Search Results (268)

Cyclic di-GMP (bis-(3′ → 5′) cyclic dimeric guanosine monophosphate) is a ubiquitous bacterial second messenger that regulates a wide range of cellular processes, including biofilm formation, motility, virulence, and environmental adaptation. Its intracellular levels are dynamically controlled by diguanylate cyclases (DGCs), which synthesize c-di-GMP from GTP, and phosphodiesterases (PDEs), which degrade it into linear pGpG or GMP. The functional effects of cytoplasmic c-di-GMP are mediated through diverse effector proteins, including PilZ domain-containing receptors, transcription factors, and riboswitches. In Leptospira interrogans, a major pathogenic species responsible for leptospirosis, the regulatory roles of c-di-GMP remain poorly understood. Here, we performed a comprehensive bioinformatics and structural analysis of all predicted c-di-GMP related proteins in L. interrogans serovar Copenhageni strain Fiocruz L1-130, a serovar generally associated with severe manifestations of leptospirosis in humans. Our analysis identified seventeen proteins containing GGDEF domain, five proteins containing both GGDEF and EAL domains, four proteins containing EAL domain, five proteins containing HD-GYP domain, twelve proteins containing PilZ domain, and one protein containing an MshEN domain. Comparative analysis with well-characterized bacterial homologs suggests that L. interrogans possess a complex c-di-GMP signaling network, likely involved in modulating biofilm formation, host–pathogen interactions, and environmental survival. These findings provide new insights into the c-di-GMP regulatory network and on signal transduction in Leptospira and lay the foundation for future functional studies aimed at understanding its roles in physiology, virulence, and persistence. Full article

In this work, we develop a disturbance suppression-oriented fuzzy sliding mode secured sampled-data controller for third-order parabolic partial differential equations that ought to cope with nonlinearities, hybrid cyber attacks, and modeled disturbances. This endeavor is mainly driven by formulating an observer model with a T–S fuzzy mode of execution that retrieves the latent state variables of the perceived system. Progressing onward, the disturbance observers are formulated to estimate the modeled disturbances emerging from the exogenous systems. In due course, the information received from the system and disturbance estimators, coupled with the sliding surface, is compiled to fabricate the developed controller. Furthermore, in the realm of security, hybrid cyber attacks are scrutinized through the use of stochastic variables that abide by the Bernoulli distributed white sequence, which combat their unpredictability. Proceeding further in this framework, a set of linear matrix inequality conditions is established that relies on the Lyapunov stability theory. Precisely, the refined looped Lyapunov–Krasovskii functional paradigm, which reflects in the sampling period that is intricately split into non-uniform intervals by leveraging a fractional-order parameter, is deployed. In line with this pursuit, a strictly $({\Phi }_1,{\Phi }_2,{\Phi }_3)-\varrho$ dissipative framework is crafted with the intent to curb norm-bounded disturbances. A simulation-backed numerical example is unveiled in the closing segment to underscore the potency and efficacy of the developed control design technique. Full article

Thoracoabdominal aortic aneurysms (TAAAs) are rare and often remain asymptomatic until rupture, leading to high morbidity and mortality. Elastin degradation, largely mediated by matrix metalloproteinases (MMPs), plays a central role in their pathogenesis. This study aimed to evaluate plasma desmosine (pDES), a specific biomarker of elastin breakdown, as a non-invasive tool for TAAA detection and risk stratification. In a prospective single-centre case–control study, 30 patients with TAAA and 30 age- and sex-matched controls were enrolled. Plasma pDES levels were quantified using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Aortic wall samples from 12 patients were analysed for elastic fibre content and MMP expression by histology and western blotting. Statistical analyses included correlation testing, propensity score matching, and receiver operating characteristic (ROC) analysis. TAAA patients exhibited significantly higher pDES levels compared with controls (0.40 ± 0.31 vs. 0.22 ± 0.15 ng/mL; p < 0.001). pDES correlated positively with MMP-2 (ρ = 0.68, p = 0.02), TIMP-1 (ρ = 0.72, p = 0.01), and the proportion of elastic fibres in the aortic media (ρ = 0.61, p = 0.03). ROC analysis showed good diagnostic performance (AUC = 0.82), with a threshold of 0.27 ng/mL yielding 78.6% sensitivity and 76.7% specificity. Elevated pDES levels reflect aortic elastolytic activity and may serve as a promising biomarker for TAAA detection and risk assessment. Full article

