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A social network analysis of eighty-nine midlevel health care professionals showed that middle managers' strategic knowledge is positively associated with championing alternative ideas and synthesizing new information for upper management. In addition, the relationship between knowledge and middle management strategic activities in informal networks is moderated by the manager's social position.
BACKGROUND: Ferroptosis plays a significant role in pulmonary arterial hypertension (PAH), although its underlying mechanisms and key pathogenic genes remain unclear. METHODS: Transcriptomic data from human PAH and control lung tissue were obtained from the Gene Expression Omnibus (GEO) database, whereas ferroptosis-related genes (FRGs) were sourced from the MsigDb and FerrDb databases. Differentially expressed FRGs (DE-FRGs) were identified through the intersection of FRGs with differentially expressed genes (DEGs). Functional enrichment analysis was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Key hub genes were identified through Least Absolute Shrinkage and Selection Operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and weighted correlation network analysis (WGCNA). Gene set enrichment analysis (GSEA) was conducted to explore the functional roles and associated pathways of hub genes. The relationship between hub genes and immune infiltration was investigated. Expression levels of potential biomarkers were validated via Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) in two PAH animal models (monocrotaline-induced and Sugen5416 plus hypoxia-induced PAH). Finally, molecular docking was employed to screen potential therapeutic compounds. RESULTS: A total of 133 DE-FRGs were identified, with KEGG and GO analyses highlighting their involvement in intracellular iron homeostasis and ferroptosis. Hub genes, notably FZD7 and NFE2, were identified using LASSO, SVM-RFE, and WGCNA. Immune infiltration analysis suggested that monocytes and neutrophils play key roles in PAH pathogenesis. Validation in PAH animal models showed significant upregulation of Fzd7 and downregulation of Nfe2 in lung tissues of both MCT- and SuHx-induced PAH models. Molecular docking identified tetrachlorodibenzodioxin (TCDD) has good binding affinity. CONCLUSION: In summary, we investigated two ferroptosis-related biomarkers, FZD7 and NFE2, in PAH using transcriptomics, offering new insights into molecular mechanisms and potential targeted therapies for the disease.
Body size is a key economic trait influencing the profitability of farmed animals. This study used genome-wide association studies (GWAS) to identify five single nucleotide polymorphisms (SNPs) significantly associated with body size in the Tibetan sheep population, advancing molecular breeding and providing a basis for genomic selection. These SNPs are located within five candidate genes. SNaPshot validated GWAS results, demonstrating significant correlations between candidate SNPs and body size traits in Tibetan sheep. Concurrently, hematoxylin and eosin staining, alongside muscle fiber analysis, confirmed pronounced morphological differences in muscle tissue between sheep of varying conformation. Therefore, transcriptome and proteomics were performed on the longest dorsi muscle from large and small Tibetan sheep of both sexes. The transcriptome, together with weighted gene co-expression network analysis (WGCNA), identified VEPH1 and PRKG1 as core genes regulating body characteristics in Tibetan sheep through their involvement in the PI3K-Akt signaling pathway and pathways related to fat deposition. The integrative analyses demonstrated significantly different expression of CARNS1 and CRYAB at both transcriptional and protein levels between the muscles of large- and small-sized Tibetan sheep of both sexes, suggesting their importance in body size traits by influencing muscle morphology. This study provides valuable genomic resources that advance sheep genetics research.
Genomic instructions for development are encoded in arrays of regulatory DNA. These specify large networks of interactions among genes producing transcription factors and signaling components. The architecture of such networks both explains and predicts developmental phenomenology. Although network analysis is yet in its early stages, some fundamental commonalities are already emerging. Two such are the use of multigenic feedback loops to ensure the progressivity of developmental regulatory states and the prevalence of repressive regulatory interactions in spatial control processes. Gene regulatory networks make it possible to explain the process of development in causal terms and eventually will enable the redesign of developmental regulatory circuitry to achieve different outcomes.
