Search Results (2,612)

Saccharomyces cerevisiae is a useful model to understand the biochemistry and biology of aging. Yeast speeds up the aging study due to its short lifespan, well-established genetics, and simple measurement for lifespan. The chronological lifespan in yeast specifically emphasizes the survival rate of the population, providing data that offer more direct feedback on experimental treatments than replicative lifespan. The advancement of the yeast chronological lifespan assay has enabled researchers to efficiently screen numerous potential antiaging compounds and delve into aging theories. Through the integration of robust genetic screening and high-throughput technologies, the yeast model has facilitated the identification of various antiaging factors with potential applications in humans, shedding light on the genetic mechanisms of aging. Many natural products, similar to calorie restriction, have been shown to effectively extend the lifespan of yeast, a benefit that is also conserved in mammals. In this review, we highlight the nutrient factors, natural compounds, and genes that contribute to extending the yeast lifespan, as well as the genetic regulations underlying the aging process in yeast. Full article

Background/Objectives: Mitochondrial Oxidative Phosphorylation (OXPHOS) is a critical metabolic dependency in many cancers. Targeting OXPHOS through Leucine-Rich PPR Motif-Containing Protein (LRPPRC) degrader-mediated OXPHOS Complex Biogenesis Inhibition (OCBI) has demonstrated promising anti-tumor activity. However, rational combination strategies to enhance therapeutic efficacy remain undefined. This study aims to identify FDA-approved drugs that synergize with LRPPRC inhibition and elucidate the underlying mechanism. Methods: We conducted a high-throughput screen of 1376 FDA-approved compounds using LRPPRC isogenic cancer cell models to identify agents that synergize with LRPPRC degrader-based OCBI therapy. The synergistic effects of the candidate compound were validated in multiple cancer cell lines with either genetic ablation or pharmacological inhibition of LRPPRC. Mechanistic studies were performed to investigate the impact on OXPHOS gene expression from both nuclear and mitochondrial genomes. Results: The clinically approved multi-kinase inhibitor Dasatinib was identified as a robust synergistic candidate, exhibiting heightened sensitivity in cancer cells with either LRPPRC knockout or pharmacological inhibition. Mechanistically, Dasatinib selectively suppressed nuclear-encoded OXPHOS genes, whereas LRPPRC inhibition preferentially impaired mitochondrial DNA-encoded OXPHOS genes, resulting in a coordinated dual-genome blockade of OXPHOS. Conclusions: This study uncovers a previously unrecognized synergistic anti-tumor effect between LRPPRC inhibition and Dasatinib, mediated by complementary suppression of nuclear- and mitochondrial genome-encoded OXPHOS pathways. These findings provide a strong mechanistic and translational rationale for combination therapies targeting LRPPRC-high tumors. Full article

The type II cadherin Cadherin-19 (CDH19) plays a crucial role in neural crest development. CDH19 regulates cell–cell junctions and migration by forming catenin–cytoskeleton complexes. Although anti-CDH19 monoclonal antibodies (mAbs) are used for specific applications such as Western blotting and immunohistochemistry (IHC), suitable anti-CDH19 mAbs for flow cytometry are limited. Therefore, developing mAbs that specifically recognize cell-surface-expressed CDH19 is essential for advancing both basic research and therapeutic strategies. Here, novel anti-human CDH19 mAbs (Ca₁₉Mabs) were created using flow cytometry-based high-throughput screening. One clone, Ca₁₉Mab-8 (IgG₁, κ), specifically recognized CDH19-overexpressed Chinese hamster ovary-K1 cells but did not bind to other 21 CDHs (including both type I and type II CDHs) in flow cytometry. Additionally, Ca₁₉Mab-8 recognized endogenous CDH19 in the human glioblastoma cell line LN229. The dissociation constant (K_D) of Ca₁₉Mab-8 for LN229/CDH19 was 9.0 × 10⁻⁹ M. Ca₁₉Mab-8 also detected endogenous CDH19 in Western blotting. Furthermore, Ca₁₉Mab-8 can detect CDH19 in IHC using human melanoma tissue. These findings suggest that Ca₁₉Mab-8 is a novel mAb that detects cell-surface-expressed CDH19 with high specificity and is suitable for various applications in basic research. Therefore, Ca₁₉Mab-8 has potential for clinical diagnosis and tumor therapy. Full article

