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Results for “New approach methodologies”

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At least 19 recordsLinked to original sources
PubMed2026

The maternal-to-zygotic transition is a critical window for PFOA-induced disruption of developmental programming.

Early embryogenesis is governed by precisely timed gene regulatory programs that coordinate cell fate specification, tissue patterning, and morphogenesis. The maternal-to-zygotic transition (MZT) represents a pivotal developmental milestone during which regulatory control shifts from maternally deposited transcripts to activation of the zygotic genome. Disruption of this transition has the potential to alter developmental trajectories with lasting consequences. Per- and polyfluoroalkyl substances (PFAS), environmentally persistent contaminants, have been linked to developmental abnormalities, yet their impact on core embryonic gene regulatory networks especially with exposure during MZT is not well understood. Using zebrafish (Danio rerio), a tractable vertebrate model and New Approach Methodology (NAM), we investigated how PFAS exposure during the MZT alters early developmental programming. Embryos were exposed starting at different times before and within the MZT time window and collected at 24 h post-fertilization (hpf) for transcriptomic analysis. Targeted qRT-PCR revealed dysregulation of genes controlling transcriptional activation, lineage specification, proliferation, and differentiation. Whole-transcriptome RNA sequencing (RNA-seq) further identified widespread perturbations in gene networks governing transcriptional regulation, cell signaling, and embryonic morphogenesis. Temporal analysis revealed that exposure beginning at 3.5 hpf, followed by 8 hpf, corresponding to early zygotic genome activation and near completion of zygotic activation, respectively, resulted in the greatest differential gene expression changes at 24 hpf. Consistent with these early gene regulatory perturbations, larvae exposed starting at 8 hpf also exhibited altered behavior at 5 days post-fertilization. Together, these findings demonstrate that PFAS exposure during MZT disrupts the establishment of embryonic gene regulatory networks, linking environmental toxicant exposure to altered developmental patterning and organismal outcomes. This work underscores the vulnerability of early developmental transitions to environmental perturbation and positions MZT as a critical window of susceptibility during development.

NAMs (new approach methodologies)↗
PubMed1975

Histochemical localization of capillary enzyme activities in brain smears.

Since the regulation of the vascular permeability in the CNS is dependent partly on the enzymes associated with the wall of brain capillaries, the histochemical demonstration of these enzymes may furnish further data on the function of the blood brain barrier (BBB), a new methodological approach, using brain smears was developed for the histochemical demonstration of several enzymes participating in the function of the BBB. The method presented renders possible also the subsequent demonstration of monoamines and the activity of different enzymes in the same tissue preparation. The usefulness of this simple technique in the study of brain capillary functions is discussed.

Acetylcholinesterase↗
PubMed1976

Pneumatonographic studies on normal and glaucomatus eyes.

A new methodological approach, embodied in the pneumatonograph, has been used to study the intraocular pressure, intraocular pulse and aqueous humor dynamics of normal and glaucomatous eyes. Comparative measurements of intraocular pressure in seated subjects by the Goldmann instrument and the pneumatonograph indicate close agreement over a wide range of pressures. On changing from the sitting to the supine position, it has been found by pneumatonometry that there is a significant increase of intraocular pressure in all eyes. In glaucomatous eyes, this postural response ranged up to as high as 12 mm Hg. Comparison of Schiotz and pneumatonometric pressure measurements on supine patients showed that the Schoitz values are significantly lower. This discrepancy of the values is in keeping with recent studies indicative that the Schiotz calibration is in error by 3-6 mm Hg. The coefficient of outflow facility was measured by a procedure of applanation tonography employing pressure-volume relations for the living human eye. The range of values found for normal eyes was significantly different from those of glaucoma eyes. It is concluded that pneumatonography is a useful method for improving the effectiveness of glaucoma diagnosis and clinical management.

Adult↗
PubMed1979

Depression and monoamine oxidase.