OBJECTIVES: The study used the social antecedent model of depression in later life proposed by Linda K. George to develop a multifactorial model of predictors of depression among aging persons with schizophrenia living in the community. METHODS: The SHORT-CARE and the Network Analysis Profile, along with supplemental items, were administered to 117 outpatients age 55 and older who received DSM-III-R diagnoses of schizophrenia before age 45. Bivariate and multivariate analyses examined associations between 27 variables derived from George's model and the presence of depression. A cutoff score for the depression scale of the SHORT-CARE was used to detect clinically significant depression. RESULTS: Forty-four percent of the sample had probable pervasive depression. Bivariate analysis indicated that 16 variables were significantly associated with depression, and logistic regression showed that six variables were strong predictors. Depression was associated with the presence of positive symptoms, physical limitations interfering with activities, younger age, diminished linkage of members of the social network, lower income, and a smaller proportion of social network members who provided sustenance such as food and money. An 11-variable model correctly classified 81 percent of cases. CONCLUSIONS: The level of depression among older outpatients with schizophrenia is approximately one and a half to three times the level in the general older population. Depression in this patient group is associated with nonclinical variables that are independent of psychoses and that resemble patterns found among general older populations. Several of the variables are potentially alterable and therefore afford opportunities to enhance the well-being of persons with schizophrenia who live in the community.
Tibolone is a synthetic steroid with estrogenic effects on brain, vagina, and bone without stimulating the endometrium. During tibolone treatment, it is thought that the progestagenic properties of tibolone stimulate cell differentiation, which effectively counterbalances the growth-stimulating effects of the estrogenic properties of tibolone. The objective of this study was to characterize the expression profile that reflects the endometrial responses to the separated estrogenic (growth-inducing) and progestagenic (growth-inhibiting) actions of tibolone, thus gaining insight into the counteracting effect of these properties of tibolone on the endometrium. The estrogenic action of tibolone was studied in the estrogen-responsive ECC1 cell line (expressing estrogen receptor alpha), and the progestagenic action was studied in the progesterone-responsive cell line Ishikawa PRAB-36 (expressing PRA and PRB). The data showed that the progestagenic and estrogenic effects of tibolone produce different expression profiles with a narrow overlap in genes; however, both properties modulate the same biological processes. The final genetic network analysis indicated that the estrogenic effect of tibolone is potentially counterbalanced by the progestagenic metabolite of tibolone via differential regulation of similar cellular processes. For example, both progestagenic and estrogenic properties stimulate proliferation, but they exert the opposite effect on apoptosis. The apoptosis network was stimulated by the progestagenic properties of tibolone; in contrast, the estrogenic effect of tibolone suppressed the apoptosis network. The current results indicate that this differential regulation is realized through modulation of a different group of genes and rarely via contraregulation of the same set of genes.
Elimination of cancer in the 21st Century is likely to depend not only on more effective individualized treatment, but also upon earlier detection and prevention of different malignancies. Screening strategies for ovarian cancer have centered on the serum tumor marker CA 125, transvaginal sonography (TVS), or sequential use of the two modalities. A single determination of CA 125 is neither sufficiently sensitive nor specific to be used as an initial stage in screening. Specificity can be improved by monitoring CA 125 over time with an algorithm that estimates risk of ovarian cancer. Sensitivity of CA125 can be improved by use of multiple markers in combination. Gene expression array analysis, proteomics and lipomics are being utilized to identify markers that can be used in combination with CA 125 to detect >95% of early stage ovarian cancers. To maintain high specificity, values for different markers are being combined using novel approaches of neural network analysis and mixed multivariate analysis. Sequential use of multiple markers and TVS could provide a cost-effective strategy to detect a disease of intermediate prevalence.
