Search Results (31,761)

Obesity-associated carcinogenesis offers a model to explore the transition from metabolic dysregulation to genomic instability and carcinogenesis. Adenosine 5′-monophosphate-activated protein kinase (AMPK), the principal cellular energy sensor, coordinates adenosine triphosphate (ATP) production with metabolic demand; however, in obesity, AMPK activity is impaired, resulting in reduced ATP, elevated Adenosine Monophosphate (AMP), and cellular energy stress. Deoxyribonucleic Acid (DNA) polymerases ε (Pol ε) and δ (Pol δ) maintain replication fidelity via a 3′→5′ exonuclease proofreading activity that removes misincorporated nucleotides. Elevated AMP directly binds and selectively inhibits the exonucleases, conserving energy at the expense of genomic accuracy. As a result, replication errors escape correction and accumulate, some conferring a selective advantage and driving carcinogenic evolution. Therapeutic and lifestyle interventions that activate AMPK—including weight loss, exercise, metformin, and aspirin—restore ATP production, lower AMP, and relieve inhibition of exonuclease proofreading, thereby preserving genomic integrity and slowing mutation-driven carcinogenesis. This framework reveals two core biological principles: 1. Energy metabolism and DNAreplication fidelity are mechanistically coupled at the DNA polymerase active site. 2. The mutation rate is an adaptive metabolic phenotype, modulated by AMP levels. These concepts redefine the metabolic–genetic interface in carcinogenesis and highlight AMPK activation as a rational target for obesity-associated cancer prevention. Full article

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective treatments for obesity, but substantial weight regain is common after therapy is discontinued. This study investigated whether probiotic strains with anti-obesity effects could enhance GLP-1RA-induced weight loss and attenuate post-treatment weight rebound. Methods: Candidate lactic acid bacteria were screened for anti-obesity efficacy in a high-fat-diet (HFD)-induced obese mouse model, and the selected strain was further characterized using metabolomic profiling of culture supernatants. To examine its interaction with GLP-1RA therapy, obese mice received dulaglutide for 4 weeks and were monitored for 2 weeks after treatment withdrawal, while the probiotic was orally administered for a total of 6 weeks. Body weight, glycemic parameters, and muscle strength were assessed throughout the study. Results: Limosilactobacillus fermentum GB102 reduced body weight and improved glycemic control in HFD-fed mice. These metabolic benefits were associated with alterations in circulating metabolic hormones, including adipokines, along with attenuated inflammatory responses in adipose tissue. Metabolomic profiling revealed that GB102 produced high levels of succinic acid, a metabolite previously linked to thermogenic activation. This strain increased whole-body energy expenditure in HFD-fed mice, produced glutamine, and showed enhanced conversion of arginine into ornithine and citrulline. When combined with dulaglutide, GB102 enhanced weight loss, preserved muscle strength, and attenuated both weight regain and glycemic rebound following dulaglutide withdrawal. Conclusions: These findings suggest that energy-metabolism-enhancing probiotics such as GB102 may enhance the metabolic effects of GLP-1RA therapy and help attenuate weight regain after treatment discontinuation. Full article

Monkeypox virus, a zoonotic DNA virus belonging to the Orthopoxvirus genus, has emerged as a global health issue because of its fast spread to 104 nations over six continents. In the current study, an immunoinformatics pipeline was used to design a multiepitope-based prophylactic vaccine targeting the A35R glycoprotein and E8L membrane proteins of the monkeypox virus. Selected target proteins were surface-exposed, non-homologous to the human proteome, and essential for viral pathogenesis. B-cell and T-cell (MHC-I and MHC-II) epitopes with high antigenicity (>0.5), non-allergenicity, non-toxicity, and highly soluble in water with strong affinity towards innate and adaptive receptors, were prioritized. Shortlisted epitopes were combined to design the final vaccine utilizing an adjuvant (50S ribosomal L7/L12) and appropriate linkers for improved immunogenicity. Population coverage analysis showed wide HLA representation with 83.57% (MHC-I) and 88.8% (MHC-II) global coverage, including 89.6% for West Africa and 87.3% for Central Africa. Docking analysis of the vaccine construct with the TLR-4 receptor revealed stable interactions (−695.6 kcal/mol). Molecular dynamics simulations and binding free energies further confirmed structural stability. Immune simulations predicted strong activation of both humoral and cellular immune responses. These results indicate that the designed multiepitope vaccine construct is a viable option for additional experimental validation against the monkeypox virus. Full article

