Search Results (9,244)

Epidermolysis Bullosa (EB) comprises a group of inherited blistering disorders caused by pathogenic variants in genes essential for skin and mucosal integrity. Nonsense mutations, which generate premature termination codons (PTCs), result in reduced or absent protein expression and contribute to severe disease phenotypes in EB. Readthrough therapies, which may continue translation past PTCs to restore full-length functional proteins, have emerged as promising approaches. This review summarizes findings from preclinical studies investigating readthrough therapies in EB models, clinical studies demonstrating efficacy in EB patients, and emerging readthrough agents with potential application to EB. Preclinical and clinical studies with gentamicin have demonstrated restored type VII collagen and laminin-332 expression, leading to measurable clinical improvements. Parallel development of novel compounds—including aminoglycoside analogs (e.g., ELX-02), translation termination factor degraders (e.g., CC-90009, SRI-41315, SJ6986), tRNA post-transcriptional inhibitors (e.g., 2,6-diaminopurine, NV848), and nucleoside analogs (e.g., clitocine)—has expanded the therapeutic pipeline. Although challenges remain regarding toxicity, codon specificity, and variable protein restoration thresholds, continued advances in molecular targeting and combination therapies offer the potential to establish readthrough therapies as localized or systemic treatments addressing both cutaneous and extracutaneous disease manifestations in EB. Full article

We investigated the role of the intermediate-conductance, Ca²⁺-activated K⁺ channel K_Ca3.1 and volume-regulatory anion channel LRRC8A in regulating C-C motif chemokine ligand 2 (CCL2) expression in THP-1-differentiated M₂ macrophages (M₂-MACs), which serve as a useful model for studying tumor-associated macrophages (TAMs). CCL2 is a potent chemoattractant involved in the recruitment of immunosuppressive cells and its expression is regulated through intracellular signaling pathways such as ERK, JNK, and Nrf2 in various types of cells including macrophages. The transcriptional expression of CCL2 was suppressed in M₂-MACs following treatment with a K_Ca3.1 activator or an LRRC8A inhibitor via distinct signaling pathways: ERK–CREB2 and JNK–c-Jun pathways for K_Ca3.1, and the NOX2–Nrf2–CEBPB pathway for LRRC8A. Under in vitro conditions mimicking the elevated extracellular K⁺ concentration ([K⁺]_e) characteristic of the tumor microenvironment (TME), CCL2 expression was markedly upregulated, and this increase was reversed by treatment with them in M₂-MACs. Additionally, the WNK1–AMPK pathway was, at least in part, involved in the high [K⁺]_e-induced upregulation of CCL2. Collectively, modulating K_Ca3.1 and LRRC8A activities offers a promising strategy to suppress CCL2 secretion in TAMs, potentially limiting the CCL2-induced infiltration of immunosuppressive cells (TAMs, T_regs, and MDSCs) in the TME. Full article

Despite the significant advancements in treatment and prevention, the fight against cancer is ongoing worldwide. This study evaluated the pharmacological properties and anticancer activity of Afzelia quanzensis bark, traditionally used by the indigenous communities of KwaZulu Natal and Eastern Cape Provinces of South Africa to treat cancer and related illnesses. Phytochemical screening, high-performance liquid chromatography–diode array detection (HPLC-DAD), and Fourier-transform infrared spectroscopy (FTIR) analyses were carried out using established protocols. The antioxidant activity was assessed via the 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging capacity and nitric oxide radicals. The anticancer activity was evaluated using the MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Phytochemical analysis revealed the presence of saponins, flavonoids, terpenoids, alkaloids, steroids, cardiac glycosides, and phlobatannins. The HPLC-DAD analysis detected seven distinctive peaks in the aqueous extract and three distinctive peaks in the methanolic extract. The FTIR spectra of the aqueous extract displayed characteristic peaks corresponding to O-H, C=O, C=C, and =C–H functional groups. Among the tested extracts, the methanol extract exhibited the strongest antioxidant activity, followed by the ethanolic extract, in both DPPH and nitric oxide. The methanol extract showed a higher cell proliferation inhibition against the DU-145 cancer cell line with the percentage of inhibition of 37.8%, followed by the aqueous extract with 36.3%. In contrast, limited activity was observed against PC-3, SK-UT-1, and AGS cell lines. The results demonstrated notable dose-dependent antioxidant and antiproliferative activities supporting the ethnomedicinal use of Afzelia quanzensis bark in cancer management. These findings warrant further investigation into its bioactive constituents and mechanisms of action. Full article

