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Neurodegenerative diseases involve the convergence of cholinergic dysfunction, neuronal loss, and sustained neuroinflammatory responses, necessitating the development of multifunctional therapeutic agents. In this study, a series of novel thieno[3,2-d]pyrimidine-phenolic Mannich base hybrids were rationally designed, synthesized, and evaluated as dual cholinesterase inhibitors with neuroprotective and anti-neuroinflammatory potential. The synthesized compounds exhibited potent inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with inhibition constants in the low nanomolar range. Among them, compounds 5 and 9 emerged as the most active derivatives, displaying Ki values of 8.79 and 14.11 nM for AChE and 7.04 and 11.75 nM for BChE, surpassing the reference inhibitors tacrine and donepezil. Molecular docking and molecular dynamics simulations supported the experimental findings, and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding free energy calculations further confirmed their superior binding affinities compared with donepezil. Cytotoxicity profiling in SH-SY5Y neuronal cells and RAW 264.7 and THP-1 immune cells identified a narrow sub-cytotoxic concentration window (EC05-EC10 = 1.2-2.1 μM), ensuring biological effects independent of nonspecific cell damage. Within this range, both compounds exerted pronounced anti-neuroinflammatory activity. Notably, compound 9 significantly downregulated pro-inflammatory mediators, reducing IL-1β, IL-6, and NF-κB1 gene expression by up to 2.78-, 3.37-, and 4.84-fold, respectively. Consistently, it suppressed nitric oxide production in LPS-stimulated macrophages to levels comparable with ascorbic acid and markedly decreased Iba1 expression in activated THP-1 cells. This integrated enzymatic, computational, and cellular investigation identifies compounds 5 and 9 as promising multifunctional lead combining dual cholinesterase inhibition with robust anti-neuroinflammatory activity. The results provide a strong foundation for future in vivo studies and further optimization toward disease-modifying agents for neurodegenerative disorders.
In this report, we identified a novel hemizygous ELF4 variant (c.1822G > C; p.Gly608Arg) in an adolescent male with chronic immune thrombocytopenia (ITP) and performed functional immunologic characterization. Peripheral blood mononuclear cells (PBMCs) of the patient and age-matched controls were characterized by flow cytometry with respect to T cell phenotype, activation, proliferation and NK cell cytotoxicity. The p.Gly608Arg substitution affects a highly conserved residue in the C-terminal regulatory domain of ELF4 and is predicted to be damaging. Immunophenotyping showed an expanded CD8+ T-cell compartment, an inverted CD4/CD8 ratio, reduced naïve T-cell populations, and accelerated acquisition of memory-like phenotypes upon activation. Both CD4+ and CD8+ T cells displayed increased proliferation following TCR stimulation, consistent with impaired ELF4-dependent regulation of effector T-cell expansion. NK cells exhibited reduced granzyme B and perforin expression and markedly diminished cytotoxicity against K562 targets, indicating defects in maturation and effector function. These findings suggest that the identified ELF4 variant is associated with combined T- and NK-cell dysfunction. This case expands the clinical spectrum of Deficiency in ELF4, X-linked and underscores the relevance of evaluating ELF4 mutations in patients with unexplained cytopenias accompanied by dysregulated lymphocyte activation and impaired cytotoxic responses.
Despite extensive research, Geopolymer concrete (GPC) lacks reinforced concrete construction and design specifications. Developing such specifications requires comprehensive studies to promote the use of GPC, which is known for its superior performance and environmental benefits compared to ordinary Portland cement concrete (OPC). This study numerically investigated and compared the behavior and strength of fly ash-based geopolymer-reinforced concrete columns with the experimental results. Comparisons with OPC were made based on existing specifications. Herein, FEM analyses were conducted on 16 GPC and 4 OPC columns under eccentric axial compressive loads. Parameters such as eccentricity, reinforcement ratio, curing method, and activation solution ratios were varied. According to average numerical results, the GPC columns have 7% more moment capacity and 30% more curvature values than OPC. Moreover, GPC columns absorbed more energy than OPC columns. Also, GPC columns have higher axial load and bending moment carrying capacities than OPC for numerical results. Error analysis between FEM and experimental data revealed a strong correlation, with MAPE values of 8.88% (axial load) and 7.20% (moment) for GPC columns, confirming the reliability of the numerical model. ACI 318 and Eurocode 2 specifications were deemed applicable for GPC columns, provided axial loads are limited per TEC 2018.
