Search Results (336)

Background/Objectives: The development of specific inhibitors for cyclooxygenase-2 (COX-2) is a challenge for public health. A series of 17 N-phthalimide hybrids was evaluated using a functional M06 meta-GGA hybrid in combination with a polarized 6-311G (d, p) basis set. The top three candidates (6, 10, and 17) were synthesized and evaluated as selective COX-2 inhibitors of PGE-2 using an integrated in silico–in vitro approach. Methods: Molecular docking against COX-2 (PDB 5KIR) and COX-1 (PDB 6Y3C), supported by homology modeling and DFT geometry optimization (B3LYP/6-31G*), revealed that the phthalimide carbonyl groups and the 3,4,5-trimethoxyphenyl or geranyl-derived moieties establish key hydrogen bonds and hydrophobic contacts with Arg120, Tyr355, Tyr385, and Ser530 in the COX-2 active site, conferring predicted selectivity ΔGCOX−2 vs. COX−1 = −1.4 to −2.8 kcal/mol. Results: The compounds complied with Lipinski’s and Veber’s rules and displayed favorable ADMET profiles. In vitro assessment in LPS-stimulated J774A.1 murine macrophages confirmed potent inhibition of PGE₂ production, 3.05 µg/mL, with compound 17 exhibiting the highest efficacy, 97.79 ± 5.02% inhibition at 50 µg/mL, and 10 showing 95.22 ± 6.03% inhibition at 50 µg/mL. Notably, all derivatives maintained >90% cell viability up to 250 µg/mL by resazurin assay and showed no evidence of cytotoxicity or mitosis potential in the tests at 24 h. Conclusions: These results demonstrate that strategic hybridization of phthalimide with natural and synthetic product-derived fragments yields highly potential PGE2 inhibitors. Therefore, compounds 6, 10, and 17 are promising lead candidates for the development of safer anti-inflammatory agents. Full article

PARP inhibitors are a clinically validated class of anticancer therapeutics that exploit synthetic lethality to target homologous recombination-deficient tumors, such as those carrying BRCA1/2 mutations. Nevertheless, the rational design of mitochondria-targeted PARP inhibitors capable of selective mitochondrial accumulation and organelle-specific PARP modulation remains an unresolved objective. To enable organelle-specific modulation of PARP activity, we synthesized a series of trialkyl(aryl)phosphonium conjugates of olaparib and rucaparib designed to target mitochondria by cardiolipin binding. Their activity was evaluated by PARP1 inhibition, cardiolipin affinity, and cytotoxicity in BRCA1-deficient HCC1937 breast cancer cells and non-malignant H9C2 cardiomyocytes. All conjugates retained potent PARP1 inhibition (IC₅₀ = 3.4–17 nM), comparable to the parent drugs. Several derivatives, particularly compounds 2d and 6c, exhibited strong cardiolipin binding (EC₅₀ = 12.99 µM and 6.77 µM, respectively) and significantly enhanced cytotoxicity in HCC1937 cells (IC₅₀ = 0.93 and 2.01 µM), outperforming olaparib and rucaparib. Notably, cytotoxicity toward H9C2 cells was lower, indicating a favorable selectivity profile. Phosphonium conjugation preserves PARP1 inhibitory activity while conferring mitochondrial targeting and enhanced anticancer potency. These findings support the development of mitochondria-targeted PARP inhibitors as a next-generation therapeutic strategy with the potential to improve efficacy and overcome resistance in HR-deficient tumors. Full article

The present work explores the viscoelastic properties of a homologous series of organosilicon fluids (polymethylsiloxane fluids) using the acoustic resonant method at a frequency of shear vibrations of approximately 100 kHz. The resonant method is based on investigating the influence of additional binding forces on the resonant characteristics of the oscillatory system. The fluid under study was placed between a piezoelectric quartz crystal that performs tangential oscillations and a solid cover plate. Standing shear waves were established in the fluid. The thickness of the liquid layer was much smaller than the length of the shear wavelength, and low-amplitude deformations allowed for the determination of the complex shear modulus G* in the linear region, where the shear modulus has a constant value. The studies demonstrated the presence of a viscoelastic relaxation process at the experimental frequency, which is several orders of magnitude lower than the known high-frequency relaxation in liquids. In this work, the relaxation frequency of the viscoelastic process in the studied fluids and the effective viscosity were calculated, and the lengths of the shear wave and the attenuation coefficients were determined. Full article

