Search Results (609)

Background: There is a high burden of influenza among individuals aged 50–64 years, with the highest rates of influenza infections other than children. The MF59-adjuvanted influenza vaccine (adjuvanted trivalent influenza vaccine [aTIV]/adjuvanted quadrivalent influenza vaccine [aQIV]) is designed to enhance response to vaccination among older adults. Among those aged ≥65 years, adjuvanted vaccine (aTIV/aQIV) has shown to be 14% more effective than standard (TIV/QIV) vaccines. This modeling study aimed to estimate the potential public health impact of aTIV/aQIV over standard influenza vaccines (TIV/QIV) among individuals aged 50–64 years over five influenza seasons. Methods: A static compartmental model was developed based on a Centers for Disease Control and Prevention model. Model inputs included vaccine effectiveness, vaccine coverage, population counts and disease burden estimates. Additional burden averted (symptomatic cases, outpatient visits, hospitalizations, intensive care unit [ICU] admissions, and deaths) was expressed as total incremental cases averted between the vaccines. Sensitivity analyses explored the influence of uncertainties in model input on the results. Results: Across the influenza seasons evaluated, on average each 5% increase in the relative vaccine effectiveness (rVE) of aTIV/aQIV vs. QIV prevented an additional 172,738 symptomatic illnesses, 74,277 outpatient visits, 1832 hospitalizations, 343 ICU admissions, and 105 deaths. This corresponds to an average seasonal incremental burden averted of 15.2%, with a range of 5.9% to 37.2%. Deterministic sensitivity analyses revealed the greatest variability was tied to rVE and burden estimates. Probabilistic sensitivity analyses results were normally distributed. Conclusions: Individuals aged 50–64 years could benefit from use of aTIV/aQIV over TIV/QIV, with an average increase in the number of influenza outcomes prevented of 15.2% per 5% improvement in vaccine effectiveness. Full article

The emergence of membrane boundaries represents a decisive transition in the origin of life, yet the molecular nature of the earliest abiotic membranes remains uncertain. Existing models based on simple fatty acids, while experimentally tractable, often lack the environmental robustness required under fluctuating prebiotic conditions. Furthermore, the absence of clear pathways linking primitive amphiphiles to later phospholipid systems highlights the need for chemically continuous intermediate frameworks. Here, we explore borate-bridged amphiphile–carbohydrate conjugates as plausible intermediates between simple prebiotic surfactants and modern lipid bilayers. These conjugates arise from low-molecular-weight polyols—including glycerol, butane-1,2,3,4-tetraol, pentane-1,2,3,4,5-pentaol, and hexane-1,2,3,4,5,6-hexitol—reacting with long-chain alkyl ethers and borate species under alkaline conditions, enabling reversible coupling to ribose and other vicinal diol-containing sugars. This chemistry integrates three essential properties for early compartmentalization: hydrolytically robust ether-linked hydrophobic domains, multivalent and highly hydrated headgroups, and environmentally responsive borate coordination. Comparative physicochemical analysis suggests that single-tail alkylglycerol derivatives preferentially form micelles and interfacial films, while di- and tri-tail tetritol and pentitol conjugates favor lamellar assemblies and vesicle formation across realistic prebiotic pH and salinity ranges. Hexitol-based systems, particularly those bearing three hydrophobic chains, may act as membrane-stabilizing components that enhance rigidity and reduce permeability under extreme conditions. We propose that heterogeneous mixtures dominated by two-tail polyol diethers, supplemented by tri-tail stabilizers and surface-active alkylglycerols, could provide mechanically robust, pH-tunable, and sugar-decorated abiotic membranes. Such borate-mediated amphiphiles offer a chemically coherent framework linking carbohydrate stabilization, ether lipid persistence, and dynamic self-assembly, potentially representing a transitional stage in the evolutionary pathway from primitive amphiphilic films to biologically encoded membranes. Full article

