alternatives. Full article

Adiabatic demagnetization refrigeration (ADR) has attracted considerable attention as an effective approach to reach ultra-low temperatures required for fundamental physics and quantum technologies. Here we directly characterize the cryogenic magnetocaloric performance of the rare-earth-based double-perovskite oxide Gd₂CuTiO₆ (GCTO) through quasi-adiabatic demagnetization measurements. Magnetization measurements show no long-range magnetic transition above 1.8 K and indicate dominant antiferromagnetic (AFM) interactions, consistent with an AFM ordering temperature of $T_{\mathrm{N}}\approx 1.15$ K reported previously. Notably, the isothermal magnetization $M\left(H\right)$ at 1.8 K deviates from an ideal single-ion Brillouin response and is better described by a molecular-field correction for the Gd sublattice, suggesting correlated paramagnetism persisting above $T_{\mathrm{N}}$. In contrast to previous studies that inferred cooling performance from thermodynamic estimates, we directly validate the achievable sub-Kelvin cooling in GCTO through quasi-adiabatic measurements. In the quasi-ADR process starting from $T_0$∼2 K, demagnetization fields of 4, 6, and 9 T yield minimum temperatures of $T_{\min }=761.5$, 452.4, and 289.2 mK, respectively, well below $T_{\mathrm{N}}$. After complete removal of the magnetic field, the sample temperature remains highly stable for at least several tens of minutes, demonstrating a long hold time under quasi-adiabatic conditions. Moreover, the $T\left(H\right)$ curves reveal a characteristic field scale around $H_{\mathrm{c}}$∼1 T, implying a field-induced modification of the low-temperature magnetic-entropy landscape that is relevant to the cooling behavior during demagnetization. These results highlight GCTO as a promising magnetic refrigerant for sub-Kelvin ADR applications and underscore the role of correlated magnetism in optimizing cryogenic magnetocaloric performance. Full article

Soil tillage practices play a key role in controlling soil’s physical properties, water infiltration, and runoff generation, particularly in erosion-prone cropping systems such as maize monocultures. The cultivation of wide-row crops is restricted on erosion-prone land; however, these crops constitute a fundamental basis for livestock feed and represent a key input raw material for biogas plants. This 4-year study evaluated the effects of three tillage practices—conventional ploughing, shallow tillage, and no tillage—on selected soil’s physical and chemical properties and on water infiltration processes in a maize (Zea mays L.) monoculture. Experimental maize stands were established in a field with a silty clay Luvic Chernozem. Field measurements were performed over multiple years and included soil bulk density, macroporosity, cone index, soil organic carbon, soil pH, soil aggregate stability, and water infiltration. Infiltration processes were assessed using a combination of double-ring infiltrometers, rainfall simulation, and dye tracer experiments to characterize water flow patterns under controlled conditions. The results demonstrated that soil tillage significantly influenced the vertical distribution of soil organic carbon and pH, soil aggregate stability, soil compaction, and pore characteristics, with the most pronounced differences observed in the upper soil layers. Soil aggregate stability in the 0–0.10 m layer showed a clear numerical trend, with the highest mean value under ST (0.42) compared with PL (0.28) and no tillage (NT) (0.26). Topsoil Cox was the highest under ST (3.591%) compared with PL (2.838%) and NT (2.634%). Differences among tillage practices were particularly evident during simulated rainfall events, affecting infiltration rates, runoff initiation, and preferential flow patterns. Ring infiltrometer measurements indicated higher infiltration in PL (e.g., 21.1 mm min⁻¹ at minute 1 in PL vs. 11.1/11.9 mm min⁻¹ in ST/NT; 10.9 mm min⁻¹ at minute 10 in PL vs. 5.3/7.6 mm min⁻¹ in ST/NT). However, rainfall simulation showed the highest runoff in PL, including the earliest runoff onset (4.5 min). Despite the soil’s high infiltration capacity due to low bulk density and higher porosity, the decisive factor promoting water infiltration into the soil is the condition of the soil surface, which is influenced by the stability of soil aggregates; this stability was enhanced by the input of organic matter from plant residues. The findings confirm that long-term soil tillage management substantially modifies soil hydraulic behaviour and highlight the importance of tillage system selection for improving soil water infiltration and reducing runoff risk in maize monoculture systems. Full article