Core–shell metal–organic framework (MOF) composites, owing to their unique structural advantages, have emerged as a prominent research focus in the field of chemistry, advanced materials and chemical engineering. By integrating MOFs with other functional components such as MOFs, covalent organic frameworks (COFs), metal oxides, carbon materials, ionic liquids or polymers into synergistic heterogeneous architectures, coreshell MOFs can markedly enhance physicochemical stability and enable diversified functional performances. This work provides a systematic overview of the major construction strategies for these materials, including in situ growth, self-templating, seed-mediated methods, one-pot synthesis and post-synthetic modification. It also summarizes recent applications in catalysis (thermal, electrocatalytic and photocatalytic processes) as well as gas adsorption and separation (such as CO₂ capture from flue gas, natural gas purification and acetylene separation). The final section discusses future research directions, including a deeper understanding of interfacial growth mechanisms, the development of green and scalable synthesis routes, the validation of engineering-oriented applications, and the integration of machine learning with high-throughput computation for structural prediction and accelerated materials screening, thereby providing important guidance for the development of high-performance core–shell MOFs. Full article

The SARS-CoV-2 public health challenges have highlighted the urgent need for coronavirus-targeting life-saving therapeutics. Given the emergence of drug-resistant strains, the development of antivirals against viral proteins beyond the commonly targeted main protease or RNA-dependent RNA polymerase is critical. The SARS-CoV-2 nonstructural protein 13 (nsp13) is a highly conserved RNA helicase and an essential component of the viral replication–transcription complex (RTC). It unwinds double-stranded RNA to facilitate viral transcription and replication, making it a strong target for drug development. To identify nsp13 inhibitors, we used an ultra-high-throughput nucleic acid unwinding assay to screen a library of FDA-approved drugs and bioactive compounds. We identified forty inhibitors with IC₅₀ values ranging from 1.4 to 10 μM. Ten were further selected for biochemical and biophysical characterization. Four of these are bound to nsp13 without interacting with the nucleic acid substrate and without inhibiting the ATPase activity of nsp13. Hydrogen–deuterium exchange coupled with Mass Spectrometry (HDX-MS) studies show compound binding causes differential exchange in two regions of nsp13. Furthermore, these compounds have antiviral activity against infectious SARS-CoV-2 in multiple cell lines, with cytotoxicity affecting, in some cases, the apparent antiviral effect. Future optimization efforts could help develop therapeutics against SARS-CoV-2 and other potential coronavirus threats. Full article

Background and Clinical Significance: Deep thalamic and periventricular lesions are uncommon in adults but can result in significant loss of function because of their convergence on three interdependent processes: thalamocortical state regulation, throughput of periventricular long association systems, and ventricular compartmental compliance. The resulting combination of executive control collapse, retrieval-weighted language fragility, and load-sensitive gait instability may occur early after a lesion forms an atrial/posterior horn interface, and pressure-linked autonomic symptoms may be late to develop. Screening deficits will likely be minimal and therefore underreported. Objective/Aim: To present a thalamic–atrial/posterior horn tumor case with quantified load-sensitive cognitive–language–gait dysfunction and to detail a physiology-guided, sequence-driven decompression approach emphasizing ventricular relaxation and perforator-preserving, interface-limited thalamic resection. Case Presentation: A 56-year-old female patient experienced a 3-month, rapidly progressive decline in her cognitive and language abilities. The clinical progression was not stepwise or punctuated by a single “sentinel” event. She had a moderate level of cognitive impairment consistent with both Broca’s and Wernicke’s aphasias (MoCA: 22/30) and suffered from significant interference effects and increased cost of task-switching. Her ability to generate novel responses and name objects was significantly impaired; however, she was able to repeat words and phrases appropriately. In addition, she exhibited a severe sustained attention signature and a high error rate during dual-task performance, indicating severe gait instability, although her overall global anchors were nearly neutral (GCS 15; FOUR 15/16; NIHSS 2). Nausea and vomiting occurred simultaneously with the cognitive and language decline, suggesting decreased intracranial compliance. MRI revealed a heterogeneous left-sided thalamic tumor extending into the posterior horn of the lateral ventricle. The tumor caused deformation of the lateral ventricle and midline displacement. The patient underwent microsurgical intervention using a physiology-conscious sequence of graded cerebrospinal fluid (CSF) equilibration and primary mechanical removal of the tumor from the ventricular system. Additionally, decompression of the thalamus was performed in a manner that was cognizant of the boundaries formed by the perforating arteries of the thalamus. Early resolution of pressure symptoms was noted postoperatively. Objective measures demonstrated significant improvement in the patient’s executive functioning, language skills, attentional errors, and dual-task performance stability. The patient remained functionally independent at discharge and at subsequent follow-up visits. Surveillance imaging did not demonstrate any evidence of tumor recurrence. Conclusions: The clinical presentation described above is supportive of a model in which the synergy between deep network damage and distortion of the posterior ventricular compartment amplifies network dysfunction. Additionally, the use of quantitative stress-phenotyping makes it possible to identify deep network pathology early in its course. Finally, the physiology-guided decompression approach that was used in this case has the potential to increase functional reserve in patients with pathology that requires millimeter transitions. Full article