Swarm coverage by unmanned underwater vehicles (UUVs) is essential for inspection, environmental monitoring, and search operations, but remains challenging in three-dimensional domains under limited sensing and communication. Pheromone-based stigmergic coordination provides a low-bandwidth alternative to explicit communication, yet conventional single-field models are susceptible to depth-dependent sensing inconsistencies and multi-source signal interference. This paper introduces a dual-trail stigmergic coordination framework in which a virtual pheromone field encodes short-term motion cues while an auxiliary coverage trail records the accumulated exploration effort. UUV motion is guided by the combined gradients of these two fields, enabling more consistent behavior across depth layers and mitigating ambiguities caused by overlapping pheromone sources. At the macroscopic level, swarm evolution is modeled by a coupled system of partial differential equations (PDEs) describing vehicle density, pheromone concentration, and coverage trail. A Lyapunov functional is constructed to derive sufficient conditions under which perturbations around the uniform coverage equilibrium decay exponentially. Numerical simulations in three-dimensional underwater domains demonstrate that the proposed framework reduces coverage holes, limits redundant overlap, and improves robustness with respect to a single-pheromone baseline and a potential-field-based controller. These results indicate that dual-field stigmergic control is a promising and scalable approach for UUV coverage in constrained underwater environments. Full article

Stochastically forced nonlinear wave systems are commonly associated with complex dynamical behavior, although little is known about the general interaction of nonlinear dispersion, irrational forcing frequencies, and multiplicative noise. To fill this gap, we consider a generalized stochastic SIdV equation and examine the effects of deterministic and stochastic influences on the long-term behavior of the equation. The PDE was modeled using a stochastic traveling-wave transformation that simplifies it into a planar system, which was studied using Darboux-seeded constructions, Poincaré maps, bifurcation patterns, Lyapunov exponents, recurrence plots, and sensitivity diagnostics. We discovered that natural, implicit, and unique seeds produce highly diverse transformed wave fields exhibiting both irrational and golden-ratio forcing, controlling the transition from quasi-periodicity to chaos. Stochastic perturbation is demonstrated to suppress as well as to amplify chaotic states, based on noise levels, altering attractor geometry, predictability, and multistability. Meanwhile, OGY control is demonstrated to be able to stabilize chosen unstable periodic orbits of the double-well regime. A stochastic bifurcation analysis was performed with respect to noise strength $\sigma$, revealing that the attractor structure of the system remains robust under stochastic excitation, with noise inducing only bounded fluctuations rather than qualitative dynamical transitions within the investigated parameter regime. These findings demonstrate that the emergence, deformation, and controllability of complex oscillatory patterns of stochastic nonlinear wave models are jointly controlled by nonlinear structure, external forcing, and noise. Full article

Lithium carbonate is one of the most prescribed mood stabilizers worldwide and remains the first-line pharmacological treatment for bipolar disorder (BD). Its therapeutic efficacy is well established; however, lithium (Li) has a narrow therapeutic index, and prolonged or excessive intake can cause renal, neurological, or endocrine toxicity. In Brazil and globally, lithium-based formulations are widely commercialized; however, only Brazil adopts a specific regulatory classification distinguishing reference, generic, and similar medicines. Despite its extensive clinical use, studies monitoring the actual Li concentration in pharmaceutical products are extremely scarce. This study quantified Li concentrations in different formulations available in Brazil to evaluate their chemical uniformity, estimated daily intake, and potential health risks. Samples were digested and analyzed using Inductively Coupled Plasma Optical Emission Spectrometry (ICP OES). Statistical analysis with the Kruskal–Wallis test revealed significant differences among formulations (p = 0.012), confirming non-uniform Li content. Measured concentrations ranged from 245.47 to 315.24 mg/kg, with generic products showing the highest values. The calculated daily intake (DI) and chronic daily intake (CDI) increased with therapeutic dose (600–1800 mg/day), and higher-dose regimens frequently exceeded the permitted daily exposure (PDE) value for Li established by International Council for Harmonisation Guideline for Elemental Impurities (Revision 2) (ICH Q3D (R2) (0.55 mg/day). Moreover, hazard quotient (HQ) values above 1 in some scenarios indicated potential health risks associated with excessive or long-term Li exposure. As one of the first studies to quantify Li in marketed formulations, this work underscores the need for systematic monitoring and stricter quality control to ensure therapeutic safety. Full article

