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Neural markers of attention processing in pediatric cochlear implant users: an ERP study
Low-dimensional templates and delayed crystallization for high-quality tin-based perovskite films and high-performance transistors
A knowledge-informed neural network integrating fuzzy AHP and PCA for SME credit risk assessment
Defect engineering in BaSnO3 and SrSnO3 thin films through nanoscale substrate patterning
Tauroursodeoxycholic acid-induced increase in ectopic muscle mineralization occurs exclusively in dystrophic muscles and is independent of endoplasmic reticulum stress
Abstract Calcification of dystrophic skeletal muscles was described previously and attributed, among others, to ER-stress, elevated phosphate concentration and chronic inflammation. Tauroursodeoxycholic acid (TUDCA) is considered an artificial chaperone protecting cells against ER-stress thus could prevent an ectopic mineralisation of soft tissues. Because an enhanced ER-stress is a feature of dystrophic muscles and it promotes soft tissue mineralisation we hypothesised that TUDCA treatment should reduce mineral deposits in dystrophic skeletal muscles, and tested this concept using two mouse models of DMD. Four-week old mdx, mdx βetageo and w/t mice were administered TUDCA in drinking water for 4 weeks. At 8 weeks, following tissue-clearing and calcium minerals staining with alizarin, mineralisation was evaluated using whole body scanning. Additionally, isolated skeletal muscles were analysed by Western blotting for ER-stress and calcification markers, and using various microscopic methods. Enzymatic activity of alkaline phosphatase was also assayed. Unexpectedly, TUDCA enhanced calcification of dystrophic but not dystrophin-positive muscles. TUDCA did not affect the elevated ER-stress markers found in dystrophic muscles nor impact pro-calcifying proteins RUNX2, Osterix and BMP2/4, which were also overexpressed in dystrophic muscles. The alkaline phosphatase levels, which were reduced in dystrophic muscles, were not affected by this treatment. The increase in ectopic calcification in dystrophic muscles induced by TUDCA is specific to muscles lacking dystrophin. This effect is not linked to the alleviation of ER stress or the overexpression of proteins directly involved in calcium mineral accumulation.
Pre-established ATF4 occupancy and chromatin organization instruct selective transcription activation during integrated stress response
Targeting SYK with miR-512-3p provides therapeutic potential in myocardial fibrosis
A European monsoon-like climate in a warmhouse world
An improved and simplified somatic embryogenesis protocol in Chir pine (Pinus roxburghii)
Abstract Forests are considered to be an important pillar for a country’s bioeconomy but unfortunately are being depleted globally. Pinus roxburghii has considerable ecological and economic importance for Pakistan. It is successfully used as a pioneer species in afforestation and reforestation programs in the era of climate change. This paper reports on a significantly improved protocol for P. roxburghii somatic embryogenesis. Successive developmental stages for zygotic as well as somatic embryos were reported first time for this important pine species. Initiation of somatic embryogenesis was affected by the developmental stage of the zygotic embryo. Immature pre-cotyledonary zygotic embryos produced 33% initiation of embryonic masses on LP-889 medium supplemented with 11 µM Naphthaleneacetic acid (NAA), 2.5 µM Benzylaminopurine (BAP), 2.5 µM kinetin and 4 µM Abscisic acid (ABA). LP-1250 medium provided with 2 µM BAP, 2 µM kinetin, 5 µM 2, 4-Dichlorophenoxyacetic acid (2, 4-D) and 5 µM ABA was used for the proliferation and maintenance of embryogenic tissue. Polarized immature somatic embryos were clearly visible during the proliferation and maintenance phase. Two media; mLV and LP-1562 were tested as well as several combinations of L-glutamine and ABA for maturation. Maximum number of somatic embryos (310 embryos per g embryogenic tissue) was obtained on LP-1562 medium (containing 450 mg/l of L-glutamine and 20 µM ABA) as compared to 204 embryos per g embryogenic tissue on mLV medium (containing 900 mg/l L-glutamine and 60 µM ABA). Mature somatic embryos were formed on maturation medium after 6–8 weeks. Successful conversion of somatic embryos resulted after 12 weeks on LP-397 medium. However, low rooting rates (7% and 3%) were observed for somatic embryos formed on maturation media, i.e. LP-1562 and mLV, respectively and precocious germination of the mature somatic embryos still remains a serious constraint.
Link between cascade phenomenon and correlated Chern insulators in magic-angle twisted bilayer graphene
A high-performance adaptive fusion network for face anti-spoofing detection
Structural and dynamic insights into the biased signaling mechanism of the human kappa opioid receptor
Abstract The κ-opioid receptor (KOR) is a member of the G protein-coupled receptor (GPCR) family, modulating cellular responses through transducers such as G proteins and β-arrestins. G-protein-biased KOR agonists aim to retain analgesic and antipruritic actions while limiting aversion and sedation. Aiming to inform G-biased KOR agonist design, we analyze signaling-relevant residues from structural and dynamic views. Here we show, using multiple complementary methods, shared residues that determine β-arrestin recruitment by nalfurafine and U-50,488H. Cryo-electron microscopy structures of the KOR-G i signaling complexes identify the ligand binding mode in the activated state. Vibrational spectroscopy reveals ligand-induced conformational changes. Cell-based mutant experiments pinpoint four amino acids (K227 5.40 , C286 6.47 , H291 6.52 , and Y312 7.34 ; Ballesteros–Weinstein numbering is shown in superscript) that play crucial roles in β-arrestin recruitment. Furthermore, MD simulations revealed that the four mutants tend to adopt conformations with reduced β-arrestin recruitment activity. Our research findings provide a foundation for enhancing KOR-mediated therapeutic effects while minimizing unwanted side effects by targeting specific residues within the KOR ligand-binding pocket, including K227 5.40 and Y312 7.34 , which have previously been implicated in biased signaling.