To address gaps in the characterization of Roman chamomile (Anthemis nobilis L., Asteraceae)—an ethnobotanically and commercially important species—we profiled its essential oil (EO), focusing on esters that are incompletely characterized or unreported. Comprehensive GC-MS of two commercial EOs and their chromatographic fractions, combined with synthesis and co-injection of reference compounds, enabled the identification of 190 constituents. We uncovered a homologous series of angelates, tiglates, and senecioates by partial-ion-current (PIC) screening (m/z 55, 83, 100, 101), augmented by co-injection and NMR confirmation. Among these EO constituents, four esters, methallyl 3-methylbutanoate (6h), methallyl senecioate (3h), 3-methylpentyl 2-methylbutanoate (5c), and 5-methylhexyl angelate (2g) are reported here as new natural products and previously unreported compounds in the literature. Selected methacrylates and related α,β-unsaturated esters underwent model Michael additions to methanethiol (generated in situ from dimethyl disulfide and NaBH₄), confirming their thiol-acceptor reactivity. In an Artemia salina assay, the EO and most esters were non-toxic; methacrylates showed only low toxicity at the highest concentrations. These results refine the chemical map of A. nobilis EO and highlight specific ester families for future mechanistic and biological evaluation. Full article

Both s-tetrazine and picric acid are widely known compounds in the realm of high-energy materials. We had previously taken an interest—mostly supramolecular, i.e., directed at the elucidation of lone pair–π interactions—in the crystal packing of phases containing s-tetrazine-based cations and picrate anions. Herein we report two novel compounds of this family: H₂L4(picr)₂ and (H₂L5)₂(picr)₄; the former is a polymorph of a previously reported compound of a homologous host series (3,6-bis(4-morpholinobutyl)-1,2,4,5-tetrazine), the latter a salt of the commercially available 3,6-di(pyridin-4-yl)-1,2,4,5-tetrazine. The new phases were investigated via XRD: main interactions, crystal packing, and potential slip planes are discussed. Thermal analysis (DSC/TGA) was conducted for L5 and (H₂L5)₂(picr)₄. Enthalpies of formation (thermochemical cycles/DFT) and in silico explosion parameters (EXPLO5) are reported for all compounds. Overall, the data herein reported improve the understanding of the correlation among supramolecular/packing details and the resulting explosive properties. Full article

Angiosperms include many taxa with dimorphic unisexual reproductive structures. These are well studied in some grasses, with maize as a key model, but other wind-pollinated lineages in Poales remain less explored. Within Poales, the family Restionaceae has the highest known proportion of dioecious species. In its Australian subfamily Leptocarpoideae, the sexually dimorphic Leptocarpus denmarkicus has raised questions about the basic flowering unit and the developmental basis of dimorphism. Here, we analyze inflorescence architecture and floral development in Eurychorda complanata, the sister lineage to the remainder of Leptocarpoideae. Using comparative morphology, light microscopy and scanning electron microscopy, we reconstruct synflorescence topology, floral organography, and ontogeny in both sexes and compare them with those in L. denmarkicus. In Eurychorda, both sexes produce polytelic paniculate synflorescences with distinct inhibition zones and many-flowered simple spikelets as the basic flowering unit. Male and female spikelets bear up to 50 and up to 15 fertile flowers, respectively. Male flowers have two stamens and a dimerous pistillode, whereas female flowers possess two long filamentous staminodes and a dimerous gynoecium. Ontogenetic series show that flowers of both sexes initiate both androecial and gynoecial structures, and that functional unisexuality is achieved through late arrest of the organs of one sex. Defining spikelets as racemose axes with lateral sessile flowers clarifies homologies of reproductive structures and supports reinterpretation of the dimorphic female unit in L. denmarkicus as a derived compound spike generated through shifts in branching rank and the timing of lateral initiation. The compound female spike of L. denmarkicus has a striking overall similarity to the simple female spikelet in Eurychorda, illustrating fascinating parallelism in the evolution of reproductive organs within Restionaceae and Poales more broadly. At the male side, Eurychorda achieves anther exsertion via filament elongation, whereas in L. denmarkicus filaments are very short and anthers remain within the perianth, but male spikelets sit on long, flexible peduncles that invert the spikelet and promote trembling, thereby ventilating the perianth chamber and aiding pollen escape. These two solutions—filament elongation versus spikelet-peduncle flexibility—represent alternative strategies of pollen release in wind-pollinated flowers. Full article

