Search Results (425)

Neurodevelopmental disorders (NDDs) comprise a heterogeneous group of conditions that may present with developmental delay, intellectual disability, language impairment, epilepsy, autism-like features, motor abnormalities, or syndromic manifestations. Ubiquitination is an essential post-translational mechanism that regulates protein stability, localization, trafficking, and signaling. Because E3 ubiquitin ligases determine substrate specificity in this process, abnormalities in E3 ligases or E3-associated complexes can selectively affect proteins required for brain development and neuronal function. This review summarizes genetic and functional evidence linking E3 ubiquitin ligases, E3-complex components, substrate-recognition factors, and related ubiquitination regulators to NDDs. Gene Ontology enrichment analysis and mechanistic studies suggest that these genes converge on several major biological themes, including early neurodevelopment, neuronal migration, synaptic and circuit maturation, proteostasis, metabolism, and intracellular trafficking. However, the strength and translational relevance of the available evidence vary across genes. UBE3A-related Angelman syndrome currently provides the clearest example of mechanism-guided therapeutic development through UBE3A restoration and paternal allele reactivation. In contrast, many non-UBE3A mechanisms remain at the stage of pathway analysis, preclinical modulation, or candidate substrate validation. Future studies should clarify variant-specific functional effects, define direct disease-relevant substrates, and establish reproducible readouts that can support mechanism-based therapeutic development. Full article

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) sustains reductive biosynthesis, antioxidant defense, oxidase activity, and redox signaling; nevertheless, studies framed as “NADPH imaging” often interrogate biochemically non-equivalent variables and analytically distinct endpoints. To resolve that ambiguity, this review organizes current methods by analyte-defining event, optical transduction or readout, acquisition modality, and deployment context. Extraction and enzyme-coupled assays can define recovered NADPH, oxidized nicotinamide adenine dinucleotide phosphate (NADP⁺), total NADP(H), or a derived ratio, albeit at the cost of subcellular information. By contrast, protein-based, genetically encoded, and chemigenetic systems enable reversible, compartment-addressable measurements of sensor-accessible cofactor binding, ligand-dependent assembly, relay output, or NADPH/NADP⁺ balance; however, quantitative interpretation remains contingent on affinity, sensor abundance, pH, maturation, calibration, and sensor-induced buffering. Reaction-based probes offer the broadest spectral and imaging flexibility—including ratiometric, near-infrared, two-photon, and photoacoustic formats—yet most rely on hydride-transfer chemistry shared by reduced nicotinamide adenine dinucleotide (NADH) and NADPH. Absent matched kinetics and simultaneous mixed-cofactor experiments, NAD(P)H-responsive remains the most defensible designation for these platforms. Label-free autofluorescence, fluorescence lifetime imaging microscopy (FLIM), and phasor analysis preserve native spatial context; even so, they report composite intensity, binding-state, or metabolic contrast rather than a universal absolute NADPH concentration. Across modalities, rigorous interpretation requires physiologically relevant concentration ranges, product or binding-mechanism verification, matrix- and organelle-specific controls, time-resolved calibration, and orthogonal measurements of pool size or flux. By aligning each signal-generating event with the endpoint it can legitimately support, the review establishes a mechanistic basis for platform selection and for interpreting NADPH-related optical changes across purified systems, cells, tissues, and biofluids. Full article

Complete surgical resection remains the cornerstone of curative therapy for early-stage non-small-cell lung cancer (NSCLC), yet a substantial proportion of patients relapse despite a macroscopically complete operation and negative conventional staging. This residual risk reflects micrometastatic disease that is below the resolution of computed tomography and that current clinicopathologic risk factors only coarsely predict. Circulating tumor DNA (ctDNA) provides a direct, blood-based readout of this molecular residual disease (MRD), its detection after definitive treatment is among the strongest known predictors of recurrence, and ctDNA frequently rises months before radiographic progression. In this narrative review, based on a literature search closed on 12 September 2026, we synthesize the foundational and translational literature underpinning ctDNA-MRD in resected NSCLC. We outline the biology of ctDNA shedding and metastatic dissemination established by serial-sampling and phylogenetic studies; the prognostic performance of landmark and longitudinal MRD, tabulated quantitatively across the major cohorts, meta-analyses and trial-nested analyses; the perioperative kinetics that dictate when sampling is informative; the analytical design of tumor-informed versus tumor-agnostic assays and the determinants of their sensitivity; and the biological and technical sources of false-negative and false-positive results, of which clonal hematopoiesis and low-shedding histologies are the most consequential. We then position MRD within the contemporary perioperative treatment landscape—adjuvant targeted therapy and immunotherapy, and neoadjuvant and perioperative chemoimmunotherapy—and review the emerging, still-investigational paradigm of MRD-guided escalation and de-escalation, including the early termination of the MRD-selected MERMAID trials. We conclude with the analytical, evidentiary and implementation barriers—and the current positions of guideline bodies and regulators—that separate a powerful prognostic biomarker from a validated predictive tool, and we set out the trial-design requirements needed to close that gap. Full article