This paper presents a unified analytical and computational framework for the study of typhoid fever transmission dynamics governed by a Caputo fractional-order compartmental model of order $\kappa \in (0,1]$. The population is stratified into five epidemiological classes, namely susceptible $\left(\mathcal{S}\right)$, asymptomatic $\left(\mathcal{A}\right)$, symptomatic $\left(\mathcal{I}\right)$, hospitalised $\left(\mathcal{H}\right)$, and recovered $\left(\mathcal{R}\right)$, and the governing system explicitly incorporates asymptomatic transmission, treatment dynamics, and temporary immunity with waning. The use of the Caputo fractional derivative is motivated by the well-documented existence of chronic asymptomatic Salmonella Typhi carriers, whose heavy-tailed sojourn times in the carrier state are naturally encoded by the Mittag–Leffler waiting-time distribution arising from the fractional operator. A complete qualitative analysis of the fractional system is carried out: the basic reproduction number ${\mathcal{R}}_0$ is derived via the next-generation matrix method; local and global asymptotic stability of both the disease-free equilibrium ${\mathcal{E}}_0$ (when ${\mathcal{R}}_0\le 1$) and the endemic equilibrium ${\mathcal{E}}^{*}$ (when ${\mathcal{R}}_0>1$) are established using fractional Lyapunov theory and the LaSalle invariance principle; and the normalised sensitivity indices of ${\mathcal{R}}_0$ are computed to identify transmission-amplifying and transmission-suppressing parameters. Existence, uniqueness, and Ulam–Hyers stability of solutions are established via Banach and Leray–Schauder fixed-point arguments. To complement the analytical results, a fractional physics-informed neural network ($\mathcal{PINN}$) framework is developed to simultaneously reconstruct compartmental trajectories and identify unknown biological parameters from sparse synthetic observations. $\mathcal{PINN}$ embeds the L1-Caputo discretisation directly into the training residuals and employs a four-stage Adam–L-BFGS optimisation strategy to recover five trainable parameters $\Theta$ = $\{\varphi ,\mu ,\sigma ,\psi ,\beta \}$ across three fractional orders $\kappa \in \{1.0,0.95,0.9\}$. The estimated parameters show strong agreement with the true values at the classical limit $\kappa =1.0$ ($\mathrm{MAPE}=2.27\%$), with the natural mortality rate $\mu$ recovered with $\mathrm{APE}\le 0.51\%$ and the transmission rate $\beta$ with $\mathrm{APE}\le 3.63\%$ across all fractional orders, confirming the structural identifiability of the model. Pairwise correlation analysis of the learned parameters establishes the absence of equifinality, validating that $\beta$ can be reliably included in the trainable set. Noise robustness experiments under Gaussian perturbations of $1\%$, $3\%$, and $5\%$ demonstrate graceful degradation ($\mathrm{MAPE}$: $0.82\%\to 3.10\%\to 7.31\%$), confirming the reliability of the proposed framework under realistic observational conditions. Full article

Generally, forest trees with medicinal value present diverse chemotypes considered key determinants of efficacy, safety, and commercial valuation. Such heterogeneity varies among tissues, genotypes, and seasons, and stress exposure. This review summarizes how regulatory controls and genome architecture affect the stability and synthesis of secondary metabolites in woody medicinally important taxa. Detailed haplotypic and chromosomal analyses have recently identified diverse and repeatable architectural drivers. Among these, LTR/transposon-mediated revamping, neofunctionalization, biosynthetic gene clusters, and tandem duplication play a special role in reshaping pathway capacity. The enzymatic regulation of these drivers translates this “capacity” into harvest-pertinent chemistry by employing conserved TF modules, hormone crosstalk, and emergent chromatin/epigenetic layers. Nevertheless, major parameters pertaining to the tissue-specific storage, transport, and compartmentalization of these chemotypes are contextualized with certain limitations. In this review, the integration of GWAS/eQTL/TWAS with multi-tissue is explained in addition to the replacement of a single reference with pangenome/haplotype frameworks, and explicit modeling of G × E further strengthen genotype-to-chemotype mapping. Therefore, in this review we summarize practical workflows for chemotype discovery utilizing staged validation models of heterologous reconstitution, isotope/spatial evidence, and chemistry. These findings were supported by data on saponins, alkaloids, iridoids, and defense response. Such an integration links mechanistic understanding to authentication, standardization, and sustainable utilization strategies in woody medicinal trees. Full article

