Differential sensitivity to longitudinal and transverse stretch mediates transcriptional responses in mouse neonatal ventricular myocytes.

To identify how cardiomyocyte mechanosensitive signaling pathways are regulated by anisotropic stretch, micropatterned mouse neonatal cardiomyocytes were stretched primarily longitudinally or transversely to the myofiber axis. Four hours of static, longitudinal stretch induced differential expression of 557 genes, compared with 30 induced by transverse stretch, measured using RNA-seq. A logic-based ordinary differential equation model of the cardiac myocyte mechanosignaling network, extended to include the transcriptional regulation and expression of 784 genes, correctly predicted measured expression changes due to anisotropic stretch with 69% accuracy. The model also predicted published transcriptional responses to mechanical load in vitro or in vivo with 63-91% accuracy. The observed differences between transverse and longitudinal stretch responses were not explained by differential activation of specific pathways but rather by an approximately twofold greater sensitivity to longitudinal stretch than transverse stretch. In vitro experiments confirmed model predictions that stretch-induced gene expression is more sensitive to angiotensin II and endothelin-1, via RhoA and MAP kinases, than to the three membrane ion channels upstream of calcium signaling in the network. Quantitative cardiomyocyte gene expression differs substantially with the axis of maximum principal stretch relative to the myofilament axis, but this difference is due primarily to differences in stretch sensitivity rather than to selective activation of mechanosignaling pathways.NEW & NOTEWORTHY Anisotropic stretch applied to micropatterned neonatal mouse ventricular myocytes induced markedly greater acute transcriptional responses when the major axis of stretch was parallel to the myofilament axis than when it was transverse. Analysis with a novel quantitative network model of mechanoregulated cardiomyocyte gene expression suggests that this difference is explained by higher cell sensitivity to longitudinal loading than transverse loading than by the activation of differential signaling pathways.

Network model of skeletal muscle cell signalling predicts differential responses to endurance and resistance exercise training.

Exercise-induced muscle adaptations vary based on exercise modality and intensity. We constructed a signalling network model from 87 published studies of human or rodent skeletal muscle cell responses to endurance or resistance exercise in vivo or simulated exercise in vitro. The network comprises 259 signalling interactions between 120 nodes, representing eight membrane receptors and eight canonical signalling pathways regulating 14 transcriptional regulators, 28 target genes and 12 exercise-induced phenotypes. Using this network, we formulated a logic-based ordinary differential equation model predicting time-dependent molecular and phenotypic alterations following acute endurance and resistance exercises. Compared with nine independent studies, the model accurately predicted 18/21 (85%) acute responses to resistance exercise and 12/16 (75%) acute responses to endurance exercise. Detailed sensitivity analysis of differential phenotypic responses to resistance and endurance training showed that, in the model, exercise regulates cell growth and protein synthesis primarily by signalling via mechanistic target of rapamycin, which is activated by Akt and inhibited in endurance exercise by AMP-activated protein kinase. Endurance exercise preferentially activates inflammation via reactive oxygen species and nuclear factor κB signalling. Furthermore, the expected preferential activation of mitochondrial biogenesis by endurance exercise was counterbalanced in the model by protein kinase C in response to resistance training. This model provides a new tool for investigating cross-talk between skeletal muscle signalling pathways activated by endurance and resistance exercise, and the mechanisms of interactions such as the interference effects of endurance training on resistance exercise outcomes.

Quantifying public and private investment in European biopharmaceutical research and development.

Robust biopharmaceutical research and development (R&D) ecosystems require investment from both the public and private sectors. In Europe, there is an interest in growing biopharmaceutical R&D given its contribution to public health and the economy, which requires an understanding of current public and private investment. In addition, recent European draft legislation has focused on the public sector's contributions to biopharmaceutical R&D to inform pharmaceutical prices. However, there is little empirical evidence on the specifics of public and private funding for medicine R&D in Europe. This paper performs aggregative data collection to quantify 2019 investment in biopharmaceutical R&D by the public and private sectors in 6 countries: Belgium, France, Germany, Norway, Poland, and the United Kingdom. We find that, across these countries, the private sector accounts for just under two-thirds of investment. We contrast results to those obtained using high-level R&D indicators from the Organization for Economic Co-operation and Development (OECD) and contextualize differences. We then provide 2013-2019 estimates for Belgium, France, Germany, and the United Kingdom (countries with data to support such analysis), and show that total spending grew over those years, although proportions attributable to each sector remained stable. These findings should provide further evidence for debates on policies to effectively grow the biopharmaceutical R&D sector.