The hepatitis C virus (HCV) Core activates the ATM-Chk2 pathway, leading to phosphorylation of p53 at Ser-15, which inhibits mouse double minute 2 (MDM2)-mediated proteasomal degradation. This study reveals that HCV Core also promotes E6-associated protein (E6AP)-mediated degradation of p53 during HCV replication. In the presence of HCV Core, E6AP expression induced p53 ubiquitination, reduced its stability, and decreased p53 levels, whereas E6AP knockdown increased p53 levels. The E3 ubiquitin ligase activity of E6AP was critical for this process, as demonstrated using the E6AP C833A mutant and the E3 ligase inhibitor Heclin. Proteasomal inhibition with MG132 confirmed that HCV Core and E6AP act together to regulate p53 levels via the proteasome. Importantly, HCV Core-induced p53 phosphorylation was essential for E6AP-mediated degradation, as shown by the impairment of degradation in the presence of the ATM inhibitor KU-55933. E6AP also targeted p53 phosphorylated at Ser-15 by etoposide, as well as phosphomimetic mutants such as p53 S15D, but not non-phosphorylatable mutants such as p53 S15A. These findings suggest that HCV Core-induced p53 phosphorylation enhances E6AP-mediated degradation while preventing MDM2 from targeting p53, thereby maintaining p53 levels that support cell survival, viral replication, and potentially oncogenesis in human hepatocytes. Full article

Receptive endometrium (RE) is essential for mammalian embryo implantation. The establishment of RE is a complex and precise dynamic process regulated by various cytokines, including non-coding RNAs (miRNAs, lncRNAs, and circRNAs). We identified candidate miR-26b-3p and circRNA3890 from our previous endometrial non-coding RNA sequencing data. CircRNA3890 adsorbs miR-26b-3p and inhibits its activity. Mouse double minute 4 (MDM4) is a target gene of miR-26b-3p, and circRNA3890 up-regulates the expression level of MDM4 by inhibiting the activity of miR-26b-3p in dairy goat endometrial epithelial cells (gEECs) in vitro. circRNA3890/miR-26b-3p/MDM4 could promote the proliferation of gEECs through the p53 signaling pathway. MiR-26b-3p could regulate the expression levels of vascular endothelial growth factor A (VEGFA) and leukemia inhibitory factor (LIF) through MDM4 in gEECs, which contributes to the development of endometrial receptivity. Furthermore, the results showed that miR-26b-3p significantly promoted the development of RE and embryo implantation. These findings demonstrate that circRNA3890 targets and adsorbs miR-26b-3p to relieve MDM4 inhibition and promotes EEC proliferation through the p53 signaling pathway. They reveal the regulatory effect of miR-26b-3p on receptive endometrial development and embryo implantation in vitro and in vivo. Full article

The p53 tumor suppressor protein plays a central role in maintaining genomic stability by regulating cell cycle arrest, apoptosis, and DNA repair under cellular stress. Mouse double minute 2 (MDM2), an E3 ubiquitin ligase, negatively regulates p53 via direct binding and proteasomal degradation. Overexpression or amplification of MDM2 can disrupt this pathway and promote tumorigenesis, even in cancers with wild-type p53. This review outlines the structural features of MDM2, particularly its N-terminal hydrophobic pocket and C-terminal RING domain, and their roles in p53 regulation. We further examine the pathological effects of MDM2 dysregulation and SNPs linked to increased cancer risk. Recent progress in small molecule MDM2 inhibitors is discussed, with a focus on non-covalent agents such as rhein-derived anthraquinone analogs, including AQ-101, which demonstrate promising anti-cancer activity with reduced toxicity. These findings support the continued development of non-covalent MDM2 inhibitors as a novel therapeutic approach for cancers involving both wild-type and mutant p53. Full article

Accurate quantification in LC–MS experiments becomes challenging when analytes overlap both chromatographically and in mass spectra, as conventional extracted ion chromatogram-based methods can yield biased results by double-counting shared isotope signals. This limitation is particularly relevant for oligonucleotides, where degradation products and synthetic impurities frequently co-elute with the intended full-length product, complicating relative quantification. To address this, we developed DECAF, a straightforward and computationally efficient procedure for deconvoluting overlapping isotope patterns directly from MS1 data. The method models experimental isotope distributions as mixtures of theoretical templates across retention time, generating deconvoluted ion chromatograms whose peak areas accurately reflect the contributions of individual components. We demonstrate the utility of DECAF on two pharmaceutically relevant oligonucleotide mixture datasets, where it reliably estimated mixing proportions and enabled visualisation of component-specific elution profiles. Analysis of a typical sample required one to two minutes, underscoring the method’s practical efficiency. DECAF provides a transparent and accessible alternative to existing commercial software, with promising applications in pharmaceutical analysis and quality control. Full article