Chickpea is a highly weed-prone crop with limited herbicide options and high labor demands, raising the following question: Can fall-planted legume–cereal cover crops (CCs) improve soil properties while reducing herbicide use and manual weeding pressure? To explore this, we evaluated the effect of fall-planted winter rye (WR) alone in 2021 and mixed with hairy vetch (HV) in 2022 and 2023 at Randolph farm in Petersburg, Virginia. The objectives were two-fold: (a) to examine the effect of CCs on soil properties using monthly growth dynamics and biomass harvested from fifteen 0.25 m²-quadrants and (b) to evaluate the efficiency of five termination methods: (1) green manure (GM); (2) GM plus pre-emergence herbicide (GMH); (3) burn (BOH); (4) crimp mulch (CRM); and (5) mow-mulch (MW) in suppressing weeds in chickpea fields. Weed distribution, particularly nutsedge, was patchy and dominant on the eastern side. Growth dynamics followed an exponential growth rate in fall 2022 (R² ≥ 0.994, p < 0.0002) and a three-parameter sigmoidal curve in 2023 (R² ≥ 0.972, p < 0.0047). Biomass averaged 55.8 and 96.9 t/ha for 2022 and 2023, respectively. GMH consistently outperformed GM in weed suppression, though GM was not significantly different from no-till systems by the season’s end. Kabuli-type chickpeas under GMH had significantly higher yields than desi types. Pooled data fitted well to a three-parametric logistic curve, predicting half-time to 50% weed coverage at 35 (MM), 38 (CRM), 40 (BOH), 46 (GM), and 53 (GMH) days. Relapses of CCs were consistent in no-till systems, especially BOH and MW. Although soil properties improved, CCs alone did not significantly suppress weed. Full article

Reinforcing PLA composites with natural fibres is a prominent strategy for improving PLA’s properties while benefiting from its intrinsic biodegradation. However, these composites may be susceptible to an inefficient stress-transferring process due to the weak intermolecular interactions between PLA and natural fibres. A well-known practice is to incorporate coupling agents to improve polymer–fibre adhesion, such as carboxylic acids (CAs) and grafted copolymers. CAs are a more affordable and biodegradable option for improving PLA/natural fibre interface strength, resulting in a material with superior mechanical and thermal properties. In this context, this research discusses the potential use of mono (C6 and C8) and di (CC6 and CC8) carboxylic acids as coupling agents in PLA/pecan nutshells (PN) composites. PLA/PN composites with four different CAs were processed in a twin-screw extruder and subsequently injection moulded. The results indicated an increase in the flexural strength of the PLA due to the presence of PN in the neat composite. The use of CAs increased the storage modulus of PLA/PN composites, while C6 and CC8 reduced the PLA composite tan δ peak height. The PLA’s T_g in PLA/PN composite shifted to lower temperatures after the incorporation of CAs while increasing the PLA crystallinity degree. These results strongly suggested that besides acting as efficient coupling agents, these acids also exerted roles as nucleating agents and plasticisers. Full article

The cement industry is a significant contributor to global carbon dioxide emissions, primarily due to the energy demands of its production process and its reliance on clinker, a material formed through the high-temperature calcination of limestone. Strategies to reduce emissions include the adoption of low-carbon fuels, the use of carbon capture and storage (CCS) technologies, and the integration of supplementary cementitious materials (SCMs) to reduce the clinker content. The effectiveness of these measures depends on a complex set of interactions involving technological feasibility, market dynamics, and regulatory frameworks. This study presents a system dynamics model designed to assess how various decarbonization approaches influence long-term emission trends within the cement industry. The model accounts for supply chains, production technologies, market adoption rates, and changes in cement production costs. This study then analyzes a number of scenarios where there is large-scale sustained investment in each of three carbon mitigation strategies. The results show that CCS by itself allows the cement industry to achieve carbon neutrality, but the high capital investment results in a large cost increase for cement. A combined approach using alternative fuels and SCMs was found to achieve a large carbon reduction without a sustained increase in cement prices, highlighting the trade-offs between cost, effectiveness, and system-wide interactions. Full article

