Search Results (880)

Background/Objectives: Isolated methylmalonic acidemia (iMMA) is a rare autosomal recessive metabolic disorder caused by defects in methylmalonyl-CoA mutase (MCM) activity or in the biosynthesis of its cofactor, adenosylcobalamin. Mutations in five genes—MMUT, MMAA, MMAB, MMADHC, and MCEE—are known to underlie this condition. This study aimed to characterize the clinical features and molecular spectrum of iMMA in Malaysian patients of diverse ethnic backgrounds. Material and Methods: Patients with biochemical evidence suggestive of iMMA, including elevated propionylcarnitine (C3), increased C3/C2 ratio, and raised urine methylmalonic acid levels in the absence of hyperhomocysteinemia, were selected for genetic testing. Sanger sequencing was performed to identify pathogenic variants in the MMUT, MMAA, MMAB, MMADHC, or MCEE genes. Results: The cohort consisted predominantly of Iban patients (n = 5), with the remaining cases comprising one Malay and one Thai–Malay individual. Age at diagnosis ranged from Day 1 of life to 6 years. All 7 patients were confirmed to have iMMA through molecular analysis. A total of seven pathogenic or likely pathogenic variants were identified, including two novel MMUT variants (c.246_250delinsGA and c.1358G>C), four known MMUT variants (c.560C>G, c.693C>G, c.982C>T, c.1106G>A), and one known MMAB variant (c.644+1G>A). Clinical presentation and disease severity varied across cases, reflecting underlying genotypic heterogeneity. Conclusions: This study highlights the molecular diversity and clinical variability of iMMA in Malaysia. Our findings reinforce the importance of integrating metabolic screening with molecular diagnostics to identify disease-causing variants and guide patient management strategies effectively. Full article

Xylaria karsticola NBIMCC 9097 is a recently described and rare fungicolous species originating from Bulgaria. Understanding its growth behavior and bioactive potential is essential for evaluating its biotechnological and pharmaceutical relevance. In the presented study, we model the in vitro growth kinetics of X. karsticola mycelium under submerged cultivation and assess its antimicrobial activity. Optimization of MCM and MYB media markedly increased biomass yields to 20.11 and 23.25 g/dm³, respectively, compared with non-optimized media (9.9 ± 0.21 and 10.8 ± 0.28 g/dm³). The maximum specific growth rate was higher in the MCM (0.803 ± 0.004 h⁻¹) in comparison with the MYB medium (0.711 ± 0.003 h⁻¹); however, the MYB medium supported greater biomass accumulation and more efficient substrate utilization, reflected by a higher utilization coefficient (0.9900 ± 0.001 versus 0.9644 ± 0.005). The antimicrobial activity was evaluated using agar disk diffusion and minimum inhibitory concentration assays against Gram-positive and Gram-negative bacteria and yeasts. Hexane and ethyl acetate extracts were most effective against Pseudomonas aeruginosa ATCC 9027 (MIC 0.067 and 0.059 mg/cm³), while notable anti-yeast activity was observed, particularly against Wickerhamomyces anomalus, Saccharomycodes ludwigii, and Pichia membranifaciens. The lowest MIC (0.02 mg/cm³) was recorded for the water biomass extract against S. ludwigii indicating potent antimicrobial activity against the tested microorganism. These findings identify X. karsticola as a potential source of antimicrobial metabolites and provide a strong motivation for comprehensive metabolomic profiling and systematic optimization of its cultivation. Full article

Background: Dendroctonus armandi, an oligophagous beetle primarily infesting Pinus armandii, is geographically restricted and persistent in central China, causing significant ecological and economic losses. However, the intrinsic factors driving its continuous occurrence remain unclear. We examined the genetic variation patterns across the species’ range to explore its phylogeographic structure. Methods: We analyzed mitochondrial DNA sequence (mtDNA) data to assess population genetic structure and estimate the divergence times of distinct lineages. Results: Phylogenetic analysis identified four haplogroups corresponding to the Minshan (MSM), Qinling (QLM), Micang (MCM), and Ta-pa (TPM) Mountains. Demographic analyses revealed that QLM and TPM haplogroups have undergone population expansion events. Divergence time estimates indicated four lineages diverged during the Late Pleistocene. Notably, D. armandi may have followed two horizontal and one vertical independent colonization routes. The first route extended from MSM into QLM and then spread eastward along the QLM; the second route progressed from MSM into MCM and continued eastward into TPM; and the third route migrated southward from QLM into TPM. Conclusions: Climate oscillations, geographical isolation, and the patchy distribution of host trees collectively shaped the phylogeographic patterns of D. armandi. These findings elucidate the evolution and adaptability of D. armandi in mountainous environments. Full article

