Evaluation of the effects of sensory denervation on osteoblasts by 3 H-proline autoradiography

The inferior alveolar nerve was unilaterally resected in 30-day-old mice; other animals were unilaterally sham-operated. At 15, 30, 60, 90, or 150 days after surgery, the mice were injected with 2μCi of 3 H-proline (sp. act. 1.0 Ci/mM) per g of body weight and killed 15, 30, or 60 min later. Autoradiographs were prepared from 5μm decalcified sagittal sections of mandibles and grain counts made over periosteal osteoblasts mesial to the first molar. In denervated mandibles, osteoblasts incorporated less isotope compared to controls with differences being maximal at the early intervals. These differences became attenuated with time, possibly due to an intrinsic compensatory mechanism, secondary to neurotrophic regulation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47675/1/441_2004_Article_BF00219365.pd

Smooth muscle–derived progenitor cell myofibroblast differentiation through KLF4 downregulation promotes arterial remodeling and fibrosis

Resident vascular adventitial SCA1+ progenitor (AdvSca1) cells are essential in vascular development and injury. However, the heterogeneity of AdvSca1 cells presents a unique challenge in understanding signaling pathways orchestrating their behavior in homeostasis and injury responses. Using smooth muscle cell (SMC) lineage-tracing models, we identified a subpopulation of AdvSca1 cells (AdvSca1-SM) originating from mature SMCs that undergo reprogramming in situ and exhibit a multipotent phenotype. Here we employed lineage tracing and RNA-sequencing to define the signaling pathways regulating SMC-to-AdvSca1-SM cell reprogramming and AdvSca1-SM progenitor cell phenotype. Unbiased hierarchical clustering revealed that genes related to hedgehog/WNT/beta-catenin signaling were significantly enriched in AdvSca1-SM cells, emphasizing the importance of this signaling axis in the reprogramming event. Leveraging AdvSca1-SM–specific expression of GLI-Kruppel family member GLI1 (Gli1), we generated Gli1-CreERT2-ROSA26-YFP reporter mice to selectively track AdvSca1-SM cells. We demonstrated that physiologically relevant vascular injury or AdvSca1-SM cell–specific Kruppel-like factor 4 (Klf4) depletion facilitated the proliferation and differentiation of AdvSca1-SM cells to a profibrotic myofibroblast phenotype rather than macrophages. Surprisingly, AdvSca1-SM cells selectively contributed to adventitial remodeling and fibrosis but little to neointima formation. Together, these findings strongly support therapeutics aimed at preserving the AdvSca1-SM cell phenotype as a viable antifibrotic approach

Contribution of inhibitory mechanisms to direction selectivity and response normalization in macaque middle temporal area

Inhibitory mechanisms contribute to directional tuning in primary visual cortex, and it has been suggested that, in the primate brain, the middle temporal area (MT) inherits most of its directional information from primary visual cortex (V1). To test the validity of this hierarchical scheme, we investigated whether directional tuning in MT was present upon blockade of local γ-aminobutyratergic (GABAergic) inhibitory mechanisms. Direction selectivity during the initial 50 ms after response onset was abolished in many MT cells when the local inhibitory network was inactivated whereas direction selectivity in later response periods was largely unaffected. Thus, direction selectivity during early response periods is often generated autonomously within MT whereas direction selectivity during later response periods is either inherited from other visual areas or locally mediated by mechanisms other than γ-aminobutyric acid type A receptor (GABA(A)) inhibition. GABAergic inhibition may also mediate contrast normalization. Our data suggest that GABA(A) inhibition implements a local direction-selective static nonlinearity, rather than a full normalization in MT. These findings put constraints on strict hierarchical models according to which MT performs more complex computations based on local motion measurements provided by earlier areas, arguing for more distributed and independent information processing

One-Hour Esophageal String Test: A Nonendoscopic Minimally Invasive Test That Accurately Detects Disease Activity in Eosinophilic Esophagitis

OBJECTIVES: Eosinophilic esophagitis (EoE), a chronic food allergic disease, lacks sensitive and specific peripheral biomarkers. We hypothesized that levels of EoE-related biomarkers captured using a 1-hour minimally invasive Esophageal String Test (EST) would correlate with mucosal eosinophil counts and tissue concentrations of these same biomarkers. We aimed to determine whether a 1-hour EST accurately distinguishes active from inactive EoE or a normal esophagus. METHODS: In a prospective, multisite study, children and adults (ages 7–55 years) undergoing a clinically indicated esophagogastroduodenoscopy performed an EST with an esophageal dwell time of 1 hour. Subjects were divided into 3 groups: active EoE, inactive EoE, and normal esophageal mucosa. Eosinophil-associated protein levels were compared between EST effluents and esophageal biopsy extracts. Statistical modeling was performed to select biomarkers that best correlated with and predicted eosinophilic inflammation. RESULTS: One hundred thirty-four subjects (74 children, 60 adults) with active EoE (n 5 62), inactive EoE (n 5 37), and patient controls with a normal esophagus (n 5 35) completed the study. EST-captured eosinophil-associated biomarkers correlated significantly with peak eosinophils/high-power field, endoscopic visual scoring, and the same proteins extracted from mucosal biopsies. Statistical modeling, using combined eotaxin-3 and major basic protein-1 concentrations, led to the development of EoE scores that distinguished subjects with active EoE from inactive EoE or normal esophagi. Eightyseven percent of children, 95% of parents, and 92% of adults preferred the EST over endoscopy if it provided similar information. DISCUSSION: The 1-hour EST accurately distinguishes active from inactive EoE in children and adults and may facilitate monitoring of disease activity in a safe and minimally invasive fashion