To meet the fast-response and wide load-current requirements of X-ray detector readout chips, a Low-Dropout Regulator (LDO) based on an improved Level-Shifted Flipped Voltage Follower (LS FVF) is proposed in a 130 nm CMOS process. A fast Flipped Voltage Follower (FVF)-based feedback loop is introduced to improve transient response, while a level shifter is introduced to relax the DC operating-point coupling between the pass-transistor gate and the control transistor drain at light loads. To further enhance response speed, dynamic current-source biasing, which senses output-voltage variations through capacitive coupling, is proposed, and it is capable of adaptively increasing the LS FVF driving capability during large load transients. A positive-feedback auxiliary circuit is proposed to further accelerate the charging and discharging of the pass-transistor gate. To maintain stability over the 0–400 mA load range, dynamic pole-zero compensation is combined with Miller compensation to track load-dependent poles and preserve sufficient phase margin across operating conditions. Post-layout simulations with a 200 pF load capacitor and a 0–400 mA load-current step show an overshoot of 100.4 mV and an undershoot of 50.5 mV, with recovery times of 0.2 μs and 0.12 μs, respectively. The proposed LDO achieves a capacitance-normalized transient figure of merit of 0.113 ps, demonstrating a favorable trade-off among performance parameters. Full article

We propose a superconducting single-mode microwave haloscope based on chiral cavity resonators for the detection of ultralight dark matter axions over the mass range 4 × 10⁻¹⁹–4 × 10⁻¹⁴ eV. Building on the single-mode chiral-cavity haloscope for detecting ultra light dark matter (ULDM) axions we develop a resonator geometry compatible with subtractive manufacturing from high-purity bulk niobium, taking advantage of the substantially lower surface resistance achievable relative to the additively manufactured Möbius cavity proposed in the earlier work. An inverse-design framework is then used to maximise a figure of merit derived to minimise the measurement time required to achieve a fixed experimental sensitivity. The resulting optimised bulk-niobium design achieves a figure of merit more than three orders of magnitude larger than the additively manufactured Möbius benchmark. An experimentally informed microwave interferometric readout model incorporating measured electronics noise and active suppression of pump amplitude noise is used to project the sensitivity of the proposed experiment. For an acquisition time of three months, the haloscope is projected to reach g_aγγ < 10⁻¹¹ GeV⁻¹ across more than four orders of magnitude in axion mass. The projected sensitivity extends approximately one order of magnitude below the current exclusion limits set by CAST, providing a practical pathway towards a high-sensitivity direct search for ultralight dark matter axions. Full article

The “unexplained failure” of rotator cuff repair is multifactorial, but its structural endpoint is anatomically consistent, i.e., the failure of the tendon-to-bone interface (enthesis) to heal. The native enthesis is a four-zone fibrocartilaginous gradient that does not regenerate but heals as a mechanically inferior fibrovascular scar, so the outcome of repair hinges on the interface’s healing capacity—which chronological age predicts poorly. This review organizes the aging biology governing bone-to-tendon healing capacity into eight domains: progenitor competence, cellular senescence and the SASP, immune aging, extracellular-matrix and collagen aging via advanced glycation end-product cross-linking, footprint angiogenesis, morphogen signaling, mechanotransduction, and bone quality. We then precisely define the DNA-methylation epigenetic clock—a continuous value produced by weighted CpG methylation, with defined units, reproducibility, and effect sizes—and propose it as a candidate quantitative readout of these domains; whether or not it truly integrates them into a single biologically meaningful measure at the enthesis is a hypothesis of this review, not an established mechanism. In 1087 twins, epigenetic age acceleration predicted fracture and osteoporosis risk, with hazard ratios of 1.29–3.17 per standard deviation; moreover, aging is tissue-specific, so the enthesis may run ahead of blood. Critically, the clock provides a single axis on which current regenerative-medicine strategies—stem cells, exosomes, immunomodulation, biomimetic gradient scaffolds, growth factors, senolytics, and epigenetic reprogramming—can be systematically categorized by how far each shifts biological age toward a healing-competent state; partial reprogramming, which rewinds the clock directly, shows that the clock is simultaneously the readout and the therapeutic target. We integrate this into a “hidden biological age of bone-to-tendon healing”, explicitly stating that this remains an unvalidated hypothesis requiring prospective validation. Full article