Carbohydrate availability and caffeine ingestion have been shown to elicit improvements in performance independently of one another. The purpose of the study was to examine the effect of a carbohydrate + caffeine beverage on performance and perceived effort in soccer players. Forty-three collegiate women’s soccer athletes were recruited to participate during a single day of simulated match play, in which each team played once. Athletes consumed either a carbohydrate + caffeine (Experimental) beverage or a control (Control) beverage (flavored water) during half-time in a double-blind, placebo-controlled, randomized control trial design. Prior to and after each game, Ratings of Perceived Exertion (RPE) and blood glucose levels were assessed. Heart rate, training impulse (TRIMP), total distance covered, high-speed distance, and velocity were recorded. Blood glucose levels after the match simulation were positively associated with total distance (r = 0.434; p = 0.01), distance per minute (r = 0.439; p < 0.01), average velocity (r = 0.438; p = 0.01), and TRIMP (r = 0.404; p = 0.018) during the second half. There was a significant main effect for half regarding blood glucose (p < 0.001), total distance (p < 0.001), high-speed distance (p < 0.001), and TRIMP (p = 0.046). There was a significant half × condition effect for blood glucose (p = 0.05). Pairwise comparisons indicated the Experimental beverage condition resulted in a +27 mg/dL (95% CI: −3.6, 58.8) difference compared to the Control beverage following the 2nd Half. In the current study, consumption of the carbohydrate + caffeine beverage during half-time resulted in higher blood glucose levels post-game compared to placebo; however, the experimental beverage did not influence the total distance covered, average velocities, average heart rate, or TRIMP values during the second half of simulated match play. Full article

The Murine Double Minute 2 (MDM2) gene encodes an E3 ubiquitin ligase that negatively regulates the tumor suppressor p53, maintaining low p53 levels through ubiquitination and proteasomal degradation. MDM2 overexpression in various malignancies leads to reduced p53 activity, contributing to tumor initiation and resistance to therapies. As such, MDM2 is a promising target for drug development. Innovative small-molecule inhibitors are being designed to disrupt the MDM2-p53 interaction, thereby restoring p53’s tumor-suppressive functions. This review focuses on clinical trials evaluating MDM2 inhibition for cancer therapy. MDM2 exerts its oncogenic effects primarily through its interaction with p53 but also has p53-independent functions involved in cell cycle progression and DNA repair. Elevated MDM2 expression is associated with poor prognosis across various cancers, including dedifferentiated liposarcoma, breast cancer, and glioblastoma. Targeting MDM2 with inhibitors has shown promising potential in clinical development, aiming to reactivate p53’s functions in tumors with wild-type TP53, improving therapeutic outcomes in cancer treatment. Full article

Objectives: This study investigated whether CoQ10 supplementation enhances physical adaptations to high-intensity interval training (HIIT) in muscular strength, power, and physical function in older adults. Method: In a double-blind, randomized controlled trial, 38 adults aged 65–75 were assigned to either a CoQ10 (Females: 8; Males: 11) or placebo (Females: 8; Males: 11) group and completed an 8-week supervised HIIT program. Lower- and upper-body strength (30s 5-repetition chair stand [5XSST], chair standing [30CST], handgrip strength [HGR/L]), balance (single-leg stand [SLS], timed up and go [TUG]), mobility (25-foot walk [25FW]), and aerobic endurance (6-minute walk [6MWT]) were assessed pre- and post-intervention. Results: The CoQ10 group demonstrated significantly greater improvements in 5XSST and 30CST compared to the placebo group (p < 0.05). Both groups showed significant within-group improvements in right and left handgrip strength, SLS, 6MWT, and TUG (all p < 0.001), with no significant between-group differences observed for these outcomes (p > 0.05). No adverse events were reported. Conclusion: While CoQ10 supplementation enhanced improvements in lower-body strength and power, as indicated by the greater gains in 5XSST and 30CST performance compared to the placebo, no between-group differences were observed in TUG, grip strength, or other functional outcomes. This suggests that the performance-related effects of CoQ10 may be more specific to muscular power output and fatigue resistance, rather than general mobility or balance-related tasks. These findings highlight the potential of CoQ10 as a targeted adjunct in exercise for supporting lower-body function and physical performance in older adults. Full article