Triple-negative breast cancer (TNBC), particularly the androgen receptor-low (AR-low) subtype, is one of the most aggressive and hard-to-treat forms of BC, characterized by a high index of proliferation, chromosomal instability (CIN), and high prevalence of TP53 mutations. These features fuel therapy resistance, metastases, and poor clinical outcomes. An integrated framework describing the dysregulated molecular networks that support the pathobiology of AR-low TNBC is lacking. Multiple published studies in breast cancer have previously proposed mechanistic links between TP53 loss, AR-low states, and heightened FOXM1-driven G2/M transcriptional programs, potentially via deregulation of E2F activity, chromatin-associated co-regulators (e.g., ATAD2), and disruption of repressive networks involving p53–p21–DREAM and SPDEF. Additional reports suggest that FOXM1-associated circuitry may be reinforced by chromatin regulators such as WDR5 and by mitotic/spindle factors such as ASPM, including through feedback interactions and condensate-associated transcriptional organization. We previously showed that FOXM1, a master regulator transcription factor, is upregulated and is a biomarker of poor prognosis in AR-low TNBC. In this study, we filtered a set of “TNBC core genes” known to promote transcriptional chaos downstream of FoxM1. We identified a set of 15 cell cycle regulators—including mitotic kinesin motors (KIF14, KIF11, KIF4A, KIF2C, and KIF20A), centromeric proteins (CENPA, CENPO, CENPL, CENPF, and OIP5), and regulators of proteolysis (UBE2C, UBE2S, UBE2T, PSMD14, and TUBA1B). These 15 genes, which were ranked highly among genes overexpressed in TNBC featured prominently in gene signatures of chromosomal instability and were also overexpressed among AR-low TNBCs and TP53-mutant breast tumors. We show that expression of each of these 15 genes correlates positively with proliferation markers (Ki67, PCNA, and MCM2) in TNBC, and that the overexpression of this gene set is associated with shorter relapse-free survival and distinct immune/stromal infiltration patterns. In light of prior work, our findings point to a FOXM1-associated 15-gene signature enriched in AR-low TNBC and associated with the high-proliferation and high-CIN phenotypes of this clinically challenging tumor type. This 15-gene set represents an actionable vulnerability with therapeutic potential for AR-low TNBC and provides a framework for rethinking how to manage highly proliferative, genomically unstable BCs. Full article

Background: Cervical cancer (CC) and ovarian cancer (OC) are among the most prevalent and lethal gynecological malignancies in women, necessitating the identification of reliable biomarkers for early diagnosis and prognosis. Methods: This study integrates bioinformatics and Healthcare 4.0 to identify key biomarkers associated with these cancers. Differentially expressed genes (DEGs) were identified from two microarray datasets. mRMR followed by SVM-RFE was applied to the identified DEGs to extract the most significant ML-based DEGs (MDEGs). The predictive ability of the selected gene subsets was further evaluated via multiple classifiers, where attention-based long short-term memory (AttLSTM) consistently achieved the best performance across both datasets. In parallel, WGCNA was conducted to identify coexpression-associated genes (CAGs) from significant modules in each dataset. A PPI network (PPIN) was constructed using the genes common to MDEGs and CAGs and was analyzed via Cytoscape. Results: Four hub genes, MCM3, FOXM1, SH3BP5, and PAPSS2, were identified via the degree method. mRNA expression analysis revealed that FOXM1 and MCM3 were upregulated, whereas SH3BP5 and PAPSS2 were downregulated in cancer tissues compared with normal tissues. ROC curve analysis demonstrated the high prognostic significance of these hub genes, with substantial AUC scores indicating strong discriminatory power. Furthermore, molecular docking analysis with an FDA-approved drug compound confirmed the significant binding affinity between these genes and the drug molecules. Conclusions: These findings suggest that FOXM1, MCM3, SH3BP5, and PAPSS2 could serve as biomarkers for early prognosis, diagnosis, and targeted therapy in patients with cervical and ovarian cancer. Full article