Patterns of colon cancer recurrence demonstrate a high degree of anatomical reproducibility, consistently aligning with mesofascial planes and compartmentalized vascular and lymphatic territories, as evidenced by pathological, surgical and imaging studies. These frameworks describe recognized routes of spread but do not provide an integrated anatomical explanation for understanding why tumor progression often aligns with mesofascial planes, embryological boundaries and cavity-specific niches, nor for why preservation of structural integrity during surgery is associated with improved oncological outcomes. This work proposes a spatial containment model of colon cancer progression, in which tumor dissemination reflects sequential breaches of anatomically defined barrier systems. The Colon Cancer Containment System is proposed as a three-tier framework in which tumor progression reflects sequential breaches of containment at the tissue (microcontainment), mesenteric (mesocontainment) and peritoneal or systemic (macrocontainment) levels. At each stage, anatomical structures function as barrier systems that constrain tumor spread and shape directionality of progression. Disruption of these barriers, whether tumor-driven or iatrogenic, is associated with relatively consistent patterns of local, regional, and distant recurrence. Within this approach, established prognostic features such as tumor–node–metastasis (TNM) stage, extramural vascular invasion, perineural invasion and margin status may also be interpreted as markers of containment integrity, in addition to their established roles as indicators of tumor aggressiveness. Surgical plane preservation is reframed as a biologically meaningful act of containment maintenance. By organizing validated observations within an anatomically patterned architecture, the containment framework provides a coherent model for interpreting reproducible recurrence patterns and clarifies the biological significance of surgical integrity. This perspective complements existing oncological paradigms, supports anatomically informed risk stratification and generates testable hypotheses for future clinical and translational research. Full article

Background/Objectives: Non-ablative vaginal Erbium-doped Yttrium Aluminium Garnet (Er:YAG) laser therapy has been proposed as a minimally invasive option for pelvic floor dysfunction (PFD), yet objective anatomical data using standardized measures remain limited. This study evaluated short-term anatomical and functional outcomes in a real-world care setting. Methods: This prospective single-arm interventional cohort study included women with PFD who underwent two sessions of non-ablative vaginal Er:YAG laser therapy. Outcomes were assessed at baseline, first follow-up (FU1), and second follow-up (FU2). Anatomical changes were measured using POP-Q parameters, including vaginal hiatus (Gh), total vaginal length (TVL), and compartmental staging. Sexual function was evaluated using the Female Sexual Function Index (FSFI). Pelvic floor muscle strength was assessed using the Oxford Scale. Non-parametric tests were used for repeated measures, and correlations between delivered laser energy and clinical outcomes were explored. Results: A total of 163 women were enrolled; 136 completed FU1 and 59 completed FU2. Median vaginal hiatus decreased significantly from baseline to FU1 and remained reduced at FU2 (p < 0.001). Improvements in anterior and posterior prolapse staging were observed, with a shift toward lower POP-Q stages at both follow-up visits. FSFI total scores did not change significantly across visits, although small changes were observed in specific domains, including a transient decrease in orgasms at FU1 (Δ = −0.2, p = 0.021) and a modest improvement in pain at FU2 (Δ = −0.4, p = 0.045). The magnitude of anatomical changes was modest, and their clinical relevance remains uncertain. Conclusions: Non-ablative vaginal Er:YAG laser therapy was associated with short-term improvements in vaginal hiatus and POP-Q prolapse staging in women with PFD, while sexual function remained stable. These findings provide objective anatomical data on early treatment effects in routine care, informing future evaluation of minimally invasive care models for pelvic floor dysfunction. Full article