BACKGROUND: Hamstring strain injury is a leading time-loss injury in football, yet trials have evaluated diverse exercise-based prevention programs with limited direct head-to-head evidence. This systematic review and network meta-analysis aimed to compare the effectiveness of exercise-based interventions for preventing hamstring injuries in football players using exposure-adjusted incidence rate ratios. METHODS: We conducted a PRISMA-aligned systematic review and random-effects network meta-analysis of randomized controlled trials in football players comparing exercise-based interventions to prevent hamstring injuries. Searches covered PubMed, Cochrane Library, Embase and Web of Science from inception to January 5, 2026. Interventions were modeled as separate nodes (Nordic hamstring exercise [NHE], FIFA 11, FIFA 11 + , FIFA 11 + Kids, bounding exercise program [BEP], usual training). The primary effect measure was incidence rate ratio (IRR) versus usual training, with ranking by P-scores; exploratory subgroup analyses were conducted by sex-restricted male-only evidence and age group. RESULTS: Eleven randomized controlled trials involving 9,282 participants were included. The network was connected but largely star-shaped, with most evidence comparing active interventions against usual training and no direct active-active comparisons. FIFA 11 + showed the most consistent exposure-adjusted association with reduced hamstring injury incidence versus usual training (IRR = 0.55, 95% CI 0.31-0.98; P-score = 0.84). FIFA 11 + Kids showed a favorable but imprecise estimate, whereas NHE showed a modest non-significant reduction and FIFA 11 and BEP showed no clear benefit. Male-only findings were broadly consistent with the primary analysis. Age-stratified analyses suggested that the apparent hierarchy was not fully identical across age strata, but subgroup networks were sparse and exploratory. RoB 2 judged three studies as high risk and eight as having some concerns; no trial was judged as overall low risk. Between-study heterogeneity was substantial, and treatment rankings were, therefore, interpreted cautiously. CONCLUSIONS: In this IRR-based network meta-analysis, FIFA 11 + showed the most consistent exposure-adjusted association with reduced hamstring injury incidence compared with usual training. However, certainty across the primary comparisons ranged from low to very low because of clinical and methodological heterogeneity, sparse direct evidence for several nodes, reliance on indirect active-active comparisons, substantial between-study heterogeneity, and moderate-to-high risk of bias across the included studies. The treatment hierarchy should, therefore, be interpreted as a low-to-very-low-certainty, population-level summary rather than as a basis for firm recommendations. Further well-reported, age- and population-specific head-to-head trials with consistent exposure, injury-definition, adherence, and intervention-dose reporting are needed. Registration Systematic review registration PROSPERO (CRD420251243576).
In this work we report on the phylogeography of the endangered tree species Caryocar brasiliense based on variability in two classes of maternally inherited chloroplast DNA sequences with different rates of molecular evolution. Eleven sequence haplotypes of a noncoding region between the genes trnT and trnF and 21 distinct 10-locus microsatellite haplotypes could be identified in a total of 160 individuals, collected in 10 widespread populations of C. brasiliense. An amova indicated that most of the variation can be attributed to differences among populations, both for DNA sequence (87.51%) and microsatellites (84.38%). Phylogeography based on a median-joining network analysis of the noncoding region showed a sharp difference from the analysis of microsatellite haplotypes. Nevertheless, both analyses indicated that multiple lineages may have contributed to the origin of C. brasiliense populations in Brazilian Cerrado. Incongruences in the microsatellite haplotypes network suggest that homoplasy, which emerged from recurrent and independent mutations, greatly influenced the evolution of the C. brasiliense chloroplast genome. We hypothesize that our results may show the outcome of the restriction of ancient relic populations to moist refugias during extended droughts coinciding with glaciation in the northern hemisphere. The subsequent spread to favourable areas throughout Central Brazil may have caused contact between different lineages during the interglacial periods. The extinction of megafauna dispersers in the last glaciation may have caused a restriction in seed movement and currently, gene flow has been occurring mainly by pollen movement.
Multicomponent essential oils Tagetes Minuta and Poleo as well as pure limonene were encapsulated in Tween doped-high methoxylated pectin gels. Optical microscopy reveals that the obtained gels containing limonene consisted in a highly heterogeneous oil-in-water emulsion stabilised by the gelled medium. The influence of limonene encapsulation in pectin gelation kinetics and the gel structural properties were followed by dynamic rheological measurements. An electronic nose device developed in our laboratory was used to follow the flavour release of the three systems in order to discriminate the samples according to the main components released to the headspace. PCA and Neural Network Analysis allowed us to discriminate Tagetes Minuta from Poleo due to the difference in their limonene content. It is remarkable that the fingerprints of encapsulated complex mixtures differ from those obtained for the non-encapsulated oils, showing a preferential release of some components. In the case of limonene, the effect of the encapsulated concentration on the detected odour was also studied.