1. The first part of the paper is devoted to a critical review on the possible relationships between depression and monoamine oxidase. 2. This study describes the results of an investigation of MAO-activity in depression, using new approaches and methodology. This methodology was developed because the literature data indicated that a) previous results are difficult to compare because of varying methods and diverse target populations used; b) previous methodological deficiencies do not allow to draw definite conclusions about the relationship between MAO-activity and depression. 3. The present investigation selected 35 psychiatric patients according to clearly defined diagnostic criteria (20 endogenous depressive, 10 neurotic depressive, and 5 manic patients) matched to 25 healthy control-subjects. 4. The Michaelis-constant (Km), the maximum reaction speed (Vmax), and the 50% enzyme inhibition by tranylcypromine (IC50) of platelet-MAO were determined during and after recovery from the depressive or manic episode using 3 substrates (tyramine, tryptamine, and phenylethylamine). 5. The present investigation, in contrast to conventional methodology, utilized three different substrates at different concentrations. Significant correlations were demonstrated for the Vmax-values of each of the three substrates, whereas the Km and the IC50 (tranylcypromine)-values varied for each substrate. 6. The results show that there were no differences between the characteristics of the platelet-MAO in depressive or manic patients and those of normal subjects. Furthermore, treatment with tricyclic antidepressants had no effect on MAO-activity. A previous investigation indicated that the MAO-properties in human brain tissue were similar to that in human platelets.

Adult↗
PubMed2026

Functional perturbation reveals context-dependent contributions of nuclear receptors to drug-induced hepatic steatosis.

Drug-induced hepatic steatosis is mediated by diverse molecular mechanisms, yet several nuclear receptors have been proposed as molecular initiating events or early key events within adverse outcome pathways for hepatic steatosis. However, direct functional evidence supporting these mechanistic roles in human-relevant experimental systems remains limited. The present study evaluated the contribution of selected nuclear receptors to drug-induced hepatic steatosis using complementary human hepatic in vitro models. Stable short hairpin RNA-mediated knockdown of individual nuclear receptors was established in HepG2 and differentiated HepaRG cells, followed by exposure to representative steatogenic drugs, including valproic acid, amiodarone, tamoxifen, and rifampicin. In parallel, primary human hepatocyte spheroids were used to compare drug-induced lipid accumulation with direct pharmacological activation of individual nuclear receptor pathways. While depletion of multiple nuclear receptors markedly affected oleic acid-induced lipid accumulation, drug-induced steatogenic responses exhibited predominantly selective and compound-specific receptor dependencies. In differentiated HepaRG cells, nuclear receptor depletion influenced basal lipid homeostasis more strongly than valproic acid-induced lipid accumulation. Conversely, direct activation of liver X receptor and peroxisome proliferator-activated receptors α and γ in primary human hepatocyte spheroids induced robust lipid accumulation, whereas most steatogenic drugs produced comparatively modest responses. These findings demonstrate that the contribution of individual nuclear receptors to drug-induced hepatic steatosis is highly compound- and context-dependent and cannot be explained by a single conserved receptor pathway. This study provides functional evidence from complementary human-relevant hepatic models that supports refinement of hepatic steatosis adverse outcome pathways and highlights the value of targeted perturbation strategies for mechanistic toxicology.

Adverse outcome pathway, HepaRG↗
PubMed1978

A radioimmuno-chromatographic scanning method for the analysis of testosterone conjugates in urine and serum.

A method for the analysis of testosterone (and 5alpha-dihydrotestosterone) conjugates in human serum and urine samples is described. The samples were grought to pH 1 and extracted with a diethyl ether-methanol mixture. After evaporation the residues were run in a thin-layer chromatography system, individual samples' paths were cut into 1-cm long pieces and eluted with methanol. The methanol was evaporated and the residue subjected to acid hydrolysis. The released steroid was extracted by diethyl ether and measured by radioimmunoassay. The methodology described represents a new approach to the qualitative and quantitative study of steroid conjugates in serum and urine, and can easily be applied to the study of steroid conjugates in other biological mateiral.

Chromatography, Thin Layer↗
PubMed1976

Methodologic problems of common terminology, measurement, and classification. 11. Modifications and new approaches to taxonomy in long-term care: advantages and limitations of the ICD.

The primary advantage of an internationally accepted classification of diseases is that data from different countries and parts of the world can be compared and even pooled. Two basic conditions have to be fulfilled if the classification is to be used by a heterogeneous group of users and the data are to be compared: there must exist significant agreement on the content of categories, and the categories must be used in the agreed sense. A brief description is given of a WHO project that has attempted to satisfy these two conditions in the field of mental disorders. Additionally, taxonomy in long-term care requires that a classification should 1) be multiaxial and include certain nondisease as well as disease factors that affect treatment and outcome; 2) be a classification of individuals rather than of diseases and reflect the presence of multiple conditions and degrees of severity; 3) allow linkage of episodes of illness and care in the same individual; 4) be suitable for use by nonmedical personnel, who often play a decisive role in long-term care; and 5) be accompanied by glossaries giving operational terms suitable for reliability and validity tests.