Monkeypox (Mpox), caused by the monkeypox virus (MPXV), has re-emerged as a significant global public health concern, particularly following the 2022 outbreaks. Understanding its transmission dynamics is essential for designing effective control strategies. In this study, we develop and analyze a deterministic compartmental model that captures both human-to-human and rodent-to-human transmission pathways in order to better reflect the zoonotic nature of the disease. The model is investigated using qualitative and quantitative analytical techniques, including stability analysis, bifurcation theory, and sensitivity analysis. The basic reproduction number, $R_0$, is derived and used to determine threshold conditions for disease persistence or eradication. We show that the disease-free equilibrium is globally asymptotically stable when $R_0<1$, while an endemic equilibrium exists and is stable when $R_0>1$. Furthermore, the model exhibits backward bifurcation, indicating that reducing $R_0$ below unity may not be sufficient for disease elimination. Sensitivity analysis identifies key parameters driving transmission, particularly the rodent-to-human and human-to-human contact rates. Numerical simulations further demonstrate that reducing cross-species transmission and improving isolation of infected individuals significantly decrease disease burden. These findings highlight the complexity of Mpox transmission and emphasize that effective control requires not only lowering $R_0$, but also targeting critical transmission pathways. This study provides useful insights for public health planning by identifying priority intervention strategies such as minimizing rodent–human interactions and strengthening isolation measures. Full article

This article compares selected fire safety regulatory systems in Japan, China, the United States, and the EU/UK, interpreted through the lens of responsive architecture and the implementation of digital technologies—building information modelling (BIM), digital twins (DTs), artificial intelligence (AI), and the Internet of Things (IoT). The study adopts a qualitative approach based on a structured review of legal acts, technical standards, public-sector reports, and the scientific and professional literature, organised using a common analytical framework. First, the analysis identifies shared foundations across regimes: the primacy of life safety, mandatory detection and alarm functions, fire compartmentation, requirements for protected means of exit, and the increasing importance of documenting the operational status of protection measures. Then, it contrasts key differences, including the permissibility of performance-based design (PBD), the degree to which digital documentation is formally recognised, organisational enforcement models, and cybersecurity approaches for integrated fire alarm/voice alarm/building management/IoT ecosystems. Japan and selected Chinese cities combine stringent requirements with openness to dynamic solutions and urban-scale data platforms. The USA relies on a decentralised code-based ecosystem with a strong role for professional and industry bodies, while the EU/UK continues to strengthen harmonised standards and digital building registers, reinforced by lessons after the Grenfell Tower fire. Against this background, Poland is discussed as broadly aligned in goals and baseline technical requirements yet lagging behind in implementing PBD pathways, digital registers, formal BIM/DT integration, and minimum cybersecurity requirements. The proposed directions for change aim to create a more predictable regulatory and technical framework for the development of responsive architecture and dynamic fire safety systems in Poland. The study contributes to the sustainability literature by framing regulatory readiness for digital fire safety as a lifecycle resilience strategy, directly relevant to safe, resource-efficient, and inclusive built environments. Full article