Background: Thoracic aortic aneurysm (TAA) is driven by complex molecular mechanisms beyond size thresholds, yet the role of cyclic nucleotide metabolism remains unclear. Phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP in compartmentalized microdomains, act as key regulators of vascular integrity and remodeling. Methods: We performed a hypothesis-driven, transcriptomic analysis of 20 PDE isoforms using the GSE26155 dataset (43 TAA vs. 43 controls). Raw microarray data underwent background correction, log2 transformation, and false-discovery adjustment. Differential expression, logistic regression, receiver-operating characteristic (ROC) curves, calibration testing, correlation analysis, and interactome/enrichment mapping were conducted. Results: Thirteen PDE isoforms were significantly dysregulated in TAA. Upregulated transcripts included PDE10A, PDE2A, PDE4B, PDE7A, and PDE8A, whereas PDE1A/B/C, PDE3B, PDE5A, PDE6C, and PDE8B were downregulated. PDE10A achieved excellent discrimination for TAA (AUC = 0.838), while other isoforms demonstrated fair discriminatory ability. Correlation architecture revealed coordinated regulation between PDE subfamilies, including inverse relationships between PDE2A and PDE8B (r = −0.68). Interactome analysis highlighted dense connections with cyclic nucleotide and purinergic signaling hubs, enriched in vascular tone, NO–cGMP–PKG, and junctional assembly pathways. Integrating these findings with epigenetic and junctional frameworks suggests that PDE dysregulation promotes endothelial barrier fragility and maladaptive smooth-muscle remodeling. Conclusions: Family-wide PDE dysregulation characterizes human TAA, with PDE10A emerging as a central transcriptomic signature. Altered cAMP/cGMP microdomain signaling aligns with junctional failure and epigenetic control, supporting the potential of PDE isoforms as biomarkers and therapeutic targets. These results provide experimental evidence that cyclic nucleotide hydrolysis is re-wired in TAA, supporting PDE10A as a novel biomarker and therapeutic target that bridges molecular dysregulation with clinical risk stratification in thoracic aortic disease. Full article

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive and antiangiogenic therapies, yet its molecular mechanisms remain poorly defined. The present study employed an analysis of microarray data (GSE7116) from peripheral blood mononuclear cells of patients with multiple myeloma, myeloma patients with MRONJ, and healthy controls. Differentially expressed genes were identified using the limma package, followed by functional enrichment analysis, weighted gene co-expression network analysis, and LASSO regression and CytoHubba network ranking. The predictive performance was validated by means of nested cross-validation, Firth logistic regression, and safe stratified 0.632+ bootstrap ridge regression. The profiling revealed distinct gene expression patterns between the groups: the upregulation of ribosomal and translational pathways, as well as the suppression of neutrophil degranulation and antimicrobial defense mechanisms, and identified key candidate genes, including PDE4B, JAK1, ETS1, EIF4A2, FCMR, IGKV4-1, and XPO7. These genes demonstrated substantial discriminatory capability, with an area under the curve ranging from 0.95 to 0.99, and were found to be functionally linked to immune system dysfunction, cytokine signaling, NF-κB activation, and a maladaptive stress response. These findings link MRONJ to systemic immune-inflammatory imbalance and translational stress disruption, offering novel insights and potential biomarkers for diagnosis and risk evaluation. Full article

Background: Erectile dysfunction (ED) affects approximately 20% of men worldwide, significantly affecting their quality of life. While phosphodiesterase type 5 inhibitors (PDE5-Is) are the standard first-line treatment, a substantial number of patients are non-responders. Second-line treatments, such as intracavernosal alprostadil, are effective but often limited by their invasive nature and the need for frequent injections. Intracavernosal onabotulinumtoxinA (BoNT-A) offers a promising new option. By inhibiting acetylcholine release and norepinephrine, as well as other neurotransmitters involved in detumescence, it facilitates cavernosal smooth muscle relaxation and enhances penile blood flow. Its effects may persist for up to six months following a single injection, potentially reducing treatment burden and improving adherence among men with refractory ED. Methods: A systematic review was performed in accordance with the PRISMA guidelines. Literature searches were conducted in PubMed, Embase, Cochrane Library, Scopus, and Clinicaltrials.gov from inception until August 2025 using a combination of keywords and MeSH terms related to ‘erectile dysfunction’ and ‘botulinum toxin’. After screening, 51 studies met the inclusion criteria. Due to significant heterogeneity in interventions (e.g., BoNT-A dosage, co-therapies), patient populations, and reported outcomes, the data were not suitable for meta-analysis. Consequently, a narrative synthesis was performed to summarize the findings. Results: Among the included studies, intracavernosal BoNT-A was associated with improvements in validated erectile function scores. Reported response rates, variably defined across studies, ranged from 40% to 77.5%. Several studies suggested that efficacy was higher in patients with mild-to-moderate ED and with repeated administration of 100 U doses. The treatment exhibited a favorable safety profile. The most common adverse event was mild, transient penile pain (reported incidence 1.5–6%). No studies reported serious systemic adverse events. The overall strength of the evidence was limited by significant heterogeneity among the included studies and their generally small sample sizes. Conclusions: Based on this systematic review, intracavernosal onabotulinumtoxinA (BoNT-A) may be a beneficial therapeutic option for patients with refractory ED, offering potential improvements in sexual function while reducing the need for invasive therapies. Future large-scale, placebo-controlled studies are essential to confirm these benefits and standardize their clinical application. Full article