Collagen VI deposition primes the glioblastoma microenvironment for invasion through mechanostimulation of ß-catenin signaling.

While glioblastoma (GBM) progression is associated with extensive extracellular matrix (ECM) secretion, the causal contributions of ECM secretion to invasion remain unclear. Here we investigate these contributions by combining engineered materials, proteomics, analysis of patient data, and a model of bevacizumab-resistant GBM. We find that GBM cells cultured in engineered 3D hyaluronic acid hydrogels secrete ECM prior to invasion, particularly in the absence of exogenous ECM ligands. Proteomic measurements reveal extensive secretion of collagen VI, and collagen VI-associated transcripts are correspondingly enriched in microvascular proliferation regions of human GBMs. We further show that bevacizumab-resistant GBM cells deposit more collagen VI than their responsive counterparts, which is associated with marked cell-ECM stiffening. COL6A3 deletion in GBM cells reduces invasion, ß-catenin signaling, and expression of mesenchymal markers, and these effects are amplified in hypoxia. Our studies strongly implicate GBM cell-derived collagen VI in microenvironmental remodeling to facilitate invasion.

Authorized Generics In The US: Prevalence, Characteristics, And Timing, 2010-19.

Authorized generics are approved brand-name drugs that are sold by brand-name manufacturers or licensees without brands on their labeling. Despite their prevalence in prescription drug markets in the US, little is known about trends in their launches, their timing relative to traditional generics, and the characteristics of their respective brand-name drugs. We linked Food and Drug Administration and IQVIA data to investigate newly launched authorized generics during the period 2010-19. We found 854 launches over this period, with launches peaking in 2014. Marketing appears strategic: In markets with traditional generics, three-fourths of authorized generics launched after the respective generic competition started. When we focused on markets where generics were eligible for the 180-day exclusivity, about 70 percent of authorized generics launched before or during the exclusivity period. These findings provide insights for future research on the effect of authorized generics on competition, prices, and access to generics.

Glioma Cells Secrete Collagen VI to Facilitate Invasion.

While glioblastoma (GBM) progression is associated with extensive extracellular matrix (ECM) secretion, the causal contributions of ECM secretion to invasion remain unclear. Here we investigate these contributions by combining engineered materials, proteomics, analysis of patient data, and a model of bevacizumab-resistant GBM. We find that GBM cells cultured in engineered 3D hyaluronic acid hydrogels secrete ECM prior to invasion, particularly in the absence of exogenous ECM ligands. Proteomic measurements reveal extensive secretion of collagen VI, and collagen VI-associated transcripts are correspondingly enriched in microvascular proliferation regions of human GBMs. We further show that bevacizumab-resistant GBM cells deposit more collagen VI than their responsive counterparts, which is associated with marked cell-ECM stiffening. COL6A3 deletion in GBM cells reduces invasion, ß-catenin signaling, and expression of mesenchymal markers, and these effects are amplified in hypoxia. Our studies strongly implicate GBM cell-derived collagen VI in microenvironmental remodeling to facilitate invasion.

Corporate Investors Increased Common Ownership In Hospitals And The Postacute Care And Hospice Sectors.

The sharing of investors across firms is a new antitrust focus because of its potential negative effects on competition. Historically, the ability to track common investors across the continuum of health care providers has been limited. Thus, little is known about common investor ownership structures that might exist across health care delivery systems and how these linkages have evolved over time. We used data from the Provider Enrollment, Chain, and Ownership System of the Centers for Medicare and Medicaid Services to identify common investor ownership linkages across the acute care, postacute care, and hospice sectors within the same geographic markets. To our knowledge, this study provides the first description of common investor ownership trends in these sectors. We found that the percentage of acute care hospitals having common investor ties to the postacute or hospice sectors increased from 24.6 percent in 2005 to 48.9 percent in 2015. These changes have important implications for antitrust, payment, and regulatory policies.