Shortwave infrared (SWIR) imaging technology, with its excellent penetration and anti-interference capabilities, is widely applied in military, medical, and industrial fields. However, traditional detectors (e.g., InGaAs) are expensive, have complex readout circuits, and exhibit insufficient low-light performance, limiting their large-scale promotion. This paper proposes and implements a single-pixel SWIR imaging system based on PbS quantum dot (QD) detectors. A single-pixel imaging system is constructed using PbS QD detectors with a formal device structure (ITO/ZnO/PbS/PbS-EDT/Au); through simulation studies, the effect of the PbS absorption layer thickness on device performance is investigated, and it is determined that a thickness of 450 nm yields optimal device performance. Based on the simulation results, a P-I-N structure PbS photovoltaic-type detector with high external quantum efficiency (EQE) and low dark current is fabricated, achieving a EQE of 62% at the 1300 nm wavelength, a dark current density of 8.54 × 10⁻⁴ mA·cm⁻² at −0.1 V bias voltage, and a −3 dB bandwidth of 324 kHz; a low-noise signal conditioning circuit is designed to optimize the −3 dB bandwidth to 337 kHz while maintaining low noise density, enabling the linear conversion of nA~μA level weak photocurrent from the detector to 0~3 V standardized voltage signals, meeting the requirements of single-pixel imaging (SPI) systems. Hadamard orthogonal encoding technology is employed to achieve spatial light modulation and signal encoding; after the PbS QD detector collects and integrates the projection signal, the image with 128 × 128 resolution is reconstructed through the inverse Hadamard orthogonal decoding algorithm. This work provides a novel solution for QD-based SWIR imaging, overcoming the cost and manufacturing limitations of traditional array systems and laying the foundation for the spectral expansion and practical application of SPI technology. Quantitative imaging characterization and low-light imaging tests are supplemented to verify the comprehensive performance of the system. Full article

Mosquito-borne viruses, including dengue, Zika and chikungunya viruses, place a substantial burden on diagnostic services, especially where molecular laboratories are inaccessible or slow to return results. Point-of-care biosensors could reduce turnaround times and bring testing closer to patients in primary care, outbreak response, and field settings. This review critically examines nucleic acid amplification, CRISPR-assisted assays, lateral-flow platforms, microfluidic systems, electrochemical and optical biosensors, paper-based devices, and smartphone-enabled readouts. These technologies are evaluated in terms of sample preparation, analytical sensitivity and specificity, matrix interference, multiplexing, workflow integration, cost, and clinical validation. Overall, nucleic-acid-amplification and CRISPR-assisted platforms often achieve low reported detection limits under controlled conditions; lateral-flow and paper-based devices offer relatively simple and minimally instrumented workflows; and microfluidic, electrochemical, and smartphone-enabled systems support increasing levels of workflow integration, quantitative readout, and connectivity. However, few platforms currently integrate these advantages into a fully integrated and clinically validated “sample-to-result” workflow. Due to sample heterogeneity, viral strains, reference methods, assay conditions, and disparities in reporting practices, conducting meaningful cross-study comparisons remains challenging. Limited comparisons and insufficient prospective clinical and field validation further restrict the assessment of practical diagnostic utility. Therefore, strong analytical performance alone should not be interpreted as evidence of clinical validity. Priority directions include unified definitions of performance and reporting units, standardized validation protocols and external quality assessment, prospective multi-site evaluation using representative populations and specimens, and earlier consideration of manufacturing scalability, reagent stability, quality systems, and applicable regulatory requirements. Future platforms should integrate simplified sample preparation, multiplex detection, objective digital or AI-assisted interpretation, and secure connectivity while demonstrating measurable benefits for patient management and outbreak surveillance. Full article