Objective: This retrospective observational study evaluated the efficacy and safety of an ovarian stimulation protocol for embryo banking that involves continuous administration of clomiphene citrate (CC) in combination with gonadotropins, without the use of GnRH antagonists. Methods: Conducted at the Serum IVF Clinic in Athens, Greece, the study included 250 women aged 25–45 who underwent IVF for embryo banking. The protocol involved administering 150 mg of CC daily from day 2 of the menstrual cycle until the day before hCG trigger, alongside 150 IU/day of Meriofert. Outcomes assessed included oocyte yield, fertilization rates, incidence of ovarian hyperstimulation syndrome (OHSS), and hormonal correlations. Comparative and regression analyses explored differences between age groups and predictors of success. Results: The protocol demonstrated a favorable safety profile with no cases of OHSS and yielded a mean of 10.25 oocytes per patient. Group analysis showed significantly more oocytes retrieved in women under 40 (mean: 12.5) versus those over 40 (mean: 8.43), while fertilization rates were paradoxically higher in the older cohort (59.16% vs. 30.68%, p < 0.0001). Regression models revealed basal FSH to be a significant inverse predictor of oocyte yield, but it was positively associated with fertilization rate. Continuous CC use effectively suppressed premature LH surges without compromising oocyte or embryo quality, allowing flexible and cost-effective stimulation with minimal monitoring. Conclusions: Continuous administration of clomiphene citrate in combination with gonadotropins presents a promising, antagonist-free ovarian stimulation protocol for embryo banking. The approach is economically efficient, reduces monitoring requirements, and maintains safety and effectiveness and is particularly notable in women over 40. Further studies are warranted to validate these findings and refine protocol mechanisms. Full article

Congenital cataracts (CCs) are a leading cause of preventable childhood blindness, with genetic factors playing a crucial role in their etiology. Nance–Horan syndrome (NHS) is a rare X-linked dominant disorder associated with CCs but is often underdiagnosed due to variable expressivity, particularly in female carriers. Objective: This study aimed to explore the genetic landscape of CCs in a Swiss cohort, focusing on two novel NHS and one novel GJA8 variants and their phenotypic presentation. Methods: Whole-exome sequencing (WES) was conducted on 20 unrelated Swiss families diagnosed with CCs. Variants were analyzed for pathogenicity using genetic databases, and segregation analysis was performed. Clinical data, including cataract phenotype and associated systemic anomalies, were assessed to establish genotype–phenotype correlations. Results: Potentially pathogenic DNA sequence variants were identified in 10 families, including three novel variants, one in GJA8 (c.584T>C) and two NHS variants (c.250_252insA and c.484del). Additional previously reported variants were detected in CRYBA1, CRYGC, CRYAA, MIP, EPHA2, and MAF, reflecting genetic heterogeneity in the cohort. Notably, NHS variants displayed significant phenotypic variability, suggesting dose-dependent effects and X-chromosome inactivation in female carriers. Conclusions: NHS remains underdiagnosed due to its variable expressivity and the late manifestation of systemic features, often leading to misclassification as isolated CC. This study highlights the importance of genetic testing in unexplained CC cases to improve early detection of syndromic forms. The identification of novel NHS and GJA8 variants provides new insights into the genetic complexity of CCs, emphasizing the need for further research on genotype–phenotype correlations. Full article

Catalytic and bioelectrocatalytic properties of four white rot fungal laccases (Trametes hirsuta, ThL; Coriolopsis caperata, CcL; Steccherinum murashkinskyi, SmL; and Antrodiella faginea, AfL) from different orthologous groups were comparatively studied in homogeneous reactions of electron donor substrate oxidation and in a heterogeneous reaction of dioxygen electroreduction. The ThL and CcL laccases belong to high-redox-potential enzymes (E⁰_T1 = 780 mV), while the AfL and SmL laccases are medium-redox-potential enzymes (E⁰_T1 = 620 and 650 mV). We evaluated the efficiency of laccases in mediatorless bioelectrocatalytic dioxygen reduction by the steady-state potential (E_ss), onset potential (E_onset), half-wave potential (E_1/2), and the slope of the linear segment of the polarization curve. A good correlation was observed between the T1 center potential of the laccases and their electrocatalytic characteristics; however, no correlation with the homogeneous reactions of electron donor substrates’ oxidation was detected. The results obtained are discussed in the light of the known data on the three-dimensional structures of the laccases studied. Full article