The development of non-noble metal catalysts provides a cost-effective and sustainable route for glucose oxidation to gluconic acid. In this study, a series of catalysts based on inexpensive transition metals (Cr, Cu, Ni, Fe) and/or Au were synthesized using siliceous supports (SiO₂ and MCM-41) and systematically evaluated. The aim was to partially or fully replace noble metals with lower-cost alternatives, while maintaining high catalytic performance. Comprehensive characterization—including ICP-AES for composition, N₂ adsorption–desorption for porosity, XRD for structure, H₂-TPR for reducibility, and NH₃-TPD for acidity—was conducted to establish structure–property relationships. Among the tested catalysts, Ni- and Fe-based systems exhibited superior stability, with NiO/SiO₂ achieving gluconic acid yields comparable to Au. The bimetallic Au–Ni/SiO₂ catalyst displayed enhanced metal–support interactions and minimal leaching (<2%), while Au–Fe/SiO₂ improved selectivity, yielding up to 23% gluconic acid, surpassing 5Fe/SiO₂ (18%) and 0.3Au/SiO₂ (15%), albeit with lower stability. These results highlight the potential of low-cost transition-metal and bimetallic catalysts as efficient and economically viable systems for selective glucose oxidation, providing insights for rational catalyst design in sustainable carbohydrate valorization. Full article

Clear-cell renal cell carcinoma (ccRCC) accounts for the majority of kidney cancer diagnoses and exhibits widely variable clinical behaviour. The dataset described here was generated to support the discovery of robust biomarkers of tumour cell-cycle arrest and to inform the risk-stratified management of ccRCC. We assembled four independent cohorts including 480 patients from the UK arm of the SORCE adjuvant trial, 300 patients from a surgically treated series in Korea, 120 patients from a retrospective Scottish cohort, and a paired primary–metastatic cohort comprising 62 patients. Formalin-fixed paraffin-embedded nephrectomy specimens were processed for routine hematoxylin and eosin (H&E) histology, and for multiplex immunofluorescence (mIF). The mIF panels detect the cyclin-dependent kinase inhibitor p21^CDKN1a, the DNA replication licencing factor MCM2, endoglin/CD105, Lamin B1 and nuclear DNA (Hoechst). Whole-slide images (WSIs) were acquired at high resolution, and artificial-intelligence pipelines were used to segment nuclei, classify individual cells into arrested phenotypes, and calculate the fraction of cells. Accompanying metadata include demographics, tumour stage, grade, Leibovich score, treatment arm (sorafenib/placebo), relapse events, and disease-free survival. All images and derived tables are released under a CC0 licence via the BioImage Archive, ensuring unrestricted reuse. This multi-cohort dataset provides a rich resource for studying cell-cycle arrest and proliferation markers, training image-analysis algorithms, and developing prognostic signatures in RCC. Full article

Modern protection relays require accurate and fast phasor estimation under harsh transient conditions, including a decaying DC component, harmonics, interharmonics, noise, and frequency instability. The original CCHDF (Cleaned Characteristic Harmonic Digital Filter) produced a harmonic cleaned signal using the Biunivocal Frequency Relationship of Phasors (BFRP) technique, but relied on DFT, Hanning windowing, and peak detection to identify interharmonic components. This paper replaces that spectral estimation block with the Modified Covariance Method (MCM) estimator, a high resolution autoregressive (AR) spectral estimator capable of superior frequency, magnitude, and phase estimation of non-harmonic components even with a short data window. The result is an improved filter named MCCCHDF (Modified Covariance CCHDF), preserving the original algorithmic pipeline, but achieving higher accuracy and faster convergence in the presence of closely spaced harmonics/interharmonics and noisy decaying DC conditions. Full article