Background/Objectives: Women and girls, particularly in sub-Saharan Africa, face high risks for both HIV and unintended pregnancy. Inconsistent condom use underscores the need for new multipurpose prevention technologies (MPTs) that combine HIV pre-exposure prophylaxis (PrEP) and contraception. Long-acting (LA) injectables are especially promising. To this end, an LA cabotegravir (CAB)/medroxyprogesterone acetate (MPA) in situ-forming implant (ISFI) has been developed. We report pharmacokinetic (PK) modeling to characterize CAB and MPA disposition and absorption to support the development of the MPT ISFI. Methods: Female BALB/c mice received single intravenous (IV) or subcutaneous (SQ) bolus doses of CAB or MPA. Sparse plasma samples were collected (~3 mice/timepoint) for PK analysis by LC-MS/MS. Noncompartmental analysis assessed SQ bioavailability. Macroparameterized compartmental PK models were fit to IV data to derive unit impulse responses (UIRs) for each drug. Results: CAB and MPA exhibited 61% and 42% bioavailability, respectively. CAB IV PK was best described by a two-compartment model with macroconstant parameters: A = 16,621 ng/mL, α = 4.52 h⁻¹, B = 30,206 ng/mL, and β = 0.053 h⁻¹. MPA IV PK was also best described by a two-compartment model, with A = 2506 ng/mL, α = 10.5 h⁻¹, B = 439 ng/mL, and β = 0.65 h⁻¹. These values define the UIR for CAB and MPA. Conclusions: Our IV PK modeling framework fully characterizes CAB/MPA disposition in mouse, enabling downstream deconvolution-based estimation of absorption from controlled-release formulations. This provides a foundation for in vitro–in vivo correlation, facilitating preclinical evaluation of long-acting formulations such as ISFIs. Full article

Background and Objectives: To study the bony compartmentalization of the jugular foramen in comparison with existing anatomical models. Materials and Methods: We carried out the study on 59 undamaged dry adult human skulls of known age and sex. Two independent examiners with 10 years of experience in anatomical studies by visual inspections determined the type of osseous septation at the inner surface of the jugular foramina. Relationships between jugular foramen morphology and laterality were assessed at the foraminal level, while associations with age groups and sex were evaluated at the skull level. The data obtained was analyzed using the chi-square statistical test to determine the possibility that two or more variables were associated. Results: Different types of jugular foramina were observed: a single foramen without bony spurs was rarely observed (0.9%). Bipartite and tripartite partial or total foramina were frequent (42.2% and 51.4%, respectively). Partial quadripartite foramina were more rarely observed (5.5%). Complete bony bridges were observed in 13 right and 11 left jugular foramina (24/109, 22.01%). Statistical analysis revealed no significant differences in the occurrence of bony bridges in relation to sex, age, laterality, or foramen partition. As regards the bipartite foramina on the left, we found that in males the frequency was higher in older subjects compared to younger ones; although statistical significance was not reached (p = 0.054). Furthermore, the absence of the intrajugular process from the occipital bone was much higher (45.9%) than that from the temporal bone (1.8%), and this difference was statistically significant (p = 0.0001). Conclusions: The jugular foramen from our studies appears mostly septate. These partitions fit well into the anatomical models existing in the literature for the jugular foramina. Our study fits into the anatomical models of the septum and subdivision of the jugular foramen, especially the bipartite and tripartite ones, even if there are differences related to the behavior of the meninges present in some current anatomical models. The existing literature relates primarily to ethnic groups other than our study, which was conducted on European skulls. Full article

Modern healthcare remains structurally and conceptually fragmented, with profound clinical and policy implications. At its root lies an ontological fracture: the prevailing biomedical model reduces patients to discrete biological systems (organs, biomarkers, and symptoms) detached from the psychological, social, and ecological contexts in which health and illness are experienced. This is compounded by epistemological fragmentation, where medical knowledge is compartmentalized into increasingly narrow specialties, limiting holistic understanding. These philosophical divisions manifest in downstream operational, informational, financial, and policy dysfunctions duplicative testing, misaligned incentives, disconnected care pathways, and population health failures. To address these multilevel fractures, we propose a unified architecture grounded in three interlocking components. First, the Precision and Personalized Population Health (P3H) framework offers a principle-based realignment toward care that is integrated, personalized, proactive, and population wide. P3H addresses the conceptual shortcomings of fragmented care by focusing on the full human trajectory across time, systems, and determinants. Second, General Purpose Technologies including artificial intelligence, biosensors, mobile diagnostics, and multimodal data systems enable the operationalization of whole-person care at scale, especially in low-resource settings. Third, the AI-WHOLE policy framework (Alignment, Integration, Workflow, Holism, Outcomes, Learning, and Equity) provides governance principles to guide ethical, equitable, and context-specific implementation. We argue that this triadic blueprint is particularly critical for Global South nations, where the lack of legacy infrastructure offers an opportunity for leapfrogging toward integrated, intelligent systems of care. Early models illustrate how policy-aligned, technology-enabled care rooted in whole-person principles can yield improvements in continuity, cost-efficiency, and chronic disease outcomes. This manuscript offers a systems-level strategy to overcome fragmentation and reimagine healthcare delivery, not only by refining clinical tools, but by redefining what it means to care for the human being in full. Full article