Equestrian sports play a significant economic role in the horse industry. In recent years, numerous equine viruses have emerged, among which are equine Pegiviruses and the re-emerging Equine coronavirus (ECoV). These viruses are distributed globally and primarily cause subclinical infections with unknown morbidity, even if ECoV can occasionally induce febrile and diarrheic episodes. To broaden the data on the Italian equine population, a study was conducted to assess their prevalence in two distinct horse populations belonging to the Carabinieri Corps (CC) and the Italian Army (IA) of the Italian Armed Forces (IAF). Samples consisted of blood serum and rectal swabs of 436 horses collected within the national surveillance program for equine infectious anemia and gastrointestinal parasite monitoring and analyzed for Pegivirus (caballi and equi) and ECoV by Real-Time RT PCR. The prevalence detected were 6.56% and 3.53%, respectively, for Pegivirus caballi and equi for the IA, while for the CC, they were 10.13% and 0.84%. Only one sample tested positive for ECoV belonging to a horse of the CC. Phylogenetic analyses were carried out on the PCR-positive samples that were sequenced using Sanger protocols. Understanding the epidemiology of these viruses is essential for evaluating the implementation of effective prevention strategies. Full article

The objective of this study was to evaluate the physical-hydric properties of a Planosol under an Integrated Crop–Livestock–Forest (ICLF) system in the Agreste region of Paraíba, Brazil, after eight years of implementation, and to compare them with areas under a conventional cropping system and secondary native vegetation. The experiment was conducted at the experimental station located in Alagoinha, in the Agreste mesoregion of the State of Paraíba, Brazil. The experimental design adopted was a randomized block design (RBD) with five treatments and four replications (5 × 4 + 2). The treatments consisted of: (1) Gliricidia (Gliricidia sepium (Jacq.) Steud) + Signal grass (Urochloa decumbens) (GL+SG); (2) Sabiá (Mimosa caesalpiniaefolia Benth) + Signal grass (SB+SG); (3) Purple Ipê (Handroanthus avellanedae (Lorentz ex Griseb.) Mattos) + SG (I+SG); (4) annual crop + SG (C+SG); and (5) Signal grass (SG). Two additional treatments were included for statistical comparison: a conventional cropping system (CC) and a secondary native vegetation area (NV), both located near the experimental site. The CC treatment showed the lowest bulk density (1.23 g cm⁻³) and the lowest degree of compaction (66.3%) among the evaluated treatments, as well as a total porosity (TP) higher than 75% (0.75 m³ m⁻³). In the soil under the integration system, the lowest bulk density (1.38 g cm⁻³) and the highest total porosity (0.48 m³ m⁻³) were observed in the SG treatment at the 0.0–0.10 m depth. High S-index values (>0.035) and a low relative field capacity (RFc < 0.50) and K_θ indicate high structural quality and low soil water storage capacity. It was concluded that the SG, I+SG, SB+SG, and CC treatments presented the highest values of soil bulk and degree of compaction in the layers below 0.10 m. The I+SG and C+SG treatments showed the lowest hydraulic conductivities and macroaggregation. The SG and C+SG treatments had the lowest available water content and available water capacity across the three analyzed soil layers. Full article

Minimizing carbon dioxide emissions is crucial due to the generation of energy from fossil fuels. The significance of carbon capture and storage (CCS) technology, which is highly successful in mitigating carbon emissions, has increased. On the other hand, hydrogen is an important energy carrier for storing and transporting energy, and technologies that rely on hydrogen have become increasingly promising as the world moves toward a more environmentally friendly approach. Nevertheless, the integration of CCS technologies into power production processes is a significant challenge, requiring the enhancement of the combined power generation–CCS process. In recent years, there has been a growing interest in process intensification (PI), which aims to create smaller, cleaner, and more energy efficient processes. The goal of this research is to demonstrate the process intensification potential and to model and simulate a hybrid integrated–intensified adsorptive-membrane reactor process for simultaneous carbon capture and hydrogen production. A comprehensive, multi-scale, multi-phase, dynamic, computational fluid dynamics (CFD)-based process model is constructed, which quantifies the various underlying complex physicochemical phenomena occurring at the pellet and reactor levels. Model simulations are then performed to investigate the impact of dimensionless variables on overall system performance and gain a better understanding of this cyclic reaction/separation process. The results indicate that the hybrid system shows a steady-state cyclic behavior to ensure flexible operating time. A sustainability evaluation was conducted to illustrate the sustainability improvement in the proposed process compared to the traditional design. The results indicate that the integrated–intensified adsorptive-membrane reactor technology enhances sustainability by 35% to 138% for the chosen 21 indicators. The average enhancement in sustainability is almost 57%, signifying that the sustainability evaluation reveals significant benefits of the integrated–intensified adsorptive-membrane reactor process compared to HTSR + LTSR. Full article