Batch production of nanomaterials is highly desired for developing commercial nanoproducts. Here, a brand-new electrospinning method, termed hole electrospinning, was developed for batch production of drug-loaded polymeric nanofibers. Using resveratrol and polyvinylpyrrolidone as model drug and filament-forming matrix, respectively, both hole and single-needle electrospinning were conducted. The resultant nanofibrous films were compared in terms of morphology, physical and thermal properties, mechanical performance, fast-dissolution rate, and antioxidant activity. Analytical and characterization results verified that nanofibers from different processes showed no significant differences in morphology, diameter, porosity, tensile strength, amorphous state, fast-dissolution performance and antioxidant activity. However, hole electrospinning provided 13.3-fold higher productivity than single-needle electrospinning, better drug encapsulation efficiency (97.3 ± 4.5% versus 83.7 ± 6.1%), and higher energy efficiency (0.0393 W/g versus 0.1247 W/g). Based on the protocols reported here, not only was a batch nano-conversion method for polymeric engineering developed, but also an attractive approach for the large-scale production of various complex configurations was proposed for potential commercial nanostructure-based products. Full article

Complex I (NADH:quinone oxidoreductase, CI) is central to cellular aerobic energy metabolism. The L-shaped structure of CI is unique, where the hydrophilic arm is responsible for the electron transfer function and the membrane arm operates proton pumping. These two functional sites are spatially far apart yet functionally connected. This basic core subunit architecture is highly conserved from bacterial to mammalian CI. Here, to gain detailed mechanistic insight into the role of the membrane subunit ND2 in the coupling mechanism, we mutated several highly conserved residues in the middle of the membrane axis of NuoN, the E. coli CI homolog of ND2. To more precisely investigate the consequences of mutational effects on highly conserved residues, we purified each mutant CI and compared the mutational effects on electron transfer and proton pumping activity using our instant membrane reconstitution method with E. coli double knockout (DKO) membrane vesicles lacking both CI and alternative NADH dehydrogenase (NDH-2). Thre results were corroborated by conventional proteoliposome reconstitution experiments. We found that Lys247 and Lys395 are absolutely essential for both electron transfer and proton pumping activities, while about 50% reduction of NADH oxidase activity but no reduction in proton pumping activity was observed in Lys217, and no significant decrease was detected in Glu133. Furthermore, unexpectedly, we were able to purify an NuoN knockout (ΔNuoN) mutant, which contained stoichiometric peripheral subunits NuoB, NuoCD, NuoE, NuoF, NuoG, and NuoI; and a substoichiometric amount of NuoH and a reduced amount of quinone. However, surprisingly, this isolated ΔNuoN CI showed CI activities (~30% of the WT) after being reconstituted into DKO membranes but not into proteoliposomes. Later, we confirmed by blue native PAGE that the wild-type CI was partially formed from ΔNuoN CI by recruiting its missing membrane subunits that existed in DKO membranes. Our data strongly suggest that ND2/NuoN plays an essential role in the coupling mechanism in CI. CI is the entry respiratory chain enzyme and is central to cellular energy metabolism. Two highly conserved lysine residues in the center of the antiporter-like membrane subunit ND2 are essential for the coupling mechanism between electron transfer and proton translocation. Full article

Ebola virus disease remains one of the most serious viral infections with no approved small-molecule treatments. The Ebola virus glycoprotein (EBOV-GP), which enables the virus’s entry to host cells, is a promising target for drug discovery. In this study, a multistage computer-aided drug discovery approach was used to identify new specific EBOV-GP inhibitors. A reliable QSAR model was built using 55 terpenoid derivatives. This model was able to predict the activity of newly designed compounds with good accuracy and validated statistical metrics ($R_{tr}^2$= 0.70; $R_{ext}^2$ = 0.73). It was subsequently applied to screen over 15,500 newly generated compounds from three lead molecules by fragment-based design tools. Predicted activity, binding affinity toward EBOV-GP, and good ADMET drug-like properties prioritized the eleven most promising hits. Through 150 ns molecular dynamics simulations, these compounds remained stable in the EBOV-GP binding site. Further binding free energy analysis (MM/PBSA) showed strong binding affinities, especially for the compounds L-60, L-832, M-1618, and L-1366. This study showed how combining QSAR, fragment-based design, docking, ADMET, and molecular dynamics could help in identifying potent and safe small molecules against the EBOV-GP. The top compounds are ready for further experimental and in vitro biological testing. Full article

