HHIP's Dynamic Role in Epithelial Wound Healing Reveals a Potential Mechanism of COPD Susceptibility.

A genetic variant near has been consistently identified as associated with increased risk for Chronic Obstructive Pulmonary Disease (COPD), the third leading cause of death worldwide. However HHIP's role in COPD pathogenesis remains elusive. Canonically, HHIP is a negative regulator of the hedgehog pathway and downstream GLI1 and GLI2 activation.

Unlocking mitochondrial dysfunction-associated senescence (MiDAS) with NAD - A Boolean model of mitochondrial dynamics and cell cycle control.

The steady accumulation of senescent cells with aging creates tissue environments that aid cancer evolution. Aging cell states are highly heterogeneous. 'Deep senescent' cells rely on healthy mitochondria to fuel a strong proinflammatory secretome, including cytokines, growth and transforming signals.

Unlocking Mitochondrial Dysfunction-Associated Senescence (MiDAS) with NAD - a Boolean Model of Mitochondrial Dynamics and Cell Cycle Control.

Unlabelled: The steady accumulation of senescent cells with aging creates tissue environments that aid cancer evolution. Aging cell states are highly heterogeneous. 'Deep senescent' cells rely on healthy mitochondria to fuel a strong proinflammatory secretome, including cytokines, growth and transforming signals.

Active perception during angiogenesis: filopodia speed up Notch selection of tip cells .

How do cells make efficient collective decisions during tissue morphogenesis? Humans and other organisms use feedback between movement and sensing known as 'sensorimotor coordination' or 'active perception' to inform behaviour, but active perception has not before been investigated at a cellular level within organs. Here we provide the first proof of concept / study demonstrating that filopodia (actin-rich, dynamic, finger-like cell membrane protrusions) play an unexpected role in speeding up collective endothelial decisions during the time-constrained process of 'tip cell' selection during blood vessel formation (angiogenesis). We first validate simulation predictions with live imaging of zebrafish intersegmental vessel growth.

Boolean model of anchorage dependence and contact inhibition points to coordinated inhibition but semi-independent induction of proliferation and migration.

Epithelial cells respond to their physical neighborhood with mechano-sensitive behaviors required for development and tissue maintenance. These include anchorage dependence, matrix stiffness-dependent proliferation, contact inhibition of proliferation and migration, and collective migration that balances cell crawling with the maintenance of cell junctions. While required for development and tissue repair, these coordinated responses to the microenvironment also contribute to cancer metastasis.

Combined Toxicity of Insecticides and Fungicides Applied to California Almond Orchards to Honey Bee Larvae and Adults.

Beekeepers providing pollination services for California almond orchards have reported observing dead or malformed brood during and immediately after almond bloom-effects that they attribute to pesticide exposure. The objective of this study was to test commonly used insecticides and fungicides during almond bloom on honey bee larval development in a laboratory bioassay. In vitro rearing of worker honey bee larvae was performed to test the effect of three insecticides (chlorantraniliprole, diflubenzuron, and methoxyfenozide) and three fungicides (propiconazole, iprodione, and a mixture of boscalid-pyraclostrobin), applied alone or in insecticide-fungicide combinations, on larval development.

Time to Decide? Dynamical Analysis Predicts Partial Tip/Stalk Patterning States Arise during Angiogenesis.

Angiogenesis is a highly dynamic morphogenesis process; however, surprisingly little is known about the timing of the different molecular processes involved. Although the role of the VEGF-notch-DLL4 signaling pathway has been established as essential for tip/stalk cell competition during sprouting, the speed and dynamic properties of the underlying process at the individual cell level has not been fully elucidated. In this study, using mathematical modeling we investigate how specific, biologically meaningful, local conditions around and within an individual cell can influence their unique tip/stalk phenotype switching kinetics.

Principles of dynamical modularity in biological regulatory networks.

Intractable diseases such as cancer are associated with breakdown in multiple individual functions, which conspire to create unhealthy phenotype-combinations. An important challenge is to decipher how these functions are coordinated in health and disease. We approach this by drawing on dynamical systems theory.

A role of stochastic phenotype switching in generating mosaic endothelial cell heterogeneity.

Previous studies have shown that biological noise may drive dynamic phenotypic mosaicism in isogenic unicellular organisms. However, there is no evidence for a similar mechanism operating in metazoans. Here we show that the endothelial-restricted gene, von Willebrand factor (VWF), is expressed in a mosaic pattern in the capillaries of many vascular beds and in the aorta.

Expression of the Robo4 receptor in endothelial cells is regulated by two AP-1 protein complexes.

Roundabout4 (Robo4) is an endothelial cell-specific gene that plays an important role in endothelial cell stability. We previously identified a 3-kb Robo4 promoter and demonstrated the importance of its proximal region in regulating Robo4 gene expression. To investigate the role of the upstream promoter in Robo4 gene regulation, we searched evolutionarily conserved promoter regions by phylogenetic footprinting and identified three conserved promoter regions.

AKT1 and MYC induce distinctive metabolic fingerprints in human prostate cancer.

Cancer cells may overcome growth factor dependence by deregulating oncogenic and/or tumor-suppressor pathways that affect their metabolism, or by activating metabolic pathways de novo with targeted mutations in critical metabolic enzymes. It is unknown whether human prostate tumors develop a similar metabolic response to different oncogenic drivers or a particular oncogenic event results in its own metabolic reprogramming. Akt and Myc are arguably the most prevalent driving oncogenes in prostate cancer.

FOXO1-mediated activation of Akt plays a critical role in vascular homeostasis.

Rationale: Forkhead box-O transcription factors (FoxOs) transduce a wide range of extracellular signals, resulting in changes in cell survival, cell cycle progression, and several cell type-specific responses. FoxO1 is expressed in many cell types, including endothelial cells (ECs). Previous studies have shown that Foxo1 knockout in mice results in embryonic lethality at E11 because of impaired vascular development.

The flow dependency of Tie2 expression in endotoxemia.

Rationale: Tie2 is predominantly expressed by endothelial cells and is involved in vascular integrity control during sepsis. Changes in Tie2 expression during sepsis development may contribute to microvascular dysfunction. Understanding the kinetics and molecular basis of these changes may assist in the development of therapeutic intervention to counteract microvascular dysfunction.

Dynamical systems approach to endothelial heterogeneity.

Endothelial cells display remarkable phenotypic heterogeneity. An important goal is to elucidate the scope and mechanisms of endothelial heterogeneity and to use this information to develop vascular bed-specific therapies. We reexamine our current understanding of the molecular basis of endothelial heterogeneity.

Vascular bed-specific regulation of the von Willebrand factor promoter in the heart and skeletal muscle.

A region of the human von Willebrand factor (VWF) gene between -2812 and the end of the first intron (termed vWF2) was previously shown to direct expression in the endothelium of capillaries and a subset of larger blood vessels in the heart and skeletal muscle. Here, our goal was to delineate the DNA sequences responsible for this effect. A series of constructs containing deletions or mutations of vWF2 coupled to LacZ were targeted to the Hprt locus of mice, and the resulting animals were analyzed for reporter gene expression.

Differential roles for ETS, CREB, and EGR binding sites in mediating VEGF receptor 1 expression in vivo.

Vascular endothelial growth factor receptor 1 (VEGFR1) is a marker for endothelial-specific gene expression. We previously reported that the human VEGFR1 promoter (between -748 and +284) contains information for expression in the intact endothelium of transgenic mice. The objective of this study was to dissect the cis-regulatory elements underlying VEGFR1 promoter activity in vitro and in vivo.