Considering the challenges posed by traditional continuous control set model predictive control (CCS-MPC) calculations, this paper proposes an event-triggered-based model predictive control (ET-MPC). First, a novel tracking error state-space model is proposed to improve tracking performance. Second, a reduced-order extended state observer (RESO) is designed to estimate and compensate for the total disturbances, thereby effectively improving robustness against the variations of the load resistance and reference voltage. At the same time, RESO significantly reduces computational complexity and accelerates the convergence speed of state estimation. Subsequently, an event trigger mechanism is introduced to enhance the MPC with a threshold function for the converter status. Finally, the reduced-order extended state observer-based model predictive control (RESO-MPC) is compared with the proposed ET-MPC through experiments. The ripple voltage of ET-MPC is within 2%, and the computational burden is reduced by more than 57%, verifying the effectiveness of the proposed ET-MPC. Full article

Wool has distinctive biological, physical, and chemical properties that contribute to its value both for the sheep and in global fibre and textile markets. Its fibres are primarily composed of proteins, principally keratin and keratin-associated proteins (KAPs). To better comprehend the genes that underpin key wool traits, this study examined the keratin-associated protein 36-1 gene (KRTAP36-1) in Chinese Tan lambs. We identified three previously reported alleles of the gene (named A, B and C) that were present in the lambs studied, with genotype frequencies as follows: 2.0% (n = 5; AA), 6.9% (n = 17; AB), 13.8% (n = 34; AC), 8.9% (n = 22; BB), 33.4% (n = 82; BC) and 35.0% (n = 86; CC). The frequencies of the individual alleles in the Chinese Tan lambs were 12.4%, 29.1% and 58.5% for alleles A, B and C, respectively. The three alleles were in Hardy–Weinberg Equilibrium. In an association analysis, it was revealed that allele C was associated with variation in the mean fibre curvature of the fine wool of the Chinese Tan lambs, but this association was not observed in their heterotypic hair fibres. This finding suggests that KRTAP36-1 might be differentially expressed in the wool follicles that produce the two fibre types, and that along with other KRTAP genes, it may be involved in determining fibre curvature and the distinctive curly coat of the lambs. Full article

In chili cultivation, obstacles to continuous cropping significantly compromise crop yield and soil health, whereas crop rotation can enhance the microbial environment of the soil and reduce disease incidence. However, its effects on the diversity of rhizosphere soil microbial communities are not clear. In this study, we analyzed the composition and characteristics of rhizosphere soil microbial communities under chili continuous cropping (CC) and chili–cotton crop rotation (CR) using high-throughput sequencing technology. CR treatment reduced the alpha diversity indices (including Chao1, Observed_species, and Shannon index) of bacterial communities and had less of an effect on fungal community diversity. Principal component analysis (PCA) revealed distinct compositional differences in bacterial and fungal communities between the treatments. Compared with CC, CR treatment has altered the structure of the soil microbial community. In terms of bacterial communities, the relative abundance of Firmicutes increased from 12.89% to 17.97%, while the Proteobacteria increased by 6.8%. At the genus level, CR treatment significantly enriched beneficial genera such as RB41 (8.19%), Lactobacillus (4.56%), and Bacillus (1.50%) (p < 0.05). In contrast, the relative abundances of Alternaria and Fusarium in the fungal community decreased by 6.62% and 5.34%, respectively (p < 0.05). Venn diagrams and linear discriminant effect size analysis (LEfSe) further indicated that CR facilitated the enrichment of beneficial bacteria, such as Bacillus, whereas CC favored enrichment of pathogens, such as Firmicutes. Fusarium solani MG6 and F. oxysporum LG2 are the primary chili root-rot pathogens. Optimal growth occurs at 25 °C, pH 6: after 5 days, MG6 colonies reach 6.42 ± 0.04 cm, and LG2 5.33 ± 0.02 cm, peaking in sporulation (p < 0.05). In addition, there are significant differences in the utilization spectra of carbon and nitrogen sources between the two strains of fungi, suggesting their different ecological adaptability. Integrated analyses revealed that CR enhanced soil health and reduced the root rot incidence by optimizing the structure of soil microbial communities, increasing the proportion of beneficial bacteria, and suppressing pathogens, providing a scientific basis for microbial-based soil management strategies in chili cultivation. Full article