Nanoemulsions are widely recognized as versatile delivery platforms capable of stably loading lipophilic active ingredients. Although low-energy phase inversion methods enable nanoemulsion formation under ambient and low-shear conditions, their scalability and applicability in practical formulation environments remain insufficiently validated. Here, we develop oil-in-water (O/W) nanoemulsions via a low-energy phase inversion process and systematically investigate their composition-dependent formation, scalability, and formulation stability. By precisely tuning the composition of a mixed nonionic surfactant system, monodisperse nanoemulsions with an average droplet size of ~110 nm and a polydispersity index (PDI ≤ 0.20) are reproducibly obtained under ambient, low-shear conditions. The optimized nanoemulsions maintain their nanoscale dispersion characteristics over 30 days of storage and exhibit consistent droplet size and distribution upon scale-up to 1 L. Furthermore, the nanoemulsions retain structural stability when incorporated into polymer-based formulations under various temperature conditions and repeated thermal cycling. These results demonstrate that low-energy phase inversion enables a scalable and formulation-compatible nanoemulsion platform, providing practical guidelines for industrial formulation and manufacturing of delivery systems for lipophilic active ingredients. Full article

This study aims to investigate the effects of low-energy diets (LE) supplemented with Lactobacillus reuteri postbiotics (HSY) on growth performance and intestinal health of broiler chickens. A total of 2400 one-day-old Ross 308 broiler chicks with an average initial body weight of 46.10 ± 0.04 g were randomly assigned to a 2 × 2 factorial arrangement of treatments with 12 pens and 50 broiler chickens/pen for 39 days. Treatments were (1) CTR (basal diet), (2) LE (CTR-70 kcal ME/kg), (3) HSY (CTR + 0.5 kg/t HSY), and (4) LEHSY (LE + 0.5 kg/t HSY). LE increased the feed conversion ratio (FCR) of broilers (p = 0.03) without altering ADG, ADFI, and final BW. Supplementation with HSY significantly reduced the FCR of broilers (p = 0.001). HSY upregulated the activities of amylase and trypsin in jejunal digesta (p < 0.01). Furthermore, LE upregulated the expression of intestinal barrier-related genes such as Mucin-2, Claudin-1 and Occludin, and HSY upregulated the expression of Claudin-1 (p < 0.05). LE upregulated the expression of nutrient transport carriers such as SGLT1 and TRPV6 (p < 0.01), and HSY upregulated the expression of TRPV6 (p < 0.01). LE upregulated the expression of immune-related genes such as MHC-II (p = 0.002), and HSY upregulated the expression of IFN-γ, IL-10, and TGF-β (p < 0.05). LE and HSY both downregulated the expression of intestinal lipid metabolism-related genes like ACC, while upregulating the expression of FABP4 (p < 0.05). 16S rRNA sequencing showed that the HSY increased the Chao1 index of the jejunal microbiota and enriched beneficial bacteria such as Lactobacillus salivarius and Lactobacillus avium. LE and HSY both increased the concentrations of propionic and butyrate (p < 0.05). In summary, HSY can improve gut health and mitigate the negative impact of low-energy treatment on broiler growth performance by increasing the content of endogenous enzymes in the jejunum, improving gut microbiota structure, and increasing the content of short-chain fatty acids in the jejunum. Full article

Fluid mechanics in disordered structures gives rise to rich multiscale dynamics through the interplay of topology, symmetry breaking, and fluid–structure interactions. Heterogeneous networks encode mechanical responses, regulate flow organization, and shape energy dissipation, enabling memory effects and emergent collective behaviors across both natural and engineered systems. These principles operate across vast scales: from seamounts with characteristic scales of $L\approx {10}^3\mathrm{m}$ and Froude numbers $Fr\approx {10}^{-2}–{10}^{-1}$ generating deep-ocean turbulent mixing, to marine tidal turbines operating at Reynolds numbers $Re\approx {10}^7–{10}^8$ and Euler numbers $Eu\approx {10}^{-1}–{10}^0$, where inertial forces dominate flow dynamics. Although the dominant physical forces may vary across scales—for example, planetary rotation and stratification in large-scale oceanic flows versus viscous or interfacial effects in microscale systems—the comparison of dimensionless parameters provides a useful framework for discussing similarities in flow organization and scaling behavior. Empirical observations, network-based descriptions, and multiscale simulations collectively demonstrate how topological features constrain symmetry, organize transport pathways, and support predictive reconstruction and inverse design. These principles underpin applications ranging from engineered systems that exploit broken symmetries to rectify chaotic transport, to biological architectures where flows mediate information transfer, locomotion, and structural self-organization. In this Review, we synthesize recent advances to propose a unifying physical paradigm: fluid flows actively interact with disorder, reorganize dissipation, and convert structural asymmetry into functional mechanical performance across scales. Full article