We evaluated whether macrophage-targeted glyco-modulation can improve day-to-day function in aging companion animals. In a multicenter, randomized, double-blind, placebo-controlled trial, 60 client-owned geriatric dogs (≥10 years) received subcutaneous EF-M2 (0.1 μg/kg, every 72 h for 4 weeks; protocolized, blinded step-up to every 48 h at day 14 for partial responders) or matched placebo, followed by 4 weeks off-treatment. Two prespecified co-primary endpoints were tested hierarchically: change in accelerometer-measured active minutes/day at week 1 and change in a day-28 vitality composite (z-score of inverted CBPI-PSS, HRQL-vitality, and appetite VAS). EF-M2 was superior to placebo on both: +23.05 min/day at week 1 (95% CI, 18.16–27.94; p < 0.001) and +2.01 z-units at day 28 (95% CI, 1.52–2.50; p < 0.001). Key secondaries favored EF-M2, including greater week-4 activity (+33.00 min/day, 26.83–39.18; p < 0.001), lower BAER auditory threshold (−5.28 dB, −7.53 to −3.04; p < 0.001), and reduced transepidermal water loss (−1.35 g/m²·h, −2.45 to −0.25; p = 0.02); multiplicity was controlled with Holm–Bonferroni procedures. Owner-reported global improvement was more frequent with EF-M2 at day 28 (93.3% vs. 10.0%) and remained higher at day 56 off-treatment (50.0% vs. 16.7%). Prespecified pharmacodynamic markers shifted in directions consistent with M2-skewing (ARG1:iNOS ratio and IL-10 increased; TNF-α decreased) by day 7. Adverse events were infrequent, mild, and similar to placebo; no treatment-related withdrawals or serious events occurred. These findings support macrophage-targeted glyco-modulation as a promising approach to rapidly improve real-world activity and multidomain vitality in older dogs, with short-term signals persisting off-treatment; longer, adequately powered trials are warranted to define durability, structural outcomes, and phenotype-specific benefits. Full article

Phase change materials (PCMs) integrated into building envelopes can store and release latent heat, reducing indoor temperature fluctuations and shifting thermal peaks. This study quantifies the time lag and comfort impact of PCM plaster under free-running conditions using two identical, instrumented model houses in Bácsalmás, Hungary. One house served as a reference, while the other was retrofitted with interior PCM plaster panels on four walls (51.2 kg paraffin, ≈8.12 MJ latent heat capacity). The temperatures of the walls, indoor air, and outdoor environment were monitored every five minutes for 105 spring/summer days. Daily peak times were extracted using moving-average smoothing, and time lags between exterior and interior wall peaks were computed. The PCM house exhibited roughly double the average lag compared with the reference (≈200 vs. ≈100 min), with lag distributions well described by lognormal fits. Comfort evaluation based on exceeded degree-hours (EDH) relative to the adaptive comfort range (EN 16798-1) revealed that larger peak-time lags correlated with lower overheating. Results confirm that PCM plaster significantly delays and attenuates daily temperature peaks, extends comfort periods, and supports passive strategies such as night ventilation and demand-side load shifting in lightweight buildings. Full article

Argumentation is a key competence (as emphasized by the European Union) for lifelong learning and democratic participation. Written argumentation is a challenging task for students, and to date, no study has investigated the impact of a combined teaching approach of debating and SRSD writing lessons on written argumentation skills. This study addresses this gap by linking debating and SRSD writing lessons for the first time in grade 9 classrooms, employing a debating format and the Self-Regulated Strategy Development (SRSD) approach. We aimed to assess the impact of the combination of debating and SRSD writing lessons on the quality of students’ argumentative writing, examining text quality across school types (higher and lower academic track) and intervention sequences (debating–SRSD and SRSD–debating). This quasi-experimental study included 357 ninth-grade students from six rural and urban German schools, split between higher (57.9%) and lower (42.1%) academic tracks. Over four measurement points, the students participated in randomized debating or SRSD-based writing lessons, each comprising six 90-minute sessions conducted by trained coaches from the research team. Text quality was measured through standardized writing tasks and the double-blinded rating of text and language pragmatics quality on a six-point scale. Both interventions improved text quality, with significant gains observed in the post-tests, and gains were especially visible for lower-track students. This study demonstrates the effectiveness of linking debating and SRSD writing lessons in improving writing skills. Our findings support the inclusion of debating as a motivational precursor to writing, emphasizing adaptability in teaching strategies to accommodate diverse student needs. We recommend confirming these findings and informing broader curricular reforms in further research. Full article