Complex nonlinear physical systems can exhibit dynamic responses that provide useful resources for information processing. In this study, an electrical circuit-based multiple-electron model was developed and implemented in a random network to investigate its dynamic electrical properties and information-processing capability. The model represents discrete electron transfer and charge accumulation using tunnel junctions and charge-storage nodes and was constructed as a two-dimensional random network inspired by carbon nanotube/polyoxometalate (CNT/POM) networks. The network exhibited time-varying current responses under a constant voltage and nonlinear and hysteretic current–voltage characteristics. The hysteresis became more pronounced as the number of charge-storage nodes increased. The information-processing capability of the network was further investigated using delayed XOR and sine waveform generation tasks. The delayed XOR task was achieved using the integrated squared current response, whereas a target sine waveform was reconstructed from multiple network responses under a constant voltage input using a linear readout, yielding a coefficient of determination of 0.816. These results demonstrate that the proposed multiple-electron network exhibits nonlinear and history-dependent electrical dynamics and can support information-processing tasks. Full article

Accessible molecular diagnostics is fundamental to effective healthcare. While most current point-of-care devices detect only the presence of a molecular biomarker(s), biomarker quantification can be equally important for decision-making on disease treatment and containment. Here, we present a diagnostic platform that enables the equipment-free quantification of molecular biomarkers with the simplicity of a binary (yes/no) readout. This capability is achieved by integrating a stoichiometric quantitative approach with widely available and easy-to-use lateral flow dipsticks. To implement the approach, we engineer negative cooperativity into target–probe binding interactions for oligonucleotide targets as a model system. The resulting threshold-based semi-quantitative assay with lateral flow dipsticks quantifies targets in the low-nanomolar range and operates reliably in complex biological backgrounds. A key advantage of this platform is its potential adaptability to new and emerging targets: repurposing will require only reagent redesign, without the need for additional fabrication. Full article

Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal cell carcinoma (RCC), representing approximately 80% of cases globally. Despite improved diagnosis and therapy, treatment of aggressive or metastatic ccRCC remains challenging due to acquisition of primary or secondary resistance. Among the dysregulated signaling mechanisms identified in ccRCC, the mechanistic target of rapamycin (mTOR) and the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) pathways play central roles in regulating various biological functions such as metabolism, inflammation, tumor growth, and survival. However, the molecular crosstalk between mTOR and NF-κB signaling in ccRCC progression and therapeutic resistance remains poorly understood. Therefore, in our current study, we aimed to investigate the interplay between mTOR and NF-κB signaling in ccRCC. We analyzed tumor tissue samples from human ccRCC patients. For validation of mTOR and NF-κB signaling, we used two human ccRCC cell lines, A498 and 786-O. Using pharmacological inhibitors of mTOR and IKK/NF-κB signaling, Torin-1 and MLN120B, respectively, we assessed the functional relationship between these two pathways employing immunoblotting, EdU-based immunocytochemistry, and functional assays. Our findings reveal that both mTOR and NF-κB pathways are aberrantly activated in human ccRCC tissues. Phosphorylation of IκBα, S6, and 4E-BP1 was increased compared with matched adjacent control tissue. In A498 and 786-O cells, pharmacological inhibition of mTOR or IKK/NF-κB altered key readouts of the reciprocal pathway, including AKT, S6, 4E-BP1, IκBα and p65 phosphorylation. Both inhibitors reduced cell number and EdU incorporation, with stronger anti-proliferative effects observed after Torin-1 treatment. Pharmacological inhibition of either pathway altered key readouts of the other pathway, supporting a reciprocal functional association between mTOR- and NF-κB-associated signaling in the ccRCC models analyzed. Our findings support a functional association between mTOR- and NF-κB-associated signaling in the ccRCC models and provide a rationale for further mechanistic studies evaluating combined pathway modulation. Full article

Macrophages are highly plastic innate immune cells that integrate diverse microenvironmental cues to adopt pro-inflammatory (M1) or anti-inflammatory (M2) functional states, which critically influence the pathogenesis of infectious, autoimmune, inflammatory, and malignant diseases. This review provides an overview of current concepts of macrophage ontogeny, functional heterogeneity, and disease-associated phenotypes, with a specific focus on experimental approaches used as M1/M2 test systems for macrophage phenotyping. The scope of the review encompasses commonly used experimental models, induction protocols for M1- and M2-like polarization, and key readouts, including gene-expression signatures and metabolic parameters. Particular emphasis is placed on reporter-based platforms (luciferase, BRET, fluorescent nanoparticle probes), label-free biophysical methods such as electrical impedance monitoring and metabolic profiling, and their application to dynamic, real-time assessment of macrophage phenotype in the context of tumor microenvironments and chemotherapeutic exposure. The potential of integrating reporter systems with single-cell omics, spatial transcriptomics, and patient-derived ex vivo platforms is considered, with a view to transforming M1/M2 test systems into clinically oriented assays capable of tracking macrophage programs during therapy and supporting the development of macrophage-targeted diagnostics and treatments. Full article