Fe₂O₃-reinforced PMMA nanocomposites were prepared by melt blending using a twin-screw micro-extruder. Fixed Fe₂O₃ loading of 2.5 wt.% was employed, and mixing times of 6 and 12 min were used to obtain nanocomposites with different dispersion characteristics. The structural and morphological properties of the samples were investigated by X-ray diffraction (XRD) and scanning electron microscopy (SEM), while their thermal degradation behavior was evaluated by differential thermal and thermogravimetric analyses (DTA/TG). The activation energies of thermal degradation were calculated using the Kissinger, Takhor, and Augis–Bennett methods. Increasing the mixing time improved nanoparticle dispersion and reduced agglomeration. The addition of Fe₂O₃ slightly decreased the characteristic degradation temperatures of PMMA, while the activation energy increased for the better-dispersed sample. The results indicate that interfacial interactions and particle dispersion play important roles in the thermal degradation behavior of PMMA/Fe₂O₃ nanocomposites. Full article

This study explored the electronic and structural tunability of fullerene (C₆₀) derivatives via functionalization with heteroatoms (O, S, Se) in mono-, di-, and tri-bridged configurations, including covalently modeled dimers. Calculations were performed using density functional theory (DFT) at the B3LYP/6-31G(d,p) level. Electronic descriptors such as total dipole moments (TDMs), HOMO–LUMO energy gaps (ΔE), global reactivity descriptors, total density of states (TDOS), molecular electrostatic potential (MESP) and non-covalent interactions (NCIs) were analyzed to elucidate how functionalization alters reactivity and stability. Key findings indicate that TDM increases and ΔE decreases in all functionalized C₆₀; for example, the TDM increased from 0 Debye for C₆₀ to 2.156 Debye for C₆₀–O–S–Se, and ΔE decreased from 2.762 eV (C₆₀) to 2.532 eV (C₆₀–Se), indicating enhanced reactivity. This aligns with global reactivity descriptors such as reduced ionization energy and hardness. Mapped MESP surfaces showed activation around heteroatom sites. Quantum theory of atoms in molecules (QTAIM) and NCI analyses revealed that while mono-bridged structures retain covalent linkages, dimeric systems such as C₆₀–O–C₆₀ and C₆₀–S–C₆₀ relax into weak, van der Waals-type interactions. OPDOS (overlap population density of states) highlighted antibonding character between the fragments in the conduction region. These results demonstrate that heteroatom functionalization enhances the electronic properties of C₆₀, making it a promising candidate for optoelectronic, organic photovoltaic, and sensor applications. Full article

Dragonflies exhibit remarkable flight stability in unsteady environments, largely due to aerodynamic interaction between their forewings and hindwings. This study investigates gust response in dragonfly-inspired micro-aerial vehicles (MAVs) from a system dynamics perspective, with emphasis on the aerodynamic role of tandem-wing interaction rather than control compensation. A six-degree-of-freedom (6DOF) rigid-body framework is developed and coupled with a quasi-steady aerodynamic model that includes explicit phase-dependent interaction between forewing and hindwing forces. Gusts are introduced as time-varying inflow perturbations, allowing physically consistent analysis of how disturbances propagate through aerodynamic loading into vehicle motion. Simulations are performed for representative flight conditions, including gliding, hovering, and gust-perturbed ascent. The results show bounded trajectory, velocity, and attitude responses under sustained gust excitation, even with conservative baseline control. Force and energy analyses indicate that wing–wake interaction redistributes aerodynamic loads in time and reduces peak force and moment fluctuations before they reach the rigid-body dynamics. This behavior is interpreted as passive aerodynamic filtering of gust disturbances inherent to the tandem-wing configuration. Comparative simulations using backstepping control and Active Disturbance Rejection Control (ADRC) further show that the dominant gust attenuation arises from aerodynamic configuration rather than from control action. Although the aerodynamic model is quasi-steady, the framework reproduces key trends reported in biological and CFD-based studies and provides a numerical foundation for future wind-tunnel and free-flight experiments on configuration-level gust attenuation. Full article