Rapeseed (Brassica napus L.) faces escalating threats from abiotic and biotic stresses, notably blackleg caused by Leptosphaeria maculans. Due to limited chemical control efficacy and stringent GMO regulations, marker-assisted selection (MAS) leveraging natural genetic variation has become an indispensable strategy for crop improvement. This study identified novel molecular markers for blackleg resistance by integrating genome-wide association study (GWAS) results with high-throughput genotyping by Diversity Arrays Technology sequencing. Phenotypic screening across the population demonstrated a wide spectrum of disease severity (scores 0–6), confirming the segregation of key resistance genes. The DArTseq platform identified nearly 104,000 markers, comprising 61% SilicoDArTs and 39% SNPs. Among the 33 most significant markers associated with resistance (p < 0.01), 76% were SilicoDArTs. Transcriptomic data further validated these findings, revealing 13 marker-linked genes expressed during infection, seven of which exhibited significant differential expression. Comprehensive functional annotation of Arabidopsis thaliana orthologs associated these genes with diverse cellular and plant-wide processes, particularly during stress responses. Collectively, these findings emphasize the complex polygenic nature of blackleg resistance and provide robust genomic tools for the accelerated breeding of resilient B. napus cultivars. Full article

Background/Objectives: Magnetite nanoparticles represent promising candidates for a broad spectrum of biomedical applications, ranging from in vitro diagnostic assays to in vivo imaging, hyperthermia, and targeted drug and gene delivery, with some nanoagents already approved for clinical use. A critical determinant of their functionality is the nanoparticle coating, which facilitates beneficial interactions within biological systems. In the context of tumor-targeted therapeutic delivery, key design parameters—particularly surface coatings—can be optimized to enhance treatment efficacy by modulating blood circulation kinetics, biodistribution, and other critical properties. However, current preclinical screening methods primarily rely on cell culture models to identify potential nanocarriers, yet these systems often poorly correlate with actual in vivo performance. This discrepancy highlights the necessity of incorporating more biologically relevant testing platforms, such as high-throughput in vivo assays. Methods: In this work, we employed an original magnetic particle quantification (MPQ) technology to systematically evaluate the blood circulation kinetics and biodistribution patterns for magnetite nanoparticles with 17 different coatings across multiple organs and tissues, including the liver, spleen, lungs, kidneys, heart, tumor, brain, peripheral blood, muscle, and bone. This methodology offers high sensitivity, user-friendly operation, and provides quantitative measurements across a broad dynamic range of nanoparticle concentrations. These advantages enabled high-throughput acquisition of precise blood circulation and biodistribution data. In addition, histological analysis was conducted to evaluate nanoparticle penetration depth within tumor tissue. Results: Here we conducted a comprehensive study of the effect of 17 different polymer-, lectin-, and small molecule-based coatings on the behavior of magnetite nanoparticles in vivo. For each type of obtained nanoparticles, we implemented passive targeting as well as magnetic targeting, the latter using an external magnetic field localized in the tumor area. Conclusions: The collected dataset provides critical insights into how surface modifications influence nanoparticle performance in complex biological systems, offering valuable guidance for optimizing therapeutic nanocarrier design. Full article

As precision polishing and post-processing advance, surface-layer absorptive defects in fused silica optics increasingly show random distribution, low quantity, and ultra-low concentration—making efficient, non-destructive inspection of large-aperture components challenging. In this study, fused silica samples made by conventional ring polishing and acid cleaning were analyzed using photothermal weak absorption (PTWA), micro-X-ray fluorescence (μ-XRF), micro-X-ray diffraction (μ-XRD), and ultraviolet fluorescence microscopy spectroscopy. Results show that process-related contaminants emit strong spontaneous fluorescence between 500 and 620 nm under 375 nm ultraviolet (UV) excitation. Using this optical signature, a high-throughput detection system was developed that combines rapid fluorescence imaging for screening with PTWA for verification. Full-area scanning of a 100 mm × 100 mm sample successfully identified absorptive defects with significantly improved efficiency over conventional methods. This work provides a practical quality control solution for large-aperture fused silica optics and supports process optimization to reduce laser damage risks in high-performance systems. Full article