Numerous mathematical methods have been adapted and developed to quantitatively reverse engineer biological networks, for example, signal transduction pathways, from experimental micro-array data. Compared with stochastic methods, such as Boolean networks, and deterministic methods, such as thermodynamic or differential equation-based models, Bayesian network analysis has the ability to assess, with scoring metrics, causal relations based on conditional probabilities and thus permit hypothesis testing. The goal of this paper is to illustrate the integration of several Bayesian based techniques into a unified Bayesian framework that can infer hepatocellular networks from metabolic data. Reverse engineering of pathways and networks provides a framework for predictive modeling and hypotheses testing to gain deeper insight into living organisms, disease mechanisms, and targeted therapeutics. Evaluating this methodology initially against the known biochemical network provides confidence in the networks that are uncovered from the experimental data using this framework. From the metabolic data we inferred the known sub-networks, such as the tricarboxylic acid (TCA) and urea cycles. In addition, we combined the relationships learned from the data and our current knowledge of the biological system to postulate several alternative metabolic sub-network models that can predict a particular cellular function, such as intracellular triglyceride accumulation.
BACKGROUND AND PURPOSE: Increased resistance in the venous drainage of intracranial arteriovenous malformations (AVMs) may contribute to their increased risk of hemorrhage. Venous drainage impairment may result from naturally occurring stenoses/occlusions, or if draining veins (DVs) undergo occlusion before feeding arteries during surgical removal, or after surgery in the presence of "occlusive hyperemia." We employed a detailed biomathematical AVM model using electrical network analysis to investigate theoretically the hemodynamic consequences and the risk of AVM rupture due to venous drainage impairment. METHODS: The AVM model consisted of a noncompartmentalized nidus with 28 vessels (24 plexiform components and 4 fistulous components), 4 arterial feeders, and 2 DVs. An expression for the risk of AVM nidus rupture was derived on the basis of functional distribution of the critical radii of component vessels. Risk was calculated from biomathematical simulations of volumetric flow rate with both DVs patent and for four stages of venous drainage obstruction: (1) 25%, (2) 50%, (3) 75%, and (4) 100%. Each stage of occlusion was applied to each DV while the other DV was patent and then to the patent DV while the other DV was totally occluded. RESULTS: For flow through the AVM when both DVs were unobstructed, the baseline risk of AVM nidus rupture ranged from 4.4% to 91.2%. Theoretical rupture occurred in nidus components proximal to the DVs when the risk exceeded 100%, as was observed with the obstruction of DV1 and a patent DV2. The ranges for risk of rupture across the nidus for the four stages were (1) 4.7% to 90.5%, (2) 5.9% to 86.9%, (3) 0% to 98.4%, and (4) 0% to 106.3%, respectively. Rupture was observed for an 86% occlusion of DV1 (ie, the DV fed by the intranidal fistula) and DV2 patent, primarily because of the dramatic shift in the hemodynamic burden toward the weaker plexiform nidus vessels. CONCLUSIONS: On theoretical grounds, venous drainage impairment was predictive of AVM nidus rupture and was strongly dependent on AVM morphology (presence of intranidal fistulas and their spatial relation to DVs) and hemodynamics. Specifically, stenosis/occlusion of a high-flow DV induces a rapid redistribution of blood into the weak plexiform vessels of the opposing region of the nidus, causing a hemodynamic overload and an increased risk of rupture. These findings should be carefully considered among all factors affecting the natural history of intracranial AVMs and the mechanisms implicated in their spontaneous rupture. They may also provide a theoretical rationale for some of the hemorrhagic complications that occur during and after surgical treatment.