Caffeine (CAF) is one of the most widely consumed psychoactive substances worldwide. It is primarily metabolized to paraxanthine (PAR), theobromine (THR), and theophylline (THY). While CAF metabolism has been extensively characterized in humans and rodent models, corresponding data in zebrafish (Danio rerio) larvae remain limited. This study provides a comprehensive characterization of CAF biotransformation in zebrafish larvae using validated LC-QQQ-MS for quantitative metabolite profiling and FTIR imaging for spatially resolved tissue distribution mapping. Zebrafish larvae at 4 days post fertilization (dpf) were exposed to CAF at concentrations of 15, 25, and 50 mg/L for 18 h. The LC–MS/MS analysis demonstrated dose-dependent conversion of CAF to PAR (up to 4.54%), THR (up to 1.32%), and THY (up to 0.27%). The PAR/CAF and THR/CAF ratios increased as CAF concentration rose, while the THY/CAF ratio declined. In parallel, FTIR imaging was applied to visualize the spatial distribution of CAF and selected metabolites in larval tissue sections, confirming the presence of CAF, PAR, and THR and revealing their localization within the tissue. However, THY was not detected by this method. Metabolite localization differed across larval tissues, indicating compartmentalized metabolic processes. This study provides the first comprehensive characterization of CAF metabolism in zebrafish larvae, revealing low but detectable CYP450-mediated metabolic activity prior to full hepatic maturation. The findings support the utility of zebrafish larvae as a model for developmental pharmacokinetic studies. Full article

Lekethromycin (LKMS) is a novel macrolide veterinary antimicrobial. Its propensity for intracellular accumulation causes discrepancies between whole blood and plasma concentrations, complicating pharmacokinetic evaluations. This study compared the pharmacokinetic characteristics, dose proportionality, and bioavailability of LKMS in whole blood and plasma following intramuscular administration in pigs. Forty-two healthy pigs received LKMS via a single intravenous reference dose (5 mg/kg) for absolute bioavailability estimation or intramuscular (1, 2.5, 5, and 10 mg/kg) injection. Pharmacokinetic parameters were calculated using non-compartmental analysis, and dose proportionality was evaluated via a power model. LKMS exhibited rapid absorption and slow elimination, with a plasma half-life of 49.25 to 67.63 h. Whole blood exposure and peak concentrations were 1.5 to 3 times higher than in plasma, indicating extensive blood cell partitioning. As the intramuscular dose increased, the whole blood-to-plasma concentration ratio decreased from 2.83 to 1.15, suggesting a saturable cell uptake mechanism. Consequently, LKMS exhibited non-linear pharmacokinetics in whole blood but demonstrated linear, dose-proportional pharmacokinetics in plasma. Absolute bioavailability based on plasma ranged from 83.2% to 119.5%. Due to saturable blood cell binding, plasma is the optimal matrix for accurately evaluating LKMS systemic exposure and bioavailability in swine. Full article

