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Transport of elements from soil to human diet: an alternative approach to pathway analysis.

Transport from soil to human dietary intake is conventionally treated by analyzing the various pathways through uptake by plant roots and transfer from animal feed into milk and meat. An alternative approach is proposed requiring only the average daily human ingestion of each element and its abundance in soil, both readily available for most elements. The two methods are compared quantitatively and give results consistent within a mean factor of four, which is roughly the standard deviation in estimates from the pathway analysis. Neither method gives consistently larger or smaller transfer rates. Each method has important advantages in some applications.

Animal Feed

Subphenogroups of acute heart failure with preserved ejection fraction: comprehensive proteomics and pathway analysis.

BACKGROUND: Heterogeneity of heart failure with preserved ejection fraction (HFpEF) results in significant challenges for treatment development. Identifying and characterising distinct HFpEF phenogroups may aid in tailoring therapeutic strategies for these patients. The objective of this study was to assess proteomic patterns of HFpEF phenogroups identified through a machine-learning-based clustering model, with the aim of uncovering specific biological pathways associated with each phenogroup. METHODS: This study represents a post-hoc analysis of the ongoing Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with preserved Ejection Fraction (PURSUIT-HFpEF) study, which is a multicentre prospective observational study of hospitalised patients with acute decompensated HFpEF. Of the overall cohort (N=1238), this study analysed 198 patients with HFpEF with available proteomics data. These patients were classified into four phenogroups using the machine-learning-based clustering model. The SomaScan assay V.4.1 was used to measure levels of >7000 plasma proteins, and subsequent pathway analysis was conducted to determine the biological differences among the phenogroups. RESULTS: We identified four distinct phenogroups: Phenogroup 1 ('rhythm trouble'), Phenogroup 2 ('ventricular-arterial uncoupling'), Phenogroup 3 ('low output and systemic congestion') and Phenogroup 4 ('systemic failure'). The proteomics revealed distinct protein expression profiles among the phenogroups, with ribonuclease 4, tax1-binding protein 1, regenerating islet-derived protein 3-gamma and alpha-1-antichymotrypsin being the most significant markers to specific identified phenogroups. Pathway analysis suggested differences in immune response, autonomic activation, cellular homeostasis and tissue repair mechanisms across the phenogroups. CONCLUSIONS: Using a comprehensive plasma proteomics approach, our study identified distinct proteomic profiles of HFpEF phenogroups, which in turn suggest specific underlying biological processes. These profiles suggest the involvement of inflammatory activation, tissue injury and regenerative responses, immune modulation and systemic stress signalling as key components of HFpEF pathophysiology. TRIAL REGISTRATION NUMBER: UMIN-CTR ID: UMIN000021831.

Humans

Gene and pathway analysis of genome-wide genetic associations of bladder cancer.

BACKGROUND: Although genetic variants associated with bladder cancer (BCa) risk have been identified through hypothesis-driven and genome-wide association studies, a systematic understanding of BCa genetic susceptibility at the gene and pathway levels remains to be achieved. MATERIALS AND METHODS: In this 2-stage functional genomics study, we used 5 independent tools for genome-wide gene mapping and ranking based on BCa genome-wide association studies summary statistics, followed by a meta-analysis of gene-level significance p values, to obtain a consensus gene ranking in terms of association with BCa. Subsequently, we performed preranked gene-set enrichment analysis to identify the functional pathways involved in BCa genetic susceptibility. Joint analysis with gene-set enrichment analysis, based on somatic alteration frequency, was performed to explore the pathway-level relationships between genetic susceptibility and somatic alterations in BCa. RESULTS: Other than the well-known BCa genes (such as FGFR3, MYC, TERT, CCNE1, and TP63), we additionally prioritized a set of novel genes likely to be genetically implicated in BCa development, including SETD2, a possible tumor suppressor gene involved in chromatin remodeling. We further demonstrated convergence between genetic associations and somatic alterations at both the gene (eg, FGFR3 and TERT) and pathway levels (eg, cell cycle and chromatin modification), as well as functional ontologies specifically implicated in germline predisposition to BCa (eg, CD8/TCR signaling, immune checkpoints, and cytokine signaling). CONCLUSIONS: We identified several novel genes associated with BCa and demonstrated that genetic variants contribute to the development of BCa by affecting antitumor immunity, response to toxic exposure, and RNA and protein homeostasis and synergizing with somatic alterations in various cancer-related pathways.