Alzheimer’s disease (AD) affects over 55 million individuals worldwide, yet no transformative disease-modifying therapies exist. Mathematical modelling provides a powerful framework to elucidate complex disease mechanisms, predict therapeutic outcomes, and enable precision medicine—capabilities urgently needed where multiscale spatiotemporal processes defy experimental analysis alone. We developed a mechanistic spatiotemporal model coupling four AD hallmarks: β-amyloid (Aβ) accumulation, T-protein (T-p) aggregation, neuroinflammation and electrical conductivity decline. Formulated as non-linear partial differential equations (p.d.es) on a 3-dimensional biological interpretation of non-linear terms (the ellipsoidal brain domain with biologically grounded parameters), the model was solved using eigenfunction expansion, Fourier analysis and numerical methods. Therapeutic interventions were simulated through mechanistically motivated parameter modifications and validated against longitudinal biomarker data from major cohort studies. Simulations reveal Aβ-initiated spatiotemporal cascades originating in the hippocampus and spreading radially at 0.15–0.20 cm/year, with T-pathology emerging after 2–3 years. Conductivity decline accelerates upon T-onset (year 5–7), reflecting the transition to symptomatic disease. Multimodal intervention at early symptomatic stages reduces peak Aβ by 36% and inflammation by 52% and preserves 41% more conductivity than untreated controls. Sensitivity analysis identifies Aβ production and inflammatory regulation as critical therapeutic targets, with dose–response curves demonstrating linear efficacy relationships. This biologically grounded framework explicitly links molecular pathology to functional decline, enabling patient-specific trajectory prediction through parameter calibration. The model establishes a foundation for precision medicine applications including individualized prognosis, optimal treatment timing and virtual clinical trial design, advancing quantitative systems biology of neurodegeneration. Full article

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse effect of antiresorptive agents, including bisphosphonates (BPs) and denosumab (DMB). We conducted a case–control epigenome-wide association study (EWAS) of 24 cancer patients treated with BPs or BPs + DMB using the Infinium^® MethylationEPIC v2.0 to explore epigenetic differences associated with MRONJ. Differentially methylated positions (DMPs) and regions (DMRs) were assessed across three analyses: MRONJ vs. controls (main), BPs-MRONJ vs. BPs-controls, and BPs/DMB-MRONJ vs. BPs/DMB-controls. Eight plasma bone biomarkers were quantified by Luminex and correlated with top methylation sites. We identified 10 DMPs and 4 DMRs at suggestive significance (p < 1 × 10⁻⁵). cg1913766 in the NOP56 promoter was hypomethylated in the main analysis (p = 2.19 × 10⁻⁷) and in BPs-MRONJ (p = 4.80 × 10⁻⁶), correlating with osteocalcin (p = 0.02 and 0.03, respectively). TNXB cg21289669 was hypermethylated in the main analyses (p = 6.31 × 10⁻⁶), and TNXB locus formed a DMR (p = 3.30 × 10⁻¹⁰) in the main and BPs-MRONJ analyses (p = 2.76 × 10⁻⁷). cg11392877 in PDE8A was hypomethylated in BPs/DMB-MRONJ (p = 5.35 × 10⁻⁷). TRIM15 was a significant DMR in BPs-MRONJ and the main analysis (p = 3.30 × 10⁻¹⁰). TRIM15, TNXB, and PDE8A regulate collagen I, while NOP56 supports ribosome biogenesis, potentially contributing to MRONJ. Given the small sample size, these findings are preliminary and validation in larger studies is warranted. Full article