OBJECTIVE: Half of all preterm births occur in women without clinical risk factors. Our goal was to assess fetal fibronectin assay, Bishop score, and cervical ultrasonography as screening tests to predict which low-risk pregnancies will end in preterm birth. STUDY DESIGN: We performed a secondary analysis of data collected at 22 to 24 weeks' gestation from low-risk subjects enrolled in the Preterm Prediction Study, an observational study of risk factors for preterm birth conducted by the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Analysis was limited to primigravid women and to women who did not have a history of preterm birth or spontaneous pregnancy loss at <20 weeks' gestation. Bishop score (> or =4), fetal fibronectin level (> or =50 ng/mL), and cervical length (< or =25 mm) at 24 weeks' gestation were evaluated alone and in sequence as tests to predict spontaneous delivery before 35 weeks' gestation. RESULTS: Of the 2929 subjects enrolled in the original study, 2197 (1207 primigravid women and 900 low-risk multiparous women) met criteria for this analysis. There were 64 spontaneous births before 35 weeks' gestation (3.04%). All three tests were significantly related to birth before 35 weeks' gestation (high Bishop score: relative risk, 3.6; 95% confidence interval, 2.1-6.3; fetal fibronectin detection: relative risk, 8.2; 95% confidence interval, 4.8-13.9; short cervical length: relative risk, 6.9; 95% confidence interval, 4.3-11.1). However, the sensitivities of the tests alone were low (23.4% for high Bishop score, 23.4% for fetal fibronectin detection, and 39.1% for short cervix), as were the sensitivities for Bishop score followed by cervical ultrasonography (14.1%) and fetal fibronectin assay followed by cervical scan (15.6%). CONCLUSION: In the setting of low-risk pregnancy, fetal fibronectin assay and cervical ultrasonography have low sensitivity for preterm birth before 35 weeks' gestation. Sequential screening with Bishop score or fetal fibronectin assay followed by cervical ultrasonography further decreased sensitivity to only 15% among low-risk women.
Unmethylated CpG motifs interact with Toll-like receptor 9 (TLR9), triggering an innate immune response characterized by the production of cytokines, chemokines and immunoglobulins. Microarray analysis of cDNA from murine spleen cells stimulated with CpG oligodeoxynucleotides (ODN) identified reproducible changes in gene expression over time. Eight genes are significantly up-regulated 2h post CpG ODN stimulation, most of which contribute to the induction of innate or adaptive immune responses. Network analysis indicates that TNF and NFKB1 are key regulators of gene expression at this early time point. At 4h, IL1B in addition to TNF and NFKB1 play dominant roles in the up-regulation of immune gene expression, whereas by 8h this function is mediated by TNF, IFNG, and MYC. Genes responsible for down-regulating CpG-induced responses were also identified, dampening what would otherwise be a continuous positive feedback loop. This work provides novel insights into the regulatory process embedded in the gene expression profile induced by CpG ODN, identifies novel genes associated with CpG-induced immune stimulation, and clarifies the breadth of the immune response elicited via TLR9.
PURPOSE: Given the existing uncertainties regarding the link between Di(2-ethylhexyl) phthalate (DEHP) exposure and gastric cancer (GC) progression, this study aimed to clarify their association, identify the toxic targets of DEHP, and elucidate the underlying molecular mechanisms. METHODS: Multiple integrated approaches were employed, including Gene Expression Omnibus (GEO) data analysis, network toxicology, molecular docking, and machine learning. STRING and Cytoscape tools were utilized to identify key targets, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the functional enrichment of intersecting targets. Machine learning and SHAP analysis were applied to screen core targets in GC. Molecular docking was performed to evaluate the binding affinity of DEHP toward core targets, and 200 ns molecular dynamics simulations were further conducted for representative complexes to validate their dynamic stability. RESULTS: A total of 18 key targets were identified using STRING and Cytoscape. GO and KEGG enrichment analyses demonstrated that these intersecting targets were primarily enriched in the extracellular region, as well as the Calcium signaling pathway and cAMP signaling pathway. Through machine learning analyses, 7 key genes (ADRB2, ESRRG, GRIA4, IL13RA2, NR3C2, PLA2G1B, and SULT2A1) were identified as core targets in GC through machine learning analyses. Molecular docking simulations revealed strong binding specificity between DEHP and the target proteins. Among them, NR3C2 and ADRB2 exhibited relatively high predictive importance in the machine learning models. DEHP showed favorable binding affinity toward these core targets, and molecular dynamics simulations further confirmed that ADRB2-DEHP and NR3C2-DEHP complexes maintained stable conformations throughout the simulation. CONCLUSIONS: Our findings identified GC associated genes that were computationally predicted as potential targets of DEHP. These results indicated structural compatibility between DEHP and its target proteins but did not prove that DEHP exposure accounts for the gene expression changes in GC.