Bladder cancer

Comprehensive Genomic Profiling Timeliness Beyond Laboratory Turnaround Time: A Patient-Facing Pathway Analysis.

AIM: We evaluated the timeliness of the patient-facing comprehensive genomic profiling (CGP) pathway by separating laboratory and post-laboratory intervals within an expert panel-mediated process, using direct disclosure of results to patients as the endpoint. METHODS: This single-center retrospective study included adult CGP test episodes performed under government-funded cancer genomic medicine at a Japanese university hospital between October 2019 and November 2025. The primary outcome was patient-centered turnaround time (TAT), defined as the interval from informed consent to direct disclosure of the CGP result to the patient. Laboratory TAT and pathway intervals were summarized descriptively, and laboratory TAT was compared across assays. RESULTS: Among 882 CGP test episodes, median laboratory TAT was 14 days (interquartile range [IQR], 12-16) among 871 evaluable episodes. Among 828 evaluable episodes, median patient-centered TAT was 41 days (IQR 35-45). The laboratory analysis retained observed long intervals, including a maximum of 72 days; no episode was excluded solely because laboratory TAT exceeded 56 days. These findings indicate that laboratory TAT was only one component of the longer consent-to-disclosure pathway. CONCLUSION: In this routine-care CGP pathway, patient-facing timeliness depended on the full process from consent to direct patient disclosure. Patient-centered TAT should be monitored alongside laboratory TAT as a care-delivery measure.

comprehensive genomic profiling

Fragment pathway analysis using automated tandem mass spectrometry on an ion-trap mass spectrometer.

A "key-sequence" procedure is presented for the automated tandem mass spectrometric analysis of compounds on a Finnigan ion-trap mass spectrometer. This allows fragmentation pathways of a range of masses or even a complete spectrum to be prepared automatically, obviating the tiresome preparation and optimization of individual scan-editor files. The procedure is limited by the speed of the driving computer; an "IBM-AT", for example, permits more than 10 mass units to be scanned per minute. It is calibrated with perfluorotributylamine and methyl stearate is used to demonstrate its results. The Finnigan ion-trap "programming option" is necessary for implementation of the procedure.

Mass Spectrometry

Global downstream BMP15 pathway analysis in human ovarian granulosa cells reveals novel genetic variations associated with primary ovarian insufficiency.

OBJECTIVES: Primary ovarian insufficiency (POI) is a fertility disorder with a well-established genetic component, but many cases still remain idiopathic. Approximately 1.5-12% of patients with POI can carry a variant in the BMP15 gene, depending on the population and the diagnostic criteria. We hypothesize that genetic variations within pathways downstream of BMP15 activity in ovarian granulosa cells (GCs) may contribute to unexplained cases of POI. The main goal of this study is to identify novel variants associated with POI in genes induced by BMP15 in GCs. STUDY DESIGN: Primary cultures of human GCs were stimulated with recombinant human BMP15. Microarray analysis profiled the BMP15-induced transcriptome in GCs. Validation was achieved by qPCR and immunoblot. Further, target exome sequencing of the differentially expressed genes was performed on 64 women with early POI onset in search of novel variants. MAIN OUTCOME MEASURES: Transcriptome profiling of human GCs stimulated with BMP15 and target exome sequencing in women with early onset of POI. RESULTS: Transcriptome analysis revealed significant upregulation of 19 genes (p&#xa0;<&#xa0;0.05). Ontology analysis of these genes converged towards two main pathways: TGF-beta signaling and regulation of stem cell pluripotency. Target exome sequencing identified six novel rare variants in five BMP15-induced genes (SAMD11, SMAD6, ID1, USP35, GPCR137C) in 9 of the 64 women with early POI (14%). CONCLUSIONS: BMP15 action in human ovarian GCs defines TGF-beta signaling and pluripotency fate in ovarian follicles. In addition, this study uncovers new potential candidate genes for the pathogenesis of POI.

