Search Results (208)

Street layout has a significant effect on accessibility and intelligibility, which ultimately affects navigation and movement efficiency. While previous research has examined planned and unplanned street patterns, most studies focus on single-scale analyses or isolated typologies, limiting understanding of how hybrid networks function across multiple spatial levels. Addressing this gap, this study investigates the effects of hybrid planned and organically evolved street layouts on spatial accessibility in Mandalay, Myanmar. The research employs space syntax analysis to assess the citywide, township-level, and micro-scale networks through measures of angular integration, choice, axial connectivity, and intelligibility. Using the Four-Point Star Model to identify Mandalay’s distinct spatial features, a global accessibility assessment compares it to 50 other cities. The results show that grid-based layouts with central townships exhibit the highest integration and connectivity, while organic and fragmented networks, particularly in Amarapura, reduce spatial coherence and accessibility. Micro-scale analysis indicates that hybrid layouts with cul-de-sacs and distorted grids can improve accessibility when they connect effectively with secondary roads. By analysing street networks across multiple spatial scales, this research presents significant implications for efficient accessibility and transport planning in mixed-pattern cities. Full article

CSN2, a highly conserved subunit of the COP9 signalosome (CSN), serves as the primary binding site for Cullin in the CSN complex. This interaction, dependent on lysine residues, positions CSN2 as a key player in approximately 20% of CRL-mediated ubiquitination reactions, a critical regulatory pathway for growth, development, and cellular processes in eukaryotes. While the role of CSN2 in human cells has been partially characterized, its function in rice (OsCSN2) remains poorly understood. Building on our previous findings regarding OsCSN2 function under natural light, this study investigates its regulatory mechanisms in rice seedlings under red and far-red light conditions. We demonstrate that under natural light, OsCSN2 mainly affects rice GA homeostasis by regulating the expression of SLR1 and influences rice photomorphogenesis by regulating the expression of the COP1-HY5 complex, thereby controlling rice growth through two pathways. Unlike under natural light, under red light, OsCSN2 promotes the expression of OsGID1, enhances the interaction between OsGID1 and OsSLR1, and promotes GA accumulation and OsPIL14 expression, leading to rice stem growth and inhibition of coleoptile elongation. Under far-red light, OsCSN2 mainly promotes the expression of OsCOP1, increasing the formation of the COP1-HY5 complex, which inhibits photomorphogenesis and coleoptile elongation. Lysine site mutations in OsCSN2 affect the interaction between the OsCSN complex and CRLs, regulating CRL-mediated ubiquitination reactions, promoting the ubiquitin-mediated degradation of OsSLR1 and OsCOP1, and thus promoting rice growth. These findings not only elucidate the functional roles of OsCSN2 in rice growth regulation but also provide valuable genetic resources for breeding rice varieties with enhanced agronomic traits. Full article

The dysregulation of CK1 isoforms is linked to various types of diseases, including neurodegeneration and different types of neoplasia such as colon, pancreatic, breast, and ovarian cancer. For CK1 isoforms, a plethora of effective small molecule inhibitors are available. However, only a few degraders of CK1α and, more recently, proteolysis targeting chimeras (PROTACs) for CK1δ/CK1ε have been reported. In this study, we applied the PROTAC concept by harnessing molecular modelling to design and synthesize a series of candidate CK1δ-targeting PROTACs based on a highly specific and potent benzothiazole-based CK1δ inhibitor that we previously developed in our lab. In the present study, we established a modular synthetic platform to systematically generate a set of PROTAC degrader candidates consisting of the CK1δ-specific inhibitor scaffold, alkyl and PEG linker motifs with various lengths, and Cereblon (CRBN)-engaging pomalidomide and thalidomide derivatives as E3 ligase binders. We demonstrate that several PROTACs degrade CK1δ/ε in various cells. The most potent PROTAC P1d inhibits the phosphorylation of downstream substrates through CK1δ/ε degradation. We establish the requirement of CUL4A^CRBN and the proteasome for the P1d-mediated degradation of CK1δ/ε. Full article