Classification↗
PubMed2024

Development of methodology to support molecular endotype discovery from synovial fluid of individuals with knee osteoarthritis: The STEpUP OA consortium.

OBJECTIVES: To develop a protocol for largescale analysis of synovial fluid proteins, for the identification of biological networks associated with subtypes of osteoarthritis. METHODS: Synovial Fluid To detect molecular Endotypes by Unbiased Proteomics in Osteoarthritis (STEpUP OA) is an international consortium utilising clinical data (capturing pain, radiographic severity and demographic features) and knee synovial fluid from 17 participating cohorts. 1746 samples from 1650 individuals comprising OA, joint injury, healthy and inflammatory arthritis controls, divided into discovery (n = 1045) and replication (n = 701) datasets, were analysed by SomaScan Discovery Plex V4.1 (>7000 SOMAmers/proteins). An optimised approach to standardisation was developed. Technical confounders and batch-effects were identified and adjusted for. Poorly performing SOMAmers and samples were excluded. Variance in the data was determined by principal component (PC) analysis. RESULTS: A synovial fluid standardised protocol was optimised that had good reliability (<20% co-efficient of variation for >80% of SOMAmers in pooled samples) and overall good correlation with immunoassay. 1720 samples and >6290 SOMAmers met inclusion criteria. 48% of data variance (PC1) was strongly correlated with individual SOMAmer signal intensities, particularly with low abundance proteins (median correlation coefficient 0.70), and was enriched for nuclear and non-secreted proteins. We concluded that this component was predominantly intracellular proteins, and could be adjusted for using an 'intracellular protein score' (IPS). PC2 (7% variance) was attributable to processing batch and was batch-corrected by ComBat. Lesser effects were attributed to other technical confounders. Data visualisation revealed clustering of injury and OA cases in overlapping but distinguishable areas of high-dimensional proteomic space. CONCLUSIONS: We have developed a robust method for analysing synovial fluid protein, creating a molecular and clinical dataset of unprecedented scale to explore potential patient subtypes and the molecular pathogenesis of OA. Such methodology underpins the development of new approaches to tackle this disease which remains a huge societal challenge.

Humans↗
PubMed1978

[Comparison of macular electroretinography and psychophysical tests in diabetic retinopathy with intraretinal edema].

Short comparison between psychophysic and electrodiagnostic tests in 20 eyes with macular edema from diabetic retinopathy. De Lange's curve, the critical flicker frequency in central fixation and the macular ERG are compared with the classical EOG and global ERG data. The methodology is briefly described. It allows a new approach of the macula and the macular ERG responses confirms the clinical tests.

Adult↗
PubMed1979

Medical care evaluation studies in long-term care facilities.

This report describes the selection, design, conduct, analysis, and application of medical care evaluation studies in long-term care facilities (skilled nursing homes) in a regional program in the Rochester region of upstate New York. Eight examples are presented to highlight methodologic approaches and problems. They are classified under four general headings: Administration Audits, Diagnosis-specific Studies, Care Modality-specific Studies, and General Outcome Indicators. The implementation of results and recommendations from the studies is discussed and an application of "tracer" methodology for assessing the components of care activities in long-term facilities is described. Problems and challenges in long-term quality care are outlined.

Catheters, Indwelling↗
PubMed1978

Use of the extended family in the treatment of multiple personality.

The author describes a patient with the diagnosis of multiple personality who was treated by several therapists with different theoretical perspectives, including psychoanalysis and family systems theory. The latter approaches to the patient's illness are compared, a new methodology of treatment is reported, and the impact of different ways of thinking about the patient is discussed.

Adolescent↗
PubMed1978

Power relationships in families: a social-exchange perspective.

Although researchers have investigated power relationships in families for twenty-five years, conclusions about normative family power patterns have been inconsistent and contradictory. Comparisons across studies have been difficult owing to different definitions of the construct, multiple methodologies, and inconsistent goals. With such confusion, a new, more integrated theoretical approach to the power issue seems warranted, as is suggested by the present paper. The current individual focus on power as a personal attribute can be replaced by a more dynamic, reciprocal, interactive process. Instead of specific or stable power patterns, power interactions should be fluid and time- or situation- specific. No one member would dominate, since power involves a mutual relationship system that changes its content, though not its rules of operation, across decision-making areas. Furthermore, family adjustment would relate to those rules and the family members' reactions to their particular exchange system but not to specific types of power structures. With these considerations, future research should analyze the process, not the content, of power operations in order to maximize the clinical and theoretical utility of its construct.