The adsorption and activation of CO₂ on Cu_xSc_y nanoclusters with x + y equal to 4 were analyzed using DFT and PDOS and TDOS signatures. The geometries of Cu₃Sc, Cu₂Sc₂, and CuSc₃ were optimized in the gas phase, and the minima were verified by frequencies in ORCA using M06-2X/def2-TZVP. Multiplicities 1, 3, and 5, temperatures between 298 and 400 K, and four CO₂ coordination modes R1 to R4 were evaluated. Naked and complex cluster comparison panels were constructed, and two energy windows, −18 to −10 eV and −8 to 6 eV around the Fermi level, were analyzed, complemented by frontier orbitals and charge maps. Thermodynamics indicated that mode and multiplicity control the adsorption energy, with ANOVA p-values of 0.002 and 0.008, while temperature was not significant (p = 0.682). In Cu₃Sc–C₂v(1), the R1 singlet at 298 K showed E_ads −33.43 kcal·mol⁻¹ with spin contamination, while alternative modes in the singlet were unfavorable. In PDOS and TDOS, the bare cluster exhibits a Cu d band at −11 to −10 eV and a valley around −5 eV. The exergonic complexes show CO₂ signals near the Fermi level, superimposed on Cu and Sc states, with state filling and broadening. Transferable indicators based on CO₂ intensity in the −8 to 6 eV range and metal–adsorbate overlap are proposed as predictors of exergonic adsorption. Full article

The porcine epidemic diarrhea virus (PEDV) causes a gastrointestinal disease generating mortality rates approaching 100% in piglets worldwide. The S glycoprotein of PEDV is the main target for the development of vaccines. Two vaccines approved by the Ministry of Agriculture and Rural Development are used in Mexico: the first vaccine is based on an inactivated virus isolated more than a decade ago, whereas the second vaccine is based on mRNA technology. The most important tool for controlling PEDV outbreaks is vaccination; however, coronaviruses are characterized by the accumulation of multiple mutations, which compromise the immune response elicited by outdated vaccines. In this work, we classified the Mexican strains of PEDV reported so far in GenBank, according to their genotypes. Subsequently, we searched for B and T cell epitopes conserved in Mexican PEDV strains using bioinformatic tools. In addition, we explored whether these epitopes can induce allergies, autoimmunity, and/or toxic effects. Next, we determined the localization of B cell epitopes in the S glycoprotein using the protein crystal and protein modeling of several S glycoproteins. Finally, we carried out molecular docking analysis to assess whether these T cell epitopes could interact with the peptide-binding groove of the Swine Leukocyte Antigens (SLAs). Five conserved B cell epitopes were found to be exposed on the surface of the S glycoprotein, whereas several promiscuous CTL and HTL epitopes were bound, with low free energy, to the peptide-binding grooves of SLA-I and SLA-II, respectively. The best epitopes were used to generate a plasmid carrying the sequence to produce a recombinant protein. This plasmid was used for transfection experiments in PK-15 cell culture. The B cell epitopes reported here were recognized by the sera from pigs infected with PEDV but not by the sera from uninfected animals. These results justify future evaluations of the ability of these epitopes to stimulate cytokine production by T cells, antibody generation, and their neutralizing activity. Full article

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease characterized by progressive cartilage destruction, and chondrocyte apoptosis plays a critical role in TMJOA progression. As chondrocytes reside in an avascular microenvironment inside the cartilage matrix, energy production via glycolysis is crucial for their survival. This study investigated the role of the key glycolytic enzyme Hexokinase 2 (HK2) in TMJOA pathogenesis and the therapeutic potential of dental pulp stem cell-derived extracellular vesicles (DPSC-EVs). In a rat experimental TMJOA model induced by monosodium iodoacetate (MIA) intra-articular injection, we observed a significantly decreased expression of HK2 along with cartilage matrix degradation. In the in vitro study, MIA induced chondrocyte apoptosis with caspase-3 activation, accompanied by impaired glycolytic function. Intervention with DPSC-EVs effectively rescued the expression of HK2 within chondrocytes, leading to a notable restoration of cellular glycolysis. Consequently, DPSC-EV treatment markedly attenuated the progression of TMJOA by reducing chondrocyte apoptosis and improved cartilage integrity. Our findings demonstrated that DPSC-EVs represent a promising cell-free therapeutic strategy for TMJOA, exerting their protective effects by targeting HK2, thereby preserving chondrocyte viability and attenuating osteoarthritis development. Full article