Background: Pembrolizumab has reshaped the neoadjuvant treatment landscape for triple-negative breast cancer (TNBC). However, the influence of BRCA1/2 mutational status on the efficacy of chemo-immunotherapy remains unclear, particularly in real-world settings. Since BRCA-mutated tumors exhibit homologous recombination deficiency (HRD) and high genomic instability, they may be more immunogenic and responsive to immune checkpoint inhibitors. This multicenter study investigated the association between BRCA1/2 mutations and pathologic complete response (pCR) in TNBC patients treated with pembrolizumab-based neoadjuvant chemotherapy (NACT). Methods: We retrospectively analyzed 184 patients with stage II–III TNBC treated between 2021 and 2024 across eleven Italian oncology centers. All received pembrolizumab combined with platinum- and taxane-based NACT followed by anthracyclines, according to the KEYNOTE-522 regimen. Germline BRCA1/2 status was determined by next-generation sequencing. The primary endpoint was pCR, defined as ypT0/is ypN0. Fisher’s exact test and logistic regression models were used to assess associations between clinical–pathological variables and pCR. Results: Among 184 patients, 25 (13.6%) harbored BRCA1 mutations, 12 (6.5%) BRCA2 mutations, and 147 (79.9%) were wild-type. pCR was achieved in 80.0% of BRCA1-mutated, 75.0% of BRCA2-mutated, and 61.1% of wild-type tumors. When pooled, BRCA1/2-mutated cases showed a higher likelihood of achieving pCR (78.4% vs. 61.1%; odds ratio [OR] = 2.17; 95% CI 1.01–4.97; p = 0.056). High tumor-infiltrating lymphocytes (≥30%) were also associated with increased pCR rates. The frequency of BRCA mutations (20.1%) was consistent with that reported in major TNBC series. No comparative analysis of toxicity or survival outcomes was performed due to the retrospective design and limited follow-up. Conclusions: In this multicenter real-world cohort, TNBC patients carrying BRCA1/2 mutations exhibited a trend toward higher pCR rates with pembrolizumab-based NACT compared with wild-type tumors. These findings suggest enhanced chemosensitivity and immune responsiveness in BRCA-deficient disease, warranting further validation in larger prospective studies with survival endpoints. Full article

This study presents a computational framework combining Dynamic Time Warping (DTW) and Persistent Homology to quantify the long-term morphological evolution of the Sendai coastline following the 2011 Tōhoku tsunami. Using multispectral satellite imagery from Landsat 5 TM, Landsat 8 OLI, and Sentinel-2 MSI (2010–2024), instantaneous shorelines were extracted via the Modified Normalized Difference Water Index (MNDWI) and reconstructed with parametric B-spline curves. DTW analysis indicated severe initial deformation, with a 90,927 m difference between pre- and post-tsunami instantaneous shorelines, followed by gradual stabilization as distances declined to 59,584 m by 2024. Persistent Homology revealed a more complex topological trajectory, with the number of 1-dimensional features (H1) rising sharply after the tsunami, consolidating by 2015, and expanding again to over 8000 by 2020–2024. The Stable Distance of Persistent Homology (SDPH) identified 2015–2020 as the key phase of transformation (38,088 m), marking a shift toward higher morphological complexity. A weak negative correlation (r = −0.362) between DTW and SDPH confirmed their complementarity in describing geometric and topological change. Overall, the results suggest that post-tsunami recovery followed a non-linear path toward a new dynamic equilibrium characterized by increased structural complexity and resilience. Full article

Colletotrichum gloeosporioides causes rubber tree anthracnose and leads to serious loss in natural rubber production. Autophagy is a highly conserved process to maintain nutrient recycling and plays important roles in growth, development and pathogenicity in plant pathogenic fungi. The process of autophagy is modulated by a series of autophagy-related (ATG) genes. ATG16 is a subunit of the ATG12-ATG5-ATG16 complex which functions in a manner analogous to an E3-like enzyme which is essential for autophagosome formation. However, the function of the ATG16 homolog in C. gloeosporioides remains unknown. In this study, the ATG16 homolog of C. gloeosporioides was identified and named as CgATG16. The expression level of CgATG16 was particularly higher in conidium, germination, appressorium, and the early stage of infection, and significantly induced by nutritional deficiency. Absence of CgATG16 led to slower colony growth, decreased conidia production and germination rate, longer germ tube cells, lower appressorium formation rate and impaired pathogenicity to rubber tree leaves. Absence of CgATG16 resulted in lower melanin content with decreased expression of polyketide synthase gene CgPKS1 and scytalone dehydratase gene CgSCD1. Moreover, absence of CgATG16 also led to the universal autophagy marker ATG8-GFP failing to enter into the vacuoles in mycelium and during appressorium development with a significantly reduced autophagosome number. Both rapamycin and cyclic adenosine monophosphate (cAMP) partially restored the appressorium formation ability in CgATG16 knockout mutant. Absence of CgATG16 increased the activity of target of rapamycin (TOR) kinase and decreased the content of cAMP. These data suggest that CgATG16 contributes to the pathogenicity of C. gloeosporioides to the rubber tree by regulating the mycelium growth, melanin synthesis and the formation of invasion structure, and this process is related to autophagy mediated by TOR and cAMP signaling. Full article