Humans

Virtual reality physical education and adolescents' exercise interest and physical fitness: An explanatory sequential mixed-methods randomized trial with exploratory pathway analysis.

Traditional physical education (PE) faces declining student interest and limited fitness gains. Virtual reality (VR) offers immersive, gamified experiences, but evidence regarding its effectiveness and explanatory pathways remains limited. This explanatory sequential mixed-methods randomized trial assigned 360 adolescents (aged 13-16) from three middle schools to either VR-supported PE (n&#xa0;=&#xa0;180) or conventional PE (n&#xa0;=&#xa0;180) for 12&#xa0;weeks, with a 4-week follow-up. Outcomes included exercise interest (validated scale), physical fitness (coordination via MABC-2, cardiorespiratory endurance via the 20-m shuttle run, explosive power via the standing long jump, and speed via the 10-m sprint), and accelerometer-measured physical activity. The qualitative component involved 38 unique students: 32 completed individual semi-structured interviews, and six additional students participated only in focus groups. Three-level linear mixed-effects models and exploratory structural equation modeling were used. The VR group showed significantly greater improvements in exercise interest (d&#xa0;=&#xa0;0.78), coordination (d&#xa0;=&#xa0;0.62), cardiorespiratory endurance (d&#xa0;=&#xa0;0.55), and speed (d&#xa0;=&#xa0;0.48) than the control group (all p&#xa0;<&#xa0;0.001), but not in explosive power (d&#xa0;=&#xa0;0.12, p&#xa0;=&#xa0;0.148). Effects were partially retained at follow-up (interest d&#xa0;=&#xa0;0.65, coordination d&#xa0;=&#xa0;0.48, endurance d&#xa0;=&#xa0;0.42, and speed d&#xa0;=&#xa0;0.30), a pattern not fully consistent with a purely novelty-driven explanation. Exploratory mediation identified exercise interest as a statistically compatible explanatory pathway (indirect effect&#xa0;=&#xa0;0.34, 95% CI [0.22, 0.46]), although the timing of measurement precludes causal interpretation. Qualitative findings contextualized these results by highlighting immersion, feedback, self-efficacy, and perceived transfer. VR-supported PE may enhance adolescents' exercise interest and selected fitness dimensions, but its limited effect on explosive power and possible novelty contribution indicate that it should complement, rather than replace, conventional PE. Longer-term studies are needed.

Humans

[Immediate complications of fulguration of ventricular tachycardia and accessory pathways. Analysis of 318 endocavitary shocks].

Abnormal events occurring immediately following electric stimulation were studied in 85 patients--mean age 38.5 years (14-78)--during the performance of 318 intracardiac shocks applied in 110 sessions. This electric stimulation was done for treatment of tachycardias related to an accessory pathway (series AP: 64 patients), or ventricular tachycardias (series VT: 21 patients). The number of shocks per session was 2.4 +/- 1.4 and 4.6 +/- 3, for the series AP and VT respectively, and the cumulative energy per session, was 405 +/- 221 J and 1,007 +/- 735 J. Only events occurring within the first 30 minutes following the shocks, were evaluated. In the series AP, the 64 patients received a total of 208 shocks in 86 sessions, and 68 abnormal events were observed (33%): 35 complete atrio-ventricular blocks, of more than 10 seconds (17%), 29 sinus pauses exceeding 3 seconds (14%) and able to stretch to 30 seconds, 3 ventricular fibrillations (1.4%) and 1 atrial fibrillation. In the series TV, 21 patients received 110 shocks in 24 sessions, and only 10 abnormal events occurred (9%): 2 transient episodes of electromechanical dissociation (1.8%), 3 uniform VT (2.7%), 1 complete atrio-ventricular block (10 min.), 1 cardiac pause (4 sec), 1 ventricular fibrillation, 1 isolated haemodynamic depression and 1 Prinzmetal syndrome. All these events were temporary, 5 ventricular arrhythmias in 6 were treated with a new intracardiac shock, and there were no deaths related to electric stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent

A pathway analysis approach for determining acceptable levels of contamination of radionuclides in soil.