Metal-graphitic nanocapsules are an emerging class of metal-graphitic hybrid nanomaterials, typically consisting of a metal core confined within a single- or few-layer graphitic shell. This unique core–shell architecture integrates the tunable physicochemical properties of metal nanomaterials with the chemical stability, Raman activity, fluorescence-quenching capability, and surface functionalization capacity of graphitic materials. In particular, the metal core can provide plasmonic enhancement as well as magnetic or catalytic auxiliary functions, while the chemically protective graphitic shell protects the core from harsh environments and provides intrinsic Raman bands that can serve as internal standards under well-controlled conditions. These features make metal-graphitic nanocapsules highly attractive as robust nanoprobes for molecular spectroscopy-based chemical analysis, biosensing, and targeted diagnosis. In this review, we first summarize the synthesis strategies, formation mechanisms, and key properties of representative metal-graphitic nanocapsules. We then discuss recent advances in their use across representative analytical and biomedical scenarios, with emphasis on the integration of spectroscopic readouts with targeted recognition strategies. Particular attention is given to how the metal core and graphitic shell cooperatively enhance signal generation, molecular enrichment, selective recognition, environmental stability, internal calibration, and reliable in situ diagnosis in real samples and living systems. Finally, we discuss current challenges and future perspectives for developing metal-graphitic nanocapsules as versatile platforms for molecular spectroscopy-based analysis and diagnosis. Full article

This study investigates the influence of mesh-structured floating-gate (FG) geometry on the electrical and DC synaptic characteristics of flash-memory-based neuromorphic transistors. Devices with mesh sizes of 3 µm × 3 µm, 1 µm × 1 µm, 500 nm × 500 nm, and 200 nm × 200 nm were comparatively evaluated while maintaining the same channel dimensions. As the mesh size decreased, the perimeter-to-area (P/A) ratio increased from 1.33 to 20.0 µm⁻¹, and the cycle-averaged memory window increased from 0.86 to 1.68 V under the same DC program/erase sequence. The 200 nm device also exhibited a read-current modulation range exceeding six orders of magnitude, compared with approximately three orders of magnitude for the 3 µm device. These trends are consistent with a greater contribution of mesh-edge regions to local electrostatic conditions and charge injection. At the same time, smaller mesh sizes produced more abrupt threshold-voltage and read-current changes during the initial program/erase steps, indicating a trade-off between response sensitivity and gradual state modulation. These results show that mesh-size scaling provides an effective geometrical design variable for tuning the memory window and readout characteristics of mesh-structured floating-gate synaptic transistors. Full article

Plant-derived natural products remain a major source of anticancer chemical diversity, yet much of the preclinical literature still describes their activity through compound-centered readouts such as IC₅₀ values, reactive oxygen species generation, mitochondrial depolarization, BCL-2-family remodeling, caspase activation, and PI3K/Akt or NF-κB inhibition. Although informative, these mechanisms do not fully explain why the same phytochemical induces apoptosis in some cancer cells, and cytostasis or adaptation in others, while normal cells frequently activate cytoprotective responses. Rather than replacing conventional compound-centered approaches, we integrate established concepts into a complementary vulnerability-state framework for interpreting plant-derived natural-product-induced selective apoptosis. In this framework, selective apoptosis occurs when phytochemical-induced stress intersects with pre-existing cancer-cell vulnerabilities, overwhelms adaptive buffering, and remains below the injury threshold of normal cells. We organize current evidence around redox imbalance, mitochondrial priming, membrane remodeling, ion-channel and cell-volume dysregulation, and survival-pathway addiction, emphasizing that pathway modulation becomes mechanistically meaningful when linked to differential cellular sensitivity. We further highlight membrane–ion biology as an underexplored contributor to phytochemical responses and discuss how chemical standardization, orthogonal cell-death assays, matched normal-cell models, organoids, and pharmacokinetic/pharmacodynamic considerations can advance the field from descriptive cytotoxicity toward mechanism-informed phytopharmacology. Full article