Medium-chain aliphatic compounds bearing oxygen-containing functional groups—such as alcohols, ketones, or carboxylic acids—have attracted increasing attention due to their potential as bioactive agents in pest management. These compounds have demonstrated diverse biocidal properties, including insecticidal, antimicrobial, fungicidal, and nematicidal activities. In this study, the nematicidal potency of three structurally related C9 aliphatic ketones—2-nonanone, 3-nonanone, and 5-nonanone—was evaluated against Bursaphelenchus xylophilus, the pinewood nematode (PWN). These isomeric ketones differ in the position of the carbonyl group, providing a useful model for examining structure–activity relationships (SAR) among positional isomers. The direct-contact bioassays, performed at 1 mg/mL, revealed that 2-nonanone exhibited the highest nematicidal activity, causing 92.3 ± 1.2% mortality on the PWN, followed by 3-nonanone at 80.1 ± 0.8%, while 5-nonanone showed significantly lower activity at 17.1 ± 0.5%. The results suggest a strong dependency of bioactivity on the position of the carbonyl group along the carbon chain. The increasing efficacy from 5- to 2-nonanone suggests that proximity of the carbonyl group to the terminal end may enhance activity, for example, by enhancing membrane interaction or disrupting nematode metabolic processes. These findings underscore the importance of molecule structure analysis in designing effective nematicidal agents and support further investigation into terminally positioned oxygenated medium-carbon chain aliphatic compounds as potential leads. This work highlights that subtle structural differences within homologous series can significantly influence bioactivity and provides a foundation for developing targeted, biodegradable nematicides derived from simple aliphatic frameworks. Full article

Imidazolium-based ionic liquids bearing a homologous series of oxychlorine anions—1-butyl-3-methylimidazolium chlorite, chlorate, and perchlorate—were synthesized and characterized to relate anion oxygenation to density, thermal expansivity, viscosity, electrical and molar conductivity, ionicity, and antimicrobial performance. Temperature-dependent measurements were carried out from 293.15 to 323.15 K: density and viscosity were recorded and modeled to obtain thermal expansion coefficients; electrical and molar conductivities were measured under identical conditions; and activation parameters were extracted by Arrhenius analysis for viscous flow and for conductivity. Ionicity was assessed from Walden plots and quantified by vertical deviation from the potassium-chloride reference (Angell approach). Complementary DFT calculations provided optimized ion-pair geometries, noncovalent contact patterns, molecular electrostatic potential maps, and frontier-orbital descriptors. In silico ADMET properties were computed to contextualize pharmacokinetic and safety flags. Antimicrobial activity was evaluated by broth microdilution against Escherichia coli, Staphylococcus aureus, Bacillus cereus, and Candida quilliermondii; [Bmim]Cl was included as a comparator to isolate the effect of anion oxygenation. The combined experimental–computational workflow delineates how chlorite, chlorate, and perchlorate shape physicochemical behavior, ionicity, and bioactivity in [Bmim] ionic liquids, providing design guidance for future applications. Full article

Background: Dose-sparing approaches can be effective in maintaining immunogenicity and safety while expanding vaccine coverage. We previously demonstrated that a half dose of ChAdOx1 nCoV-19 is as effective and immunogenic for primary vaccination. Methods: This non-inferiority, non-randomized controlled trial evaluated the effectiveness, humoral, and cellular immune responses of a third booster dose—comparing half-dose and full-dose regimens—in individuals aged 18–49 years, with a 1-year follow-up. Results: A total of 2801 participants were enrolled: 2352 received half doses and 449 received full doses. The incidence rate of COVID-19 was 225.0 per 1000 person-years in the half-dose group and 173.8 in the full-dose group, with no significant difference in effectiveness (β = −0.05; 95% CrI: −0.24 to 0.15). No deaths occurred, and hospitalization rates were similar. In a subsample (n = 558), anti-S IgG levels peaked 28 days post-dose and declined by day 180 after the primary series [175 (121–252) vs. 121 (71–208) GMT, p < 0.001], but remained elevated after the booster [192.1 (124–297) vs. 550 (380–797) GMT, p < 0.001]. Booster antibody levels were similar between groups [592.4 (318–1140) vs. 550 (380–797) GMT]. The half-dose group showed high titers against Omicron and robust T/B-cell responses (e.g., EMCD4, EMCD8, IFN⁺CD4⁺, CD19⁺TNF⁺). Conclusions: Fractional half dose of ChAdOx nCov-19 was effective and non-inferior to a full booster dose. Homologous regimen with 3 half doses or 3 full doses induced a similar increase in antibody titers and robust cellular response. ClinicalTrials.gov (NCT05059106). Full article