A methodology for determining acceptable levels for decontamination of soil containing radionuclides at waste sites is described. This methodology calculates the annual radiation dose that an individual receives while living on property that has been decommissioned and decontaminated. Pathways of exposure include direct radiation from ground surfaces, ingestion of contaminated food, inhalation of resuspended radionuclides and drinking contaminated water. Results calculated using this methodology were compared with U.S. Department of Energy (DOE) guidelines for a southeastern U.S. site. There is good agreement between the two methods provided similar assumptions are used.

Animals

Comparative pathway analysis of radiocesium in the Hudson River Estuary: environmental measurements and regulatory dose assessment models.

This work summarizes the measurements and associated environmental dosimetry of reactor-released 137Cs and 134Cs and weapons-produced 137Cs in samples of water, shoreline sediment and fish collected from 1971 to 1980 in the Hudson River Estuary. Trends observed in annual mean concentrations and the resultant dose implications for man from each source are discussed. The human exposure pathways examined are: fish consumption, water consumption, swimming and recreational use of the shoreline. Based on environmental measurements, a maximum, adult, whole-body, 50-y committed effective dose equivalent (CEDE) of 0.79 mu Sv (79 mu rem) is estimated from fish consumption in 1971, the year of maximum reactor discharge of the radiocesiums. For comparison, during the period 1974-79, mean estimates (+/- 1 SD) of the CEDE based on environmental measurements and attributed to other pathways are as follows: consumption of indigenous fish species caught downstream of the reactor outfall, 0.05 +/- 0.02 mu Sv (5 +/- 2 mu rem); consumption of fresh water sampled upstream of the reactors, 0.02 +/- 0.03 mu Sv (2 +/- 3 mu rem); and swimming, 10(-4) +/- 10(-4) mu Sv (0.01 +/- 0.01 mu rem). In addition, external, whole-body exposure resulting from recreational use of the shoreline 1.6 km downstream of the reactors is estimated to be 1.2 X 10(-8) C kg-1 (46 +/- 11 mu R yr-1). The above dose estimates are based on consumption factors of 3.9 and 803 kg y-1 (fish and water, respectively) and on usage factors of 50 and 140 h y-1 (swimming and shoreline recreation, respectively). Differences in dose estimates obtained from these long-term environmental measurements and from assessment models currently recommended for use by the U.S. Nuclear Regulatory Commission (NRC) are discussed.

Adult

Adolescent depression as a systemic multimorbidity catalyst: integrated genetic and metabolic pathway analysis.

BACKGROUND: Although adolescent depression has been linked to individual chronic conditions, its broader role in shaping multimorbidity risk remains understudied. METHODS: A total of 87,562 UK Biobank participants were included, of whom 18,851 had documented adolescent depression. Cox proportional hazards models were applied to evaluate associations between adolescent depression and 24 chronic diseases, followed by stratified analyses by sex and age. Two-sample Mendelian randomization (MR) was then conducted to infer causality for diseases showing significant associations. Genomic colocalization analyses were performed using relevant GWAS data to identify shared causal variants. Mediation analyses were performed to detect possible mediating factors, including the frailty index, KDM biological age acceleration, allostatic load and 30 circulating biomarkers. RESULTS: Adolescent depression was associated with elevated risk for 12 chronic diseases, with strongest associations for hypothyroidism (HR&#xa0;=&#xa0;1.29 [1.18-1.42]), diabetes (HR&#xa0;=&#xa0;1.25 [1.13-1.38]) and chronic obstructive pulmonary disease (COPD) (HR&#xa0;=&#xa0;1.74 [1.50-2.01]). Risks were notably higher among females and younger adults. MR confirmed likely causal relationships for hypothyroidism (OR&#xa0;=&#xa0;1.45 [1.03-2.05]), diabetes (OR&#xa0;=&#xa0;1.01 [1.01-1.02]) and COPD (OR&#xa0;=&#xa0;1.04 [1.02-1.06]). Genomic colocalization revealed a shared genetic signal at the CDSN/PSORS1C1 locus between adolescent depression and hypothyroidism. Mediation analyses revealed disease-specific pathways: creatinine for hypothyroidism, testosterone for diabetes, KDM biological ageing for COPD and frailty index across all three conditions. CONCLUSIONS: Adolescent depression confers systemic vulnerability through genetic and metabolic mechanisms, with amplified risks in females and individuals aged &#x2264;55&#xa0;years. These findings support early, integrated interventions to mitigate long-term multimorbidity.