Clarifying the mechanical properties and failure patterns of layered coal–rock combinations in coal-measure strata is critical to guiding hydraulic fracturing design in petroleum and mining engineering. This paper investigates the mechanical properties, failure patterns, and stress distributions of sandstone–coal–sandstone (SCS) and mudstone–coal–mudstone (MCM) combinations under different confining pressures and thickness ratios based on the 3D combined finite–discrete element method (3D FDEM). The results show that the mechanical strength of the SCS combination is higher than that of the MCM combination under the same conditions. As the thickness ratio increases, the overall peak stress and elastic modulus of the combination decrease gradually and eventually approach those of the pure coal. As confining pressure increases, the peak stress of layered coal–rock combinations rises gradually, plastic behaviors become increasingly prominent, and the failure mode of the mudstone layer transitions from tensile-dominated to shear-dominated. Under different thickness ratios and confining pressures, the coal layer in the combinations primarily develops shear-dominated cracks, whereas the sandstone layer mainly generates tensile-dominated cracks. An increase in confining pressure elevates the critical thickness ratio for sandstone layer failure in the SCS combination. Essentially, the changes in stress state caused by rock types, thickness ratios, and confining pressures are important reasons for the variations in the failure patterns of each layer in layered coal–rock combinations. The key findings of this paper are expected to provide theoretical guidance for the field design of petroleum and coal mine engineering. Full article

The huge number of possible permutations of genes, proteins and small molecules make the random emergence of cellular networks problematic. How, therefore, do interactomes come into existence? What selects for their stability and functionality? I hypothesize that interactomes originate from molecularly complementary modules (MCMs) that are selected for stability and retain their interactivity when mixed and matched with other such modules to create novel molecules and complexes displaying emergent properties not present in the individual components of the network. Because evolution can only proceed by working upon existing variants, and these variants emerge from selection of MCMs, the resulting systems must exhibit the characteristics of pleiofunctional, epistatic interactomes (PEIs). The resulting systems should display “molecular paleontology”, providing clues as to the historical process by which these MCMs were incorporated into the system. The MCM mechanism of PEI evolution is illustrated here by two case studies. The first concerns the prebiotic emergence of the glutathione–ascorbate anti-oxidant system and its later incorporation into regulation of glucose transport and catecholamine receptor activity. The second concerns the MCM evolution of the ribosome as, perhaps, the first PEI, and its role as a module for the later construction of the first cellular genomes. Full article

Catalytic dry reforming of ethanol offers a sustainable pathway for syngas and hydrogen production through CO₂ utilization, though its efficiency depends heavily on the strategic synthesis of catalysts and the optimization of reaction parameters. This study employs Box–Behnken Design (BBD) and Response Surface Methodology (RSM) to optimize hydrogen yield from CO₂ reforming of ethanol over a Yttrium-promoted Ni-Co/MCM-41 catalyst. The catalyst was synthesized using sequential wet impregnation method and characterized for its physicochemical properties. The catalyst was tested in fixed-bed reactor using experimental data obtained from BBD considering the effects of temperature (550–700 °C), ethanol flowrate (0.5–1 mL/min) and CO₂ flowrate (15–30 mL/min) on the hydrogen yield. The experimental conditions were optimized using RSM quadratic model. The characterization revealed that the ordered mesoporous nature of the MCM-41 is maintained providing a high surface area of 597.75 m²/g for the catalyst. The addition of Yttrium as a promoter facilitates the formation of well crystallized nanoparticles. Maximum hydrogen yield of 85.09% was obtained at 700 °C, 20.393 mL/min and 0.877 mL/min for temperature, CO₂ and ethanol flowrate, respectively. The predicted hydrogen yield obtained is strongly correlated with the actual values as indicated by R² of 0.9570. Full article

Ionic liquids (ILs) have attracted considerable attention for light olefin separation owing to their negligible vapor pressure, excellent thermal stability, and tunable molecular structures. However, their intrinsically high viscosity severely restricts gas diffusion, leading to poor mass-transfer efficiency and limited separation performance in bulk form. Herein, we report the develop a high-performance adsorbent by immobilizing a silver-functionalized ionic liquid within ordered mesoporous MCM-41 to overcome the diffusion limitations of bulk ILs. The IL@MCM-41 composites were prepared via an impregnation–evaporation strategy, and their mesostructural integrity and textural evolution were confirmed by XRD and N₂ sorption analyses. Their C₂H₄/C₂H₆ separation performance was subsequently evaluated. The composite with a 70 wt% IL loading achieves a high C₂H₄ uptake of 25.68 mg/g and a C₂H₄/C₂H₆ selectivity of 15.59 in breakthrough experiments (298 K, 100 kPa). X-ray photoelectron spectroscopy results are consistent with the presence of reversible Ag⁺–π interactions, which governs the selective adsorption of C₂H₄. Additionally, the composite exhibits excellent thermal stability (up to 570 K) and maintains stable separation performance over 10 adsorption–desorption cycles. These IL@MCM-41 composites have significant potential for designing sorbent materials for efficient olefin/paraffin separation applications. Full article