In Haiti, uncontrolled urbanization is increasing pressure on agricultural landscapes, compromising both their ecological integrity and productivity. This study examines spatio-temporal land-use changes across three agricultural plains, Cul-de-Sac, Maribahoux, and Léogâne, between 1997 and 2024, using Landsat imagery and landscape metrics of composition (percentage of landscape, PLAND) and configuration (largest patch index, LPI). The findings reveal a rapid expansion of built-up areas, primarily at the expense of farmland. In the Cul-de-Sac plain, built-up areas and bare soil grew by 152%, from 41.26 km² to 104.11 km², while agricultural land became highly fragmented (LPI dropping from 94.51% to 57.63%). In Maribahoux, urbanization was more moderate, partly offset by a temporary rise in woody vegetation that peaked at 20.04% in 2022 before declining. The Léogâne plain experienced a 17.38 km² increase in built-up areas and bare soil, alongside a slight decrease in woody vegetation. Population density showed limited differences in Maribahoux and Léogâne, but marked disparities in Cul-de-Sac, where landscape transformation was more pronounced. These findings highlight increasing fragmentation of agricultural landscapes, threatening ecological connectivity and functionality, and stress the urgent need for land-use planning that curbs urban growth, protects farmland, and safeguards biodiversity. Full article

This study reports the development of polyvinylidene fluoride (PVDF) membranes decorated with a copper(II) complex (CuL) for the removal of organic pollutants from wastewater. Using Drimaren Red X-6BN (DRX-6BN) as a probe, the PVDF membrane with the lowest CuL loading (PVDF/PDA/CuL-4) reached an adsorption capacity of 19.78 mg/g at 300 min, with removal of up to 50% DRX-6BN. Kinetic analysis favored Elovich (R² > 0.9928; RMSE < 0.4489) and the pseudo-second-order model (R² > 0.9540; RMSE < 1.1388), consistent with chemisorption. Intraparticle diffusion occurred in two steps. In the presence of 20 mg/L of hydrogen peroxide (H₂O₂), the removal was >80% within 180 min at higher CuL loadings (PVDF/PDA/CuL-40). In oily wastewater, PVDF/PDA/CuL-4 achieved ~100% COD removal in 120 min with H₂O₂, whereas pristine PVDF achieved 38.5%. Storage stability tests demonstrated the preservation of catalytic and separation performance for at least three months. All tests were conducted at pH ≈ 6.0 and a temperature of 25 °C. In contrast to many catalytic membranes, these membranes operate at near-neutral pH and ambient temperature in the absence of radiation. The results highlight PVDF membranes decorated with CuL as a robust and sustainable approach for the treatment of oily effluents, particularly by combining Fenton-like processes under mild conditions. Full article

Autism spectrum disorder (ASD) is a heritable neurodevelopmental condition with a complex genetic architecture. Dissecting the interplay between inherited variants and high-impact de novo variants is critical for understanding its etiology. We conducted a family-based study involving 42 families with ASD (139 individuals). Using a targeted next-generation sequencing (NGS) panel of 236 genes, we identified and characterized rare inherited and de novo variants in affected probands, parents, and unaffected siblings. Our analysis revealed a complex genetic landscape marked by diverse inheritance patterns. De novo variants were predominantly observed in individuals with atypical autism, while biparental (homozygous) inheritance was more common in Asperger syndrome. Maternally inherited variants showed significant enrichment in intronic regions, pointing to a potential regulatory role. We also detected variants in several high-confidence ASD risk genes, including SHANK3, MYT1L, MCPH1, NIPBL, and TSC2, converging on pathways central to synaptic function and neurogenesis. Across the cohort, five variants of uncertain significance (VUS) were identified, comprising two inherited variants in ABCC8 and additional variants in CUL23, TSC2, and MCPH1. Our findings underscore the profound genetic heterogeneity of ASD and suggest that distinct genetic mechanisms and inheritance patterns may contribute to different clinical presentations within the spectrum. This highlights the power of family-based genomic analyses in elucidating the complex interplay of inherited and de novo variants that underlies ASD. Full article