Landfill leachate is considered one of the most recalcitrant wastewaters due to its high organic strength, elevated ammonia concentrations, and complex chemical composition. This study evaluates integrated technologies for treating highly loaded landfill leachate from the Wadi Al-Asla landfill, Jeddah Saudi Arabia, using GPS-X^TM modeling combined with regulatory compliance and techno-economic assessment (TEA). The characterized mature leachate exhibited extremely high average concentrations of COD (17,050 mg L⁻¹), BOD₅ (10,058 mg L⁻¹), ammonia-N (989 mg L⁻¹), and total nitrogen (1223 mg L⁻¹), indicating severe pollution levels requiring integrated treatment technologies. Five (5) different scenarios involving integrated biological, physicochemical, and membrane-based processes were modelled, simulated and evaluated against local discharge standards complaince. Conventional and municipality-proposed upgrade configurations achieved ~80–83% COD removal, producing effluent COD > 2900 mg L⁻¹ and 1790–1801 mg L⁻¹ BOD₅, indicating persistent non-compliance for organic pollutants. Nitrogen removal improved substantially (93.7–95.7% ammonia-N and 91–93% total nitrogen removal), yet residual ammonia-N (44–63 mg L⁻¹) and total nitrogen (92–108 mg L⁻¹) remained above regulatory limits. Advanced hybrid systems achieved complete TSS removal and strong phosphorus control (TP ≤ 0.42 mg L⁻¹), while three(3) compartmental aerobic–anoxic membrane bioreactor coupled with reverse osmosis (MBR + RO) achieved near-complete nitrogen removal and reduced 90% COD removal. The lifecyle economic assessment indicated OPEX ranging from USD 1.1 to 5.6 m⁻³ of treated leachate with the aerobic–anoxic MBR + RO configuration yieding footprint advantage, lower CAPEX and moderate OPEX By combining process modeling, regulatory compliance evaluation, and economic assessment, this study provides a practical screening framework for selecting sustainable treatment strategies for high-strength landfill leachate and wastewater matices. Full article

Background/Objectives: Congenital anomalies of the kidney and urinary tract (CAKUTs) represent the leading cause of pediatric chronic kidney disease, yet the molecular mechanisms underlying these malformations remain incompletely understood. While genetic studies have identified numerous CAKUT-associated genes, conventional knockout approaches often result in embryonic lethality or fail to reveal tissue-specific gene functions. This review aims to synthesize findings from conditional knockout mouse studies that have elucidated the spatiotemporal requirements of key signaling pathways during kidney development. Methods: We conducted a narrative synthesis of studies employing Cre-loxP conditional gene targeting in mouse models, identified through systematic searches of PubMed and cross-referencing of key primary research. Studies were selected based on their use of lineage-specific Cre drivers (Six2-Cre, Hoxb7-Cre, Foxd1-Cre) to investigate nephron progenitor maintenance, ureteric bud branching morphogenesis, and stromal–epithelial interactions. Results: Conditional knockout studies have redefined CAKUT pathogenesis as a disorder of dose-dependent signaling, temporal regulation, and inter-compartmental communication. WNT/β-catenin signaling operates in a biphasic, dose-dependent manner in nephron progenitors, with Six2-Cre-mediated β-catenin deletion causing premature progenitor depletion. BMP and FGF pathways demonstrate dose-dependent and context-specific functions in progenitor maintenance, while GDNF/RET signaling is essential for ureteric bud outgrowth and branching. Importantly, stromal-specific deletions have uncovered non-cell-autonomous mechanisms regulating nephron formation. Haploinsufficiency studies demonstrate that partial pathway disruption can reduce nephron endowment without overt CAKUT, predisposing to adult-onset hypertension and chronic kidney disease. Conclusions: Conditional gene targeting has mechanistically redefined CAKUT from a collection of structural malformations to a spectrum of disorders arising from quantitative perturbations in lineage-specific signaling networks. These findings establish that phenotypic severity is determined by the degree of pathway disruption, the developmental timing of insult, and the compartment affected, providing a framework for interpreting oligogenic interactions and variable penetrance in human CAKUTs. Full article