This study was conducted to elucidate the molecular and metabolic differences in ileal development according to birth weight in neonatal piglets. A total of 126 neonatal piglets born from Yorkshire × Landrace × Duroc crossbred sows were used, and the top 5% (H group, 1.77 ± 0.02 kg) and bottom 5% (L group, 0.72 ± 0.03 kg) of birth weights were selected for analysis. Ileal tissues were collected for transcriptomic (RNA-seq) and targeted metabolomic (GC–MS) analyses, and selected genes were validated using RT-qPCR. A total of 112 differentially expressed genes (DEGs) were identified, among which RFC3, PCNA, MCM3, MCM10, AURKA, AURKB, CCNB2, CCNA2, CCNF, and SI were significantly upregulated in the H group (p < 0.05). These genes were mainly involved in pathways related to DNA replication, cell division, and nutrient digestion and absorption. In addition, metabolomic analysis revealed that pyruvic acid concentrations were significantly higher in the H group (p < 0.05), indicating the activation of energy metabolic pathways. These results indicate that high-birth-weight piglets possess a genetic foundation for enhanced cellular proliferation and energy metabolism, and they further highlight potential molecular targets for improving growth performance and intestinal development in low-birth-weight piglets. Full article

Leishmaniasis, a widespread, neglected infectious disease with limited effective treatments and increasing drug resistance, demands innovative therapeutic approaches. In this study, we report the fabrication of pentamidine (PTM)-loaded polycaprolactone (PCL) nanofibers using solution blow spinning (SBS) as a potential topical delivery system for cutaneous leishmaniasis (CL). Homogeneous PCL fiber mats were produced using a simple SBS set-up with a commercial airbrush after optimizing several working parameters. Drug release studies demonstrated sustained PTM release profile over time, which was mechanistically modeled by utilizing the complete nanofiber diameter distribution, obtained from SEM analysis of the blow-spun material. FTIR and XRD analyses were performed to investigate the drug–polymer interactions, revealing molecularly dispersed PTM at low-proportion drug/polymers and partial crystallinity at high loadings. The released PTM exhibited significant leishmanicidal activity against Leishmania major promastigotes. Biological investigations showed that SBS-formulated PTM treatment was consistent with the downregulation of parasite genes involved in cell division and DNA replication (cycA, cyc6, pcna, top2, mcm4) and upregulation of the drug response gene (prp1). The controlled delivery of PTM within SBS-fabricated PCL nanofibers provides an effective therapeutic approach to tackle CL and, through the incorporation of additional drugs, could be extended to address a broader range of cutaneous infections. Full article

Background: The emergence of antibiotic-resistant bacteria is one of the top health concerns. Escherichia coli is a Gram-negative bacterium that commonly causes severe infections. However, this research exposed its antibiotic-producing potential. Methods: Rifampicin-resistant mutants of E. coli C91 were generated to activate cryptic BGCs. Mutants (C91-R1, R2 and R3) were tested for antimicrobial production using agar-well diffusion assays. Metabolite profiling was performed by LC-MS/MS. Siderophore production was tested by construction of a Δycao deletion mutant. Growth of this mutant was assessed under iron-limited conditions versus iron-rich conditions using dipyridyl. qRT-PCR was used to analyze gene expression entB, mcmA and mchF. Genome mining was performed using antiSMASH and BAGEL4. Results: Compared to the wild type, Mutant C91-R1(S531L) displayed clear antibacterial activity against Staphylococcus aureus. LC-MS/MS revealed unique metabolites, including a novel peak at m/z 410.5, specific to the mutant C91-R1. A reduction in siderophore production of 61% was demonstrated in the Δycao mutant, and downregulation of entB, mcmA and mchF. Conclusions: Genome mining predicted non-ribosomal peptide, thiopeptide and polyketide BGCs. E. coli C91 offers antibiotic-producing potential that can be activated through ribosome-engineering-type approaches. Moreover, E. coli C91-R1 has unique metabolites and is considered as a promising candidate for novel antibiotic discovery. Full article