The phosphodiesterase 1 genes PDE1A, PDE1B, and PDE1C encode calcium-regulated cyclic nucleotide phosphodiesterases that mediate the interplay between calcium and cyclic nucleotide signaling in the brain, heart, and vasculature. While an inhibitory domain and a calmodulin-binding domain have been identified in PDE1, the mechanism of regulation is not understood. In this study, we investigated the regulatory mechanism through a series of experiments. The experimental data, supported by AlphaFold structure predictions, consistently point to the following model of PDE1 regulation: In the absence of calcium, the inhibitory domain of PDE1 binds to and blocks the catalytic site via molecular interactions that closely resemble those observed in autoinhibited PDE4. Upon calcium/calmodulin binding to PDE1’s calmodulin-binding domain, steric constraints prevent the inhibitory domain from reaching the catalytic site, thereby activating PDE1. Understanding this mode of PDE1 regulation may open new avenues for pharmacological intervention. Moreover, it establishes PDE1 and PDE4 as a second mechanistic class of phosphodiesterase regulation in addition to the GAF-domain-mediated regulation known to control the activity of several other PDEs. Full article

Cyclic di-GMP (c-di-GMP), a universal second messenger in bacteria, orchestrates a wide array of essential life processes. Its intracellular dynamics are meticulously regulated by diguanylate cyclases (DGCs) and phosphodiesterases (PDEs), ensuring precise spatiotemporal control. The functional output of c-di-GMP signaling hinges on effector proteins—molecular decoders that translate c-di-GMP signals into specific cellular responses. This review systematically examines diverse classes of c-di-GMP effectors, using several representative bacterial species as model systems, to dissect their structural and mechanistic diversity. Particular emphasis is placed on their pivotal roles in bacterial pathogenicity, antibiotic tolerance, and host–pathogen interactions, offering fresh insights into the regulatory mechanisms underlying c-di-GMP signaling. Full article

The freezing method is widely employed in the construction of a vertical shaft in soft soil and water-rich strata. As the construction depth increases, investigating the water–heat–force coupling effects induced by the hydration heat (internal heat source) of concrete is crucial for the safety of the lining structure and its resistance to cracking and seepage. A three-dimensional coupled thermal–hydraulic–mechanical analysis model was developed, incorporating temperature and soil relative saturation as unknown variables based on heat transfer in porous media, unsaturated soil seepage, and frost heave theory. The coefficient type PDE module in COMSOL was used for secondary development to solve the coupling equation, and the on-site temperature and pressure monitoring data of the frozen construction process were compared. This study obtained the model-related parameters and elucidated the evolution mechanism of freeze–thaw and freeze–swelling pressures of a frozen wall under the influence of hydration heat. The resulting model shows that the maximum thaw depth of the frozen wall reaches 0.3576 m after 160 h of pouring, with an error rate of 4.64% compared to actual measurements. The peak temperature of the shaft wall is 73.62 °C, with an error rate of 3.76%. The maximum influence range of hydration heat on the frozen temperature field is 1.763 m. The peak freezing pressure is 4.72 MPa, which exhibits a 5.03% deviation from the actual measurements, thereby confirming the reliability of the resulting model. According to the strength growth pattern of concrete and the freezing pressure bearing requirements, it can provide a theoretical basis for quality control of the lining structure and a safety assessment of the freezing wall. Full article

With the increasing application of smart-material-based actuators for vibration suppression in flexible spacecraft, there is a growing need for advanced control strategies suited to distributed-parameter systems. This paper proposes a distributed cooperative control (DCC) scheme to address phase inconsistencies in actuator outputs within a decentralized control framework. The piezoelectric actuators embedded in flexible appendages are modeled as a multi-agent system that utilizes local information to improve coordination. A consensus-based cooperative controller is designed to synchronize actuator actions, with closed-loop stability rigorously established via Lyapunov’s direct method. The robustness of the controller is evaluated through Monte Carlo simulations under varying initial conditions. Comparative numerical results demonstrate that the proposed DCC achieves superior performance and energy efficiency over conventional decentralized control, along with inherent fault tolerance due to its distributed topology. Furthermore, the practical implementability of the approach is supported by discrete-time controller validation and automatic code generation, confirming its readiness for real-time embedded deployment. The study highlights the potential of DCC for enhancing vibration suppression in next-generation flexible spacecraft. Full article