New energy vehicles face a critical challenge in balancing the thermal safety management of high-specific-energy battery systems with the simultaneous improvement of energy density. With the large-scale application of high-energy-density systems such as silicon-based anodes and solid-state batteries, their inherent thermal runaway risks pose severe challenges to battery thermal management systems (BTMS). Currently, the thermal insulation performance, temperature resistance, and fire protection capabilities of flame-retardant materials (e.g., foam cotton, fiber felts) used in automotive batteries are inadequate to meet the demands of intense combustion and high temperatures generated during thermal failure in high-energy-density batteries. Against this backdrop, thermal insulation and fireproof aerogel materials are emerging as a revolutionary solution for the next generation of power battery thermal protection systems. Leveraging their nanoporous structure’s exceptional thermal insulation properties (thermal conductivity of 0.013–0.018 W/(m·K) at room temperature) and extreme fire resistance (temperature resistance > 1100 °C/UL94 V-0 flame retardancy), aerogels are gaining prominence. This article provides a systematic review of thermal runaway phenomena in automotive batteries and corresponding protective measures. It highlights recent breakthroughs in the selection of material systems, optimization of preparation processes, and fiber–matrix composite technologies for automotive fireproof aerogel composites. The core engineering values of these materials, such as blocking thermal runaway propagation, reducing system weight, and improving volumetric efficiency, are quantitatively validated. Furthermore, the paper explores future research directions, including the development of low-cost aerogel composites and the design of organic–inorganic hybrid composite structures, aiming to provide a foundation and industrial pathway for the research and development of next-generation high-performance battery thermal management systems. Full article

TRIM48 is a human-specific tripartite motif (TRIM) family protein with E3 ubiquitin ligase activity that plays a significant role in the oxidative stress response and tumor suppression. However, the mechanisms regulating TRIM48 expression remain unknown. In this study, we demonstrate that TRIM48 is targeted for ubiquitination-dependent degradation by S-phase kinase-associated protein 1 (Skp1)-Cullin1 (Cul1)-F-box protein (SCF) ubiquitin ligase complex, containing F-box protein 22 (FBXO22) as a substrate recognition subunit. We found that TRIM48 is a rapid turnover protein, as evidenced by the fast and drastic decrease in its protein expression level in the presence of a protein synthesis inhibitor cycloheximide, which was suppressed by knocking down either Skp1, Cul1 or FBXO22. Exogenous FBXO22 expression promoted K48-linked polyubiquitination and degradation of TRIM48. FBXO22 deficiency accelerated oxidative stress-induced activation of apoptosis signal-regulating kinase 1 (ASK1) and cell death, which was reversed by additional TRIM48 knockdown. Collectively, our findings identify the FBXO22 SCF complex as a key negative regulator of TRIM48-driven ASK1-activation and cell death under oxidative stress. The dysregulation of this axis may underlie human-specific pathologies, such as tumorigenesis and oxidative stress-associated disorders, highlighting its potential as a target for novel therapeutic interventions. Full article

Cadmium (Cd) pollution poses a serious threat to freshwater ecosystems. The freshwater mussel Anodonta woodiana is increasingly used as a bioindicator for monitoring Cd pollution in aquatic environments. However, the primary routes of Cd accumulation in A. woodiana remain unclear, and the molecular regulatory mechanisms underlying Cd accumulation are poorly understood. To address these gaps, this study employed a novel stable isotope dual-tracer technique to trace Cd from water (waterborne ¹¹²Cd) and the green alga Chlorella vulgaris (dietary ¹¹³Cd) during the simultaneous exposure experiment. Comparative transcriptomic analysis was then conducted to characterize molecular responses in A. woodiana following Cd exposure. The results showed that although newly accumulated ¹¹²Cd and ¹¹³Cd increased with exposure concentration and duration, the relative importance of ¹¹²Cd (91.6 ± 2.8%) was significantly higher than that of ¹¹³Cd (8.4 ± 2.8%) (p < 0.05). Cd exposure induced differentially expressed genes primarily enriched in the metabolic processes, cellular processes, and/or the ubiquitin-mediated proteolysis pathway. Within the ubiquitin-mediated proteolysis pathway, TRIP12 (E3 ubiquitin-protein ligase TRIP12) and Cul5 (cullin-5) were significantly upregulated. The findings will provide critical insights for interpreting Cd biomonitoring data in freshwater environments using mussels as bioindicators. Full article