Background/Objectives: X-linked hypophosphatemia (XLH) is the most common form of inherited rickets, caused by pathogenic mutations in the PHEX gene (phosphate-regulating endopeptidase homolog, X-linked). These mutations increase fibroblast growth factor 23 (FGF23) activity, resulting in renal phosphate wasting and defective bone mineralization. The disorder manifests with variable skeletal, dental, and extraskeletal involvement. Conventional therapy with oral phosphate and active vitamin D offers limited benefit, whereas burosumab, an anti-FGF23 monoclonal antibody, has transformed disease management. Methods: The index case, a 43-year-old woman, remained undiagnosed until adulthood, leading to severe deformities, osteoarthritis, chronic pain, and complete edentulism. Her 55-year-old sister presented with a milder phenotype. The 20-year-old nephew, diagnosed in childhood and intermittently treated with phosphate and alfacalcidol, developed short stature, genu varum, and early degenerative joint disease. Following genetic confirmation, he began burosumab therapy, which normalized phosphate metabolism, reduced pain, and improved mobility. Results: XLH demonstrates marked intrafamilial phenotypic variability despite identical PHEX mutations. In this series, delayed recognition in adults led to irreversible skeletal deformities, osteoarthritis, and dental loss, whereas earlier diagnosis in the younger patient allowed timely intervention. Conventional therapy only partially mitigated complications, while burosumab achieved rapid biochemical correction and symptomatic improvement. This contrast highlights the importance of early genetic testing, family screening, and prompt initiation of targeted treatment. Conclusions: This family cluster underscores the critical need for early diagnosis, genetic confirmation, cascade screening, and lifelong multidisciplinary care. Burosumab represents a therapeutic paradigm shift in XLH, capable of altering disease trajectory when initiated early. Full article

Change points caused by extreme events in global economic markets have been widely studied in the literature. However, existing techniques to identify change points rely on subjective judgments and lack robust methodologies. The objective of this paper is to generalize a novel approach that leverages topological data analysis (TDA) to extract topological features from time series data using persistent homology. In this approach, we use Taken’s embedding and sliding window techniques to transform the initial time series data into a high-dimensional topological space. Then, in this topological space, persistent homology is used to extract topological features which can give important information related to change points. As a case study, we analyzed 26 stocks over the last 12 years by using this method and found that there were two financial market volatility indicators derived from our method, denoted as $L_1$ and $L_2$. They serve as effective indicators of long-term and short-term financial market fluctuations, respectively. Moreover, significant differences are observed across markets in different regions and sectors by using these indicators. By setting a significance threshold of 98 % for the two indicators, we found that the detected change points correspond exactly to four major financial extreme events in the past twelve years: the intensification of the European debt crisis in 2011, Brexit in 2016, the outbreak of the COVID-19 pandemic in 2020, and the energy crisis triggered by the Russia–Ukraine war in 2022. Furthermore, benchmark comparisons with established univariate and multivariate CPD methods confirm that the TDA-based indicators consistently achieve superior F1 scores across different tolerance windows, particularly in capturing widely recognized consensus events. Full article

We propose a strictly causal early–warning framework for financial crises based on topological signal extraction from multivariate return streams. Sliding windows of daily log–returns are mapped to point clouds, from which Vietoris–Rips persistence diagrams are computed and summarised by persistence landscapes. A single, interpretable indicator is obtained as the $L_2$ norm of the landscape and passed through a causal decision rule (with thresholds $\alpha ,\beta$ and run–length parameters $s,t$) that suppresses isolated spikes and collapses bursts to time–stamped warnings. On four major U.S. equity indices (S&P 500, NASDAQ, DJIA, Russell 2000) over 1999–2021, the method, at a fixed strictly causal operating point $(\alpha =\beta =3.1,s=57,t=16)$, attains a balanced precision–recall ($F_1\approx 0.50$) with an average lead time of about 34 days. It anticipates two of the four canonical crises and issues a contemporaneous signal for the 2008 global financial crisis. Sensitivity analyses confirm the qualitative robustness of the detector, while comparisons with permissive spike rules and volatility–based baselines demonstrate substantially fewer false alarms at comparable recall. The approach delivers interpretable topology–based warnings and provides a reproducible route to combining persistent homology with causal event detection in financial time series. Full article