The escalation of antibiotic resistance constitutes a significant global health crisis, urgently demanding innovative strategies to restore and amplify the effectiveness of our existing antimicrobial arsenal. This review systematically explores the diverse landscape of antibiotic adjuvants, beginning with an elucidation of their classifications and profound mechanisms of action. We meticulously detail various categories of these agents, encompassing both synthetic compounds and naturally derived molecules, highlighting their crucial functions in potentiating antibiotic activity through mechanisms such as enhancing bacterial cell permeability, modulating the expression of resistance-conferring genes and optimizing drug–target interactions. Furthermore, we critically assess current screening methodologies, particularly the advancements in high-throughput approaches, and their implications for the identification and validation of novel adjuvant candidates. The review underscores the potential of antibiotic adjuvants as a promising frontier in our global endeavor to overcome bacterial resistance and ensure the sustained utility of antimicrobial medicine. Full article

While traditional 2D in vitro models have been widely used for drug screening, 3D tissue culture systems are gaining traction due to their superior ability to replicate in vivo tumor microenvironments. In this study, we utilize Microtissues™, a validated, scaffold-free, high-throughput 3D tissue culture platform, as the basis for a microscale tissue-engineered model to study drug absorption and transport dynamics. Despite their physiological relevance, such 3D constructs pose analytical challenges, particularly in quantifying trace drug levels within the microenvironment. We developed and validated an integrated experimental workflow combining optimized liquid–liquid extraction and protein precipitation with LC-MS/MS analysis to accurately quantify paclitaxel absorption in Microtissues™ molds using small sample volumes. The assay achieved a validated lower limit of quantification of 0.03 μM, with robust linearity across analytical runs (R² ≥ 0.90; best-run performance > 0.99) and precision (CV ≤ 10%) across both MRMs. This microengineered in vitro system allows for precise characterization of drug–tissue interactions in MCF7 breast cancer Microtissues™, enabling in vitro-to-in vivo extrapolation (IVIVE) relevant to therapeutic optimization. The platform’s scalability and modularity support its application in precision medicine, where patient-derived microtissues can guide individualized treatment decisions. Full article

Atractylodes macrocephala Rhizoma (AMR) is a frequently used medicinal herb for treating gastrointestinal disorders, with its quality influenced by factors such as origin and cultivation duration. Traditional quality control methods for AMR are time-consuming and invasive, making the development of faster and more efficient alternatives urgently needed. This study aims to utilize electronic nose (E-nose) and electronic tongue (E-tongue) to achieve the acquisition of odor–taste two-dimensional information of AMR. Integrating this approach with machine learning (ML) enables intelligent transformation from “experience-driven” to “data-driven” quality assessment, thereby developing a rapid and cost-effective quality control strategy for AMR. Feature-extraction and feature-selection techniques were employed to optimize back-propagation neural network (BPNN) classification and regression models for eight key quality markers, selecting the optimal feature subset. Additionally, nine machine-learning algorithms were applied with the optimal feature subset to establish classification models for different AMR grades and quantitative regression models for eight components based on E-nose and E-tongue data. The results demonstrated that the E-tongue combined with the k-nearest neighbors (KNN) algorithm could achieve a rapid classification of AMR grades with an accuracy of 95.56%. It also successfully predicted the contents of the extract, volatile oil, polysaccharides, atractylenolide I, atractylenolide II, atractylenolide III, bis-atractylenolide, and atractylone, with the test set’s coefficient of determination (R²) values of 0.8874, 0.8313, 0.9628, 0.8406, 0.8736, 0.8532, 0.7758, and 0.8101, respectively. In conclusion, this study provides a comprehensive and rapid solution for AMR grade classification and quality evaluation, significantly improving efficiency compared with traditional methods. This strategy holds substantial promise for real-world applications, as it enables a high-throughput, non-destructive screening of AMR in settings such as post-harvest processing and market quality surveillance, thereby supporting the sustainable and intelligent development of the herbal medicine industry. Full article