Adolescent↗
PubMed2025

Omics in Nonsteroidal Anti-Inflammatory Drugs-Exacerbated Respiratory Disease: Current Evidence From the Upper and Lower Airways.

Nonsteroidal anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (N-ERD) is a mainly type 2 inflammatory condition that combines asthma, nasal polyps, and hypersensitivity to NSAIDs. Its pathogenesis involves both upper and lower airways, yet most studies to date have examined these compartments separately. It remains unclear whether the molecular mechanisms in the nose, sinuses, and lungs are distinct or overlapping-an important gap, given that clinical manifestations of N-ERD involve both sites. In this review, we summarize available omics studies-transcriptomics, proteomics, metabolomics, and epigenomics-performed on upper and lower airways in patients with N-ERD. While omics approaches have revealed new molecular insights, comparisons across studies are limited by heterogeneity in design, controls, and methodology. We emphasize the need for integrated multi-omics analyses and standardized frameworks to better characterize the disease across airways. Such efforts are essential for identifying robust biomarkers and therapeutic targets and for moving toward a systems-level understanding of N-ERD.

Humans↗
PubMed1978

Progress in community pediatric research.

This review examines three major facets of progress in community pediatric research. The number of publications with this orientation has increased substantially over a 10-year period, and abstracts submitted to the Ambulatory Pediatric Association meetings have doubled. New methodologies are identified and their application to ambulatory pediatric care is described. In particular, procedures and approaches are examined in the context of recognized criteria for sociomedical research.

Child↗
PubMed1976

On the structure-activity relationship of antiviral substances.

The significance of the study on structure-activity relationship in the antiviral substances is considered for: 1. directed synthesis of highly active and selective antivirals; 2. elucidation of the mechanism of action of antiviral substances by revealing the chemical structures which determine the inhibition of a given step in the virus growth cycle. The basic trends in conducting directed synthesis of antiviral substances are pointed out: synthesis of new inhibitors with a broad antiviral spectrum, as well as improvement by structural modifications of known ones. The basic methodological approaches in the structure-activity studies are considered. A classification of the available antiviral synthetic substances is presented.

Anti-Bacterial Agents↗
PubMed2025

Multi-Omics and Integrative Analytics in Natural Products Discovery.

Natural products (NPs) have long been an essential source of new bioactive compounds for drug discovery; however, traditional methods for screening and isolating these compounds can be slow and often yield diminishing returns. Fortunately, advanced multi-omics and computational approaches present powerful solutions to these challenges. This review highlights innovative methodologies that integrate metabolomics, genomics, transcriptomics, and proteomics with bioinformatics and analytical chemistry to accelerate NP discovery. For instance, untargeted metabolomics platforms like high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) and Global Natural Products Social (GNPS) molecular networking allow for comprehensive profiling of new compounds, while targeted isotope-labeling strategies enhance this process. Additionally, genome and metagenome mining tools such as antibiotics and secondary metabolite analysis shell (antiSMASH), Deep Biosynthetic Gene Cluster (DeepBGC), and Pipeline for Reconstructing Integrated Syntheses of Metabolites (PRISM) quickly identify biosynthetic gene clusters (BGCs) in both cultured and uncultured organisms, often using heterologous expression to validate products. Transcriptomic analyses, including RNA sequencing (RNA-seq), co-expression networks, and fluxomics, help clarify how pathways are regulated, while quantitative proteomics techniques like tandem mass tags/isobaric tags for relative and absolute quantitation (TMT/iTRAQ) and label-free methods, along with chemoproteomics approaches such as cellular thermal shift assay and thermal proteome profiling (TPP), uncover molecular targets and their mechanisms of action. This review also places significant emphasis on the role of artificial intelligence (AI) and machine learning (ML) in integrating multi-omics data, spanning activities from constructing gene-metabolite correlation networks to leveraging knowledge graphs and graph neural networks for data fusion and functional prediction. Finally, this review concludes by discussing the synergistic benefits of multi-omics for natural-product discovery, addressing current technical challenges, and exploring future directions toward high-throughput, intelligent data integration for next-generation NP research.

Biological Products↗