BACKGROUND: Orofacial clefts (OFCs) and other palate abnormalities (PAs) are among the most common birth defects worldwide and are characterized by the abnormal formation of the lip and/or palate. Genetic studies have traditionally classified OFC cases as either syndromic, involving OFCs alongside other congenital anomalies, or nonsyndromic, which represent the majority of cases and occur in isolation. Emerging genomic evidence indicates that genes traditionally associated with syndromic forms of OFC can also harbor variants contributing to isolated cases, challenging the notion of a strict dichotomy between these categories and supporting their integration for gene discovery. METHODS: In this study, we applied multiple analytic approaches to characterize the genetic architecture of OFC and PAs by integrating genomic data from 2,497 trios with probands diagnosed with an OFC (n=2,080) or PA (n=417). We compared these findings across OFC subtypes and syndromic status with those from 5,515 control trios to identify enriched biological pathways and mechanisms and to prioritize candidate genes using variant burden testing. RESULTS: We observed a significant enrichment of de novo protein-truncating and damaging missense variants in cases compared to controls (OR = 2.17, p = 1.21×10-32), with particularly strong signals in biologically relevant gene sets involving OFC-associated, constrained, Mendelian disorder, and mouse candidate genes. Variant burden testing identified 39 OFC risk genes at FDR ≤ 0.05, which we then integrated with 593 established OFC genes to interrogate the functional underpinnings of OFC via network analysis. This analysis revealed 309 high-order interactor genes not previously associated with OFC. Notably, this OFC network clustered into ten distinct biological pathways, with nucleosome-associated genes showing significant enrichment among cases in our cohort (OR = 14.8, p = 8.1×10-4). In a final integrative step, we combined evidence across all analyses to nominate 231 candidate genes, 32 of which contained at least two deleterious de novo variants in our cohort. CONCLUSIONS: These findings underscore the value of integrating diverse OFC and PA subtypes, syndromic status, and variant classes to elucidate the genetic architecture of these disorders, highlighting both phenotypic expansion of known disease genes and the emergence of novel gene-phenotype associations.
Human induced pluripotent stem cell (iPSC)-derived microglia (iMG) provide an in vitro experimental system for studying human microglial biology, neuroinflammation, and genetic risk mechanisms associated with neurological disease. This chapter describes a standardized, scalable, and reproducible protocol for the differentiation of human iPSCs into functional microglia-like cells, with particular emphasis on applications in transcriptional and epigenomic network analysis. The protocol supports high-viability floating iMG production, compatibility with pooled CRISPR perturbation approaches, and downstream multiomic profiling, including single-cell RNA sequencing, chromatin accessibility assays, and proteomics. Detailed procedures are provided for iPSC maintenance, hematopoietic progenitor cell generation, microglial maturation, functional genomics integration, and quality control.
After decades of decline in developed countries, there was a resurgence of tuberculosis in the mid-1980s accompanied by increased recognition that this infectious disease has long remained a major public health problem at the global level. New methods from molecular biology, in particular DNA 'fingerprinting' (of Mycobacterium tuberculosis), made it clear that current transmission and recent infection (in contrast to reactivation of earlier, latent infection) were much more significant than previously believed. Studies of tuberculosis outbreaks using these new tools pointed to complex networks through which infection was spreading and highlighted the need for new approaches to outbreak investigation and disease control. In the study reported here a new approach--combining methods from molecular biology, epidemiology and network analysis--was used to examine an outbreak of tuberculosis in Houston, Texas. Initial investigation using conventional strategies revealed few contacts among 37 patients with identical (six-band) DNA (IS6110-based) fingerprints but subsequent research uncovered over 40 places (including many gay bars) to which patients in this outbreak could be linked. Network methods were used to reconstruct an outbreak network and to quantify the relative importance (here, 'betweenness' centrality) of different actors (persons and places) playing a role in the outbreak. The multidisciplinary work provides the basis for a new approach to outbreak investigation and disease control.