Background/Objectives: Immune-mediated necrotizing myopathy (IMNM) is a severe inflammatory myopathy marked by proximal muscle weakness, elevated creatine kinase (CK), and the presence of anti-HMGCR antibodies. Statin exposure is a recognized trigger for anti-HMGCR-positive IMNM, which may persist despite statin withdrawal. This pilot case series explores, for the first time, the use of bempedoic acid—a liver-specific lipid-lowering agent with minimal muscle toxicity—as an alternative to statins in these patients. Methods: We report 10 anti-HMGCR-antibody-positive IMNM patients (6 females, 4 males) previously on statins for primary prevention (8 on atorvastatin, 2 on simvastatin) without prior cardiovascular events. Statins were discontinued at myositis onset. All patients received prednisone and immunosuppressants (methotrexate in 7, mycophenolate in 3), plus bempedoic acid. Anti-HMGCR antibodies were measured using a chemiluminescence method. Results: Their mean anti-HMGCR antibody levels decreased significantly from 390.93 ± 275.22 to 220.89 ± 113.37 CU/L (p = 0.027) after 6 months of treatment. Their CK levels dropped from 1278.9 ± 769.39 to 315.1 ± 157.72 IU/L (p = 0.001), and aldolase dropped from 11.63 ± 2.18 to 6.61 ± 1.22 U/L (p = 0.0001). The mean LDL-C value was 96.1 ± 8.16 mg/dL. No disease recurrence was observed. Autoimmune panels were negative for other myositis-associated and/or -specific antibodies. Conclusions: Bempedoic acid appears to be a safe, effective, and cost-efficient lipid-lowering alternative in statin-intolerant IMNM patients. Larger studies are warranted to confirm its efficacy across different subgroups and to optimize dyslipidemia management in this setting. Full article

Background: Vitiligo, a chronic depigmentation disorder driven by oxidative stress and immune dysregulation, remains poorly understood mechanistically. The Keap1/NRF2/ARE pathway is critical for melanocyte protection against oxidative damage; however, the role of Cullin-3 (CUL3), a scaffold for E3 ubiquitin ligases that regulate NRF2 degradation, and its interplay with inflammatory mediators in vitiligo pathogenesis are underexplored. This study investigates CUL3, NRF2, and the associated regulatory networks in vitiligo, integrating clinical profiling and computational docking to identify therapeutic targets. Methods: A case-control study compared non-segmental vitiligo patients with age-/sex-matched controls. Lesional skin biopsies were analyzed by qRT-PCR for the expression of CUL3, NRF2, miRNA-146a, FOXP3, NF-κB, IL-6, TNF-α, and P53. Molecular docking was used to evaluate vitexin’s binding affinity to Keap1, validated by root mean square deviation (RMSD) calculations. Results: Patients with vitiligo exhibited significant downregulation of CUL3 (0.27 ± 0.03 vs. 1 ± 0.58; p = 0.013), NRF2 (0.37 ± 0.26 vs. 1 ± 0.8; p = 0.001), and FOXP3 (0.09 ± 0.2 vs. 1 ± 0.3; p = 0.001), alongside the upregulation of miRNA-146a (4.7 ± 1.9 vs. 1 ± 0.8; p = 0.001), NF-κB (4.7 ± 1.9 vs. 1 ± 0.5; p = 0.001), IL-6 (2.8 ± 1.5 vs. 1 ± 0.4; p = 0.001), and TNF-α (2.2 ± 1.1 vs. 1 ± 0.3; p = 0.001). P53 showed no differential expression (p > 0.05). Docking revealed a strong binding of vitexin to Keap1 (RMSD: 0.23 Å), mirroring the binding of the control ligand CDDO-Im. Conclusions: Dysregulation of the CUL3/Keap1/NRF2 axis and elevated miRNA-146a levels correlate with vitiligo progression, suggesting a role for oxidative stress and immune imbalance. Vitexin’s high-affinity docking to Keap1 positions it as a potential modulator of the NRF2 pathway, offering novel therapeutic avenues. This study highlights the translational potential of targeting the ubiquitin–proteasome and antioxidant pathways in the management of vitiligo. Full article