Genomic insights into biosynthetic gene cluster diversity and structural variability in marine bacteria
Permeation enhancer-induced membrane defects assist the oral absorption of peptide drugs
Abstract The passive membrane permeation of small-molecule drugs and small hydrophobic peptides is relatively well understood. In contrast, how long polar peptides can pass through a membrane has remained a mystery. This process can be achieved with permeation enhancers, contributing significantly to the oral transcellular absorption of important peptide drugs like semaglutide — the active pharmaceutical ingredient in Ozempic, which is used as Rybelsus in a successful oral formulation. Here we now provide a detailed, plausible molecular mechanism of how such a polar peptide can realistically pass through a membrane paired with the permeation enhancer salcaprozate sodium (SNAC). We provide both simulation results, obtained with scalable continuous constant p H molecular dynamics (C p HMD) simulations, and experimental evidence (NMR, DOSY, and DLS) to support this unique permeation mechanism. Our combined evidence points toward the formation of permeation-enhancer-filled, fluid membrane defects, in which the polar peptide can be submerged in a process analogous to quicksand.
Sialyl-Tn expression correlates with reduced c-Myc and immune modulation in triple negative breast cancer
Abstract Triple negative breast cancer (TNBC) is an aggressive, heterogeneous cancer with lack of targeted therapies. The cancer-associated sialyl-Tn (STn) antigen has a significant role in cancer, yet its involvement in TNBC remains unexplored. This study investigates STn’s role in TNBC, analysing its expression in the primary tumour tissues of 126 TNBC patients alongside other biomarkers and clinical features. STn was detected in 23.8% of cases, exhibiting significantly reduced survival and lower c-Myc expression. Additionally, data from The Cancer Genome Atlas (TCGA) TNBC cohort confirmed this association, showing that high levels of ST6GALNAC1 , gene encoding the enzyme responsible for the STn synthesis, were inversely correlated with MYC expression and positively associated with TGF-β signalling genes and immunosuppressive cell infiltrates, such as macrophages M2 and regulatory T cells. Accordingly, STn-positive TNBC cell lines exhibited increased proliferation and lower c-Myc protein expression, while co-culture with macrophages enhanced M2 polarization. This study discloses, for the first time, a subgroup of TNBC patients expressing the STn antigen, pointing to an immunosuppressive environment that may lead to the observed negative correlation between STn and c-Myc. These results introduce STn as a potential prognostic biomarker and therapeutic target, laying the groundwork for more effective, personalized treatments for TNBC.
Cell autonomous polarization by the planar cell polarity signaling pathway
Conservation hints for Pinna nobilis from a century-old genetic time capsule
Abstract The noble pen shell, Pinna nobilis, is an iconic marine bivalve endemic to the Mediterranean Sea, playing a key role as an ecosystem engineer. Over the past century, it has faced severe threats from overharvesting, pollution, and catastrophic mass mortality events. This study analysed 119 mitochondrial COI gene sequences from historical (1700s, 1920s, 1970s, 1990s) and modern (2000s) samples, including survivors of recent mass mortality crises. We standardised a protocol to extract DNA from ancient byssus samples over a century old and dated the emergence of the mitochondrial lineages of Pinna nobilis , uncovering its evolutionary history in unprecedented detail. Our findings suggest two main temporal origins for the species’ genetic variation: (i) a group of modern lineages directly descended from Pinna nobilis early ancestors originating 2.5 mya, and (ii) a large group derived from the first Pleistocene radiation of the species, approximately 1.5 mya. Importantly, our research depicts the evolutionary response of Pinna nobilis to three major challenges in the last century: human overexploitation, pollution, and environmental changes. Our results highlight the species’ remarkable resilience, likely mediated by Pleistocene genetic traits, whose persistence over time mainly depends on the maintaining of a high effective population size to ensure successful recruitment.
Liquid metal interface enables glassy MOF membranes with defect-mediated CO₂ transport
Abstract Glassy metal–organic frameworks (MOFs) combine structural disorder with thermal processability, yet their use as membranes has been hindered by difficulties in fabricating thin, continuous and defect-free films. Here we show a float glass–inspired strategy in which liquid gallium guides the vitrification of ZIF-62 into freestanding glassy MOF membranes. By matching surface energy between melt and bath, dewetting is suppressed, enabling uniform membranes with tunable thickness. In pure glassy MOF membranes, uncoordinated nitrogen sites generated during melting enhance CO₂ diffusion, experimentally validating a sorption-assisted transport mechanism. Post-synthetic methylation of these sites reverses CO₂/H₂ selectivity and raises activation energy. We further identify a glassy impurity phase of ZIF with zni topology that emerges under specific conditions, diminishing CO₂ uptake and membrane performance. These results establish how interfacial control and defect engineering together enable high-performance glassy MOF membranes and provide an experimental foundation for probing structure–transport relationships in disordered porous materials.