CD38 is a multifunctional enzyme that plays a pivotal role in NAD⁺ metabolism and calcium signaling, and its abnormal activity is closely associated with multiple myeloma, age-related metabolic decline, neurodegenerative diseases, and other disorders. Although monoclonal antibodies such as daratumumab have been approved for clinical application, their inherent limitations necessitate the development of novel small-molecule CD38 inhibitors. In this study, we employed DNA-encoded library (DEL) technology for the high-throughput screening of CD38 inhibitors, using a DEL library containing more than 100,000 unique compounds to screen against recombinant human CD38. A total of 1043 enriched compounds were initially identified, and after rigorous validation and screening to exclude non-specific binding and previously reported active compounds, eight hit compounds with diverse chemical scaffolds were obtained, among which Fenbendazole—a clinically approved antiparasitic drug—was included. Surface plasmon resonance (SPR) assays confirmed the direct binding of these hit compounds to CD38, with dissociation constants (KD) ranging from 7.74 × 10⁻⁵ M to 2.15 × 10⁻⁴ M. Fluorescence-based enzymatic activity assays demonstrated that these compounds exert dose-dependent inhibitory effects on both the hydrolase (with ε-NAD as substrate) and cyclase (with NGD as substrate) activities of CD38. Further structure–activity relationship (SAR) analysis of Fenbendazole analogues revealed the critical structural features that regulate CD38 inhibitory potency, and Flubendazole was found to exhibit excellent inhibitory activity, with an IC₅₀ of 14.78 ± 4.21 μM against CD38 hydrolase and 26.31 ± 3.40 μM against cyclase. Molecular docking and 100 ns molecular dynamics (MD) simulations further elucidated the molecular mechanism of CD38 inhibition by lead compounds, confirming that van der Waals interactions are the main driving force for the binding of small-molecule ligands to CD38, with conserved aromatic residues in the active site mediating ligand recognition. This study validates DEL technology as an efficient and reliable platform for the discovery of CD38 inhibitors, and the identified lead compounds—especially Fenbendazole and its analog Flubendazole—provide valuable molecular scaffolds for the further structural optimization of CD38 inhibitors. These findings lay a solid foundation for the development of novel therapeutic agents for the treatment of CD38-associated diseases. Full article

The manuscript describes an optical sensing microplate for the high-throughput screening of imidazolinone herbicides in soil extracts. As far as we know, imprinted proteins (IPs) specific to imidazolinone herbicides have not been synthesized and used as a recognition element for their solid-phase extraction before. Imprinted bovine serum albumin (BSA) and glucose oxidase (GOx) were synthesized in the presence of imazamox as a template and then these IPs were immobilized at the bottom of microplate wells. The sorption capacity (Q) of aminated silica nanoparticles modified by IPs (IP–BIS) was 6.38 mg g⁻¹ while the imprinting factor ($IF$) equaled 2.6. The concentration of imazamox was determined by a “turn-off” solid-phase assay using alloyed CdZnSeS/ZnS quantum dots (QDs) as a component of fluorescent substrate. Alloyed CdZnSeS/ZnS QDs were stabilized in an aqueous phase by positively charged cysteamine that, as far we know, had not been used as this type of ligand before. Our method allows for determining the concentration of imazamox in the range of 0.5–9.2 μg mL⁻¹, with a limit of quantification limit of quantitation (LOQ) equal to 0.45 μg mL⁻¹ The sensing microplate enables parallel detection of up to 96 samples containing herbicides using standard fluorescence microplate readers or smartphones. The paper describes how such sensing microplates can be used for the analysis of artificially contaminated soil samples. The proposed approach combines pre-concentration of analyte at the IPs with its subsequent determination on a single analytical platform, thus allowing for both highly sensitive determination in laboratory conditions and mass screening in the field. Full article

In 2023, the Russian Federation expanded its national newborn screening (NBS) program from 5 to 36 conditions, 29 of which are inherited metabolic diseases (IMDs). This study presents the first nationwide results and outcomes of the expanded NBS program. Between January 2023 and December 2024, dried blood spots from 2,466,615 newborns (98.53% of the birth cohort) were analyzed for IMDs using MS/MS. Screen-positive cases were referred to the national reference center for confirmatory testing, which included biochemical (MS/MS and GC-MS) and genetic analyses (NGS). A total of 41,728 neonates (1.69%) screened positive, of whom 37,733 underwent confirmatory testing. It resulted in 834 confirmed diagnoses of IMDs (1 in 2900 live births). Phenylketonuria was the most prevalent IMD (n = 538; 1 in 4600), followed by MCADD (n = 99; 1 in 25,000). Distinct regional and ethnic variations were observed, including a high prevalence of tyrosinemia type 1 in the Chechen Republic and MCADD in North Ossetia. The integration of NGS was essential for resolving complex cases, such as identifying heterozygous carriers and dual diagnoses. These findings underscore the program’s clinical utility, highlight unique epidemiological patterns, and identify challenges such as false positives and diagnostic complexities, which will guide future refinements. Full article