The Sakesar Formation in the Salt Range, Pakistan, represents a well-developed Eocene carbonate ramp deposited along the southern Tethyan margin. This study integrates petrographic analysis, palynofacies evaluation, organic geochemical measurements and sequence stratigraphic interpretation to characterise the depositional environments, diagenetic evolution, and petroleum system potential of the formation. Six microfacies (MF1-MF6) were identified through thin-section petrography ranging from high-energy shoal grainstones to low-energy lagoonal marls. Quantitative palynofacies analysis shows energy dependent trends in organic matter composition, with shoal facies dominated by opaque phytoclasts and lagoonal facies enriched in amorphous organic matter (AOM). Organic geochemical measurements including Total Organic Carbon (TOC), Hydrogen Index (HI), Oxygen Index (OI), and Rock-Eval pyrolysis parameters, combined with vitrinite reflectance (Ro) data, indicate that lagoonal marl-micrite facies (MF6) contain Type II kerogen with the highest TOC values (2.80%), elevated HI (293 mg hydrocarbons per gram TOC), and peak oil-window maturity (0.72% Ro). These attributes identify MF6 as the primary oil-prone source rock. Mid-ramp wackestones and packstones (MF3-MF4) possess moderate generative potential and serve as internal seals or baffles, whereas high-energy shoal facies (MF1-MF2) show favourable reservoir characteristics but limited source potential. Sequence-stratigraphic analysis demonstrates that maximum flooding surfaces (MFS) frequently coincide with organic-rich MF6 intervals, producing predictable vertical stacking of source, seal, and reservoir units at parasequence scale. The integrated petrographic, palynofacies, and geochemical framework confirms the dual role of the Sakesar Formation as both a reservoir and a source-seal interval, with metre-scale cyclicity enhancing hydrocarbon charge and trapping efficiency. These findings refine the depositional and petroleum system model of the Sakesar carbonate ramp and provide valuable predictive analogues for Eocene carbonate exploration within the Himalayan foreland basin and related Tethyan settings.
Utilising high-CO2 biogas in compression-ignition engines poses significant challenges due to poor mixture reactivity, inefficient combustion, and increased energy degradation. This work addresses these difficulties by conducting experimental research on a port-injection at the valve reactivity-controlled compression ignition (PIVE-RCCI) strategy. This study addresses these concerns by conducting experiments on a PIVE-RCCI technique to improve mixture distribution and combustion efficiency in biogas-diesel engines. The engine was modified to provide biogas through the inlet valve, allowing for controlled variations of biogas injection pressure (BIP: 1-4 bar) and port swirl ratio (PSR: 0-80%) at 1600 rpm and 4.9-5.7 bar IMEP. Energy and exergy analyses were used to determine the effect of intake flow dynamics on temperature uniformity, heat transfer, and power generation during combustion. The results reveal that normal airflow conditions minimise accounted heat loss, indicating higher thermal efficiency (ITE) and increased output power across all BIPs. In contrast, introducing a strong intake swirl dramatically improves combustion performance. The 80% PSR configuration resulted in the lowest exergy destruction and the maximum energy recovery potential, with an ITE of 26.54% at 4 bar BIP. Increasing BIP increased power output, whereas the optimal combustion work was found at 1 bar BIP and 40% PSR. The optimal working conditions were 1 bar BIP, 80% PSR, and 5.45 bar IMEP, which resulted in 26.00% exergy destruction, 39.38% destruction-to-released exergy ratio, 86.00% exergy-energy ratio of heat transfer, and 63.78% exhaust exergy-energy ratio. This work's novelty lies in integrating biogas injection, intake swirl control, and exergy-based evaluation to measure mixture distribution and energy recovery in high-COQ biogas RCCI combustion. The findings offer useful operational guidance for increasing energy efficiency and advancing the commercialization of renewable gaseous fuels in RCCI engines. As a result, operating the engine at half load, 80% PSR, and atmospheric air pressure (1 bar) conditions significantly enhanced the combustion efficiency and energy utilisation.