Humans

[Dorsal root potential evoked by stimulation of periaqueductal gray and its efferent pathway analysis in rats].

When periaqueductal gray (PAG) was stimulated with concentric electrodes, a steady negative potential called PAG-DRP was recorded from L5 dorsal root. PAG-DRP with properties of spatial and temporal summation propagates decrementally along the dorsal root and is inhibited by picrotoxin. Lesions of NRM had no effect on the PAG-DRP evoked by stimulation of dorsal PAG, but showed obvious reduction up to about 40% on the PAG-DRP evoked by stimulation of ventral PAG. It is suggested that the descending inhibition of PAG includes some presynaptic inhibition and that the ventral PAG-DRP is relayed partly via NRM while the dorsal PAG-DRP is not associated with NRM.

Animals

Snell's Law: optimum pathway analysis.

An analysis is made of the various possible paths traveling from one medium to another. It is demonstrated that the most efficient possible path for traveling in the shortest possible time is the path determined by Snell's Law. Conversely, when light is refracted as it passes from one medium to another, it is completing the trip in the minimum possible time, less time than if it had passed through the various media in a straight line.

Humans

[Effects of stimulation of arcuate nucleus on intragastric pressure and peripheral pathway analysis in rats].

The effect of electrical stimulation of arcuate nucleus (ARC) on intragastric pressure (IGP) was examined on 68 Wistar rats anaesthetized with urethan. The results were as follows: (1) Stimulation of ARC could induce an obvious decrease of IGP. (2) This effect was not blocked by atropine but partially by vagotomy. (3) Extirpation of celiac neural plexus or intramuscular injection of phentolamine could obviously reduce the suppression of IGP induced by ARC stimulation, but intramuscular injection of propranolol had no such effect. (4) After vagotomy plus extirpation of celiac neural plexus, IGP could still be made a decrease by stimulating ARC. In view of the present investigation, it is suggested that (1) Both sympathetic nerve and vagus are involved in the reduction of IGP induced by ARC stimulation, the former and the latter routes being respectively mediated by alpha-adrenoceptor and non-cholinergic, non-adrenergic fibres. (2) Humoral factors may be also involved in this effect of ARC stimulation.

Animals

The role of protein structure in the mitochondrial import pathway. Analysis of the soluble F1-ATPase beta-subunit precursor.

A series of proteins containing defined internal and presequence deletions in the F1-ATPase beta-subunit precursor have been synthesized in vitro using a linked transcription-translation system. These different forms of the protein have been analyzed by the combination of gel filtration and in vitro mitochondrial import studies. These studies reveal that the soluble F1 beta-subunit precursor (55 kDa) forms a homooligomeric assembly of apparent molecular weight 230,000 on gel filtration analysis. The formation of this tetrameric beta-protein was dependent on the sequence between residues 122 and 144 of the precursor and was independent of the presence of a mitochondrial presequence within the first 19 residues of the precursor. When the tetrameric F1 beta-precursor was partially purified from the translation reaction it was incompetent for import into mitochondria. However, import of the partially purified beta-subunit could be restored by addition of reticulocyte lysate protein. In the absence of the tetramer-forming sequence, the protein behaved as an aggregate complex approximately 400 kDa in size. Formation of the high molecular weight aggregate and import into mitochondria was dependent upon a functional presequence at the amino terminus of the precursor. These studies are discussed in terms of the maintenance of an import competent structure for mitochondrial precursors and role of soluble factors in this process.

Amino Acid Sequence