A Sanskrit manuscript of the Prajñāpāramitā or Perfection of Wisdom in eight thousand verses, now in the Cambridge University Library, Add.1643, is one of the most ambitiously designed South Asian manuscripts from the eleventh century, with the highest number of painted panels known among the dated manuscripts from medieval South Asia until 1400 CE. Thanks to the unique occurrence of a caption written next to each painted panel, it is possible to identify most images in this manuscript as representing those of famous pilgrimage sites or auspicious images of specific locales. The iconographic program transforms Add.1643 into a portable device containing famous pilgrimage sites of the Buddhist world known to the makers and users of the manuscript in eleventh-century Nepal. It is one compact colorful package of a book, which can be opened and experienced in its unfolding three-dimensional space, like a virtual or imagined pilgrimage. Building on the recent research focusing on early medieval Buddhist sites across Monsoon Asia and analyzing the representational potentials and ontological values of painting, this essay demonstrates how this early eleventh-century Nepalese manuscript (Add.1643) and its visual program document and remember the knowledge of maritime travels and the transregional and intraregional activities of people and ideas moving across Monsoon Asia. Despite being made in the Kathmandu Valley with a considerable physical distance from the actual sea routes, the sites remembered in the manuscript open a possibility to connect the dots of human movement beyond the known networks and routes of “world systems”. Full article

In this study, 3-chlorothiophene-2-carboxylic acid (HL) was used as a main ligand to successfully synthesize four novel complexes: [Cu(L)₂(Py)₂(OH₂)₂] (1), [Co(L)₂(Py)₂(OH₂)₂] (2) (Py = pyridine), [{Ni(L)₂(OH₂)₄}₂{Ni(L)(OH₂)₅}]L•5H₂O (3), and [{Co(L)₂(OH₂)₄}₂{Co(L)(OH₂)₅}]L•5H₂O (4). All four compounds were identified by elemental analysis and ESI mass spectrometry, and subsequently characterized by IR spectroscopy, UV-visible diffuse reflectance spectroscopy, electron paramagnetic resonance spectroscopy, thermogravimetric analysis, single-crystal X-ray crystallography, and cyclic voltammetry. X-ray analyses revealed that complexes 1 and 2 exhibit a centrosymmetric pseudo-octahedral coordination geometry; the copper (II) and cobalt (II) metal ions, respectively, are located at the crystallographic center of inversion. The coordination sphere of the copper (II) complex is axially elongated in accordance with the Jahn–Teller effect. Intriguingly, for charge neutrality, compounds 3 and 4 crystallized as three independent mononuclear octahedrally coordinated metal centers, which are two $\left[\mathrm{M}{\mathrm{L}}_2{\left({\mathrm{O}\mathrm{H}}_2\right)}_4\right]$ complex molecules and one ${\left[\mathrm{M}\mathrm{L}{\left({\mathrm{O}\mathrm{H}}_2\right)}_5\right]}^{+}$ complex cation (M = ${\mathrm{N}\mathrm{i}}^{\mathrm{I}\mathrm{I}}$ and ${\mathrm{C}\mathrm{o}}^{\mathrm{I}\mathrm{I}}$, respectively), with the ligand anion ${\mathrm{L}}^{-}$ serving as the counter ion. The anticancer activities of these complexes were systematically assessed on human leukemia K562 cells, lung cancer A549 cells, liver cancer HepG2 cells, breast cancer MDA-MB-231 cells, and colon cancer SW480 cells. Among them, complex 4 shows significant inhibitory effects on leukemia K562 cells and colon cancer SW480 cells. Full article

This article stems from the PRIN GOV_REL (Urban Governance of Interreligious Dialogue) research project carried out in four Italian cities in 2023–2025 and reports on some preliminary results of the empirical enquiry held in the city of Brescia. The Brescia area is characterised by high rates of residents with an immigrant background and a consolidated presence of religious minorities (Muslim, Orthodox, Sikh, Hindu and Protestant groups), many recognised centres (mosques, temples and Christian non-Catholic churches) and a significant commitment of ethnic–religious communities to local public life. This paper examines the creation of grassroots-level interreligious dialogue, seen as a communicative process. The empirical evidence is based on material collected by participant observations and semi-structured interviews regarding four initiatives that occurred in 2024. A sociocultural analysis outlines the communicative frame: text; context; aims; acts; interlocutors and their power/freedom of expression; interactions; results. The article examines the communicative pattern of each initiative, considering an intercultural orientation and a pluralistic model of interfaith dialogue. It seeks to answer the following questions: what was the fundamental message that the promoters wanted to convey? How do the single actors communicate their perspective of religious “others”, and what results did they achieve or not achieve? The analysis leads to identifying the patterns that facilitate and/or hamper dialogue, taking into account misunderstandings and “cul-de-sac” aspects. Final recommendations highlight the recurrent breaking points that should be prevented and some premises to guarantee successful communication between members of different religions in multicultural urban spaces. Full article