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"Brock, Pope"
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Charlatan : America's most dangerous huckster, the man who pursued him, and the age of flimflam
Tells the story of the little-known Dr. John Brinkley and his unquenchable thirst for fame and fortune and Morris Fishbein, a quackbuster extraordinaire who relentlessly pursued the greatest charlatan of the 1920s and 1930s.
Book
Functional kinome profiling reveals brain protein kinase signaling pathways and gene networks altered by acute voluntary exercise in rats
Regular exercise confers numerous physical and mental health benefits, yet individual variability in exercise participation and outcomes is still poorly understood. Uncovering the neurobiological mechanisms governing exercise behavior is essential for promoting physical activity and developing targeted interventions for related disorders. While genetic studies have provided insights, they often cannot account for protein-level alterations, such as changes in kinase activity. Here, we employ protein kinase activity profiling to delineate brain protein kinase activity and signaling networks modulated by acute voluntary exercise in rats. Focusing on the dorsal striatum, which governs voluntary exercise, as well as the hippocampus, which is susceptible to modulation by physical activity, we aim to understand the molecular basis of exercise behavior. Utilizing high throughput kinome array profiling and advanced pathway analyses, we identified protein kinase signaling pathways implicated in regulating voluntary exercise. Pathway analysis using Gene Ontology (GO) revealed significant alterations in 155 GO terms in the dorsal striatum and 206 GO terms in the hippocampus. Changes in kinase activity were observed in the striatum and hippocampus between the exercise (voluntary wheel running, VWR) and sedentary control rats. In both regions, global serine-threonine kinase (STK) activity was decreased, while global phospho-tyrosine kinase (PTK) activity was increased in VWR rats compared to control rats. We also identified specific kinases altered in VWR rats, including the IKappaB Kinase (IKK) and protein kinase delta (PKD) families. C-terminal src Kinase (CSK), epidermal growth factor (EGFR), and vascular endothelial growth factor receptor (VEGFR) tyrosine kinase were also enriched. These findings suggest regional heterogeneity of kinase activity following voluntary exercise, emphasizing potential molecular mechanisms underlying exercise behavior. This exploratory study lays the groundwork for future investigations into the causality of variations in exercise outcomes among individuals and different sexes, as well as the development of targeted interventions to promote physical activity and combat associated chronic diseases.
Journal Article
Paneth-cell-disruption-induced necrotizing enterocolitis in mice requires live bacteria and occurs independently of TLR4 signaling
Necrotizing enterocolitis (NEC) remains a leading cause of morbidity and mortality in premature infants. Both human surgical specimens and animal models suggest a potential involvement of Paneth cells in NEC pathogenesis. Paneth cells play critical roles in epithelial homeostasis, innate immunity and host-microbial interactions. Yet, the complex interplay between Paneth cell disruption, epithelial barrier dysfunction and microbial-driven inflammation remains unclear in the immature intestine. In this study, mucosal intestinal injury consistent with human NEC was induced in postnatal day 14-16 (P14-P16) mice by disrupting Paneth cells, followed by gavage with
Mucosal injury was determined by histology, serum cytokine levels and epithelial barrier dysfunction. Toll-like receptor 4 (TLR4) activation was examined using protein expression, gene expression, and
mice. Finally, the role of bacteria was evaluated using heat-killed bacteria, conditioned media,
and cecal slurries. We found that live bacteria were required to induce injury; however, TLR4 activation was not required. NEC induced by Paneth cell disruption results in altered localization of tight junction proteins and subsequent loss of barrier function. Prior research has shown a requirement for TLR4 activation to induce NEC-like damage. However, many infants develop NEC in the absence of Gram-negative rod bacteremia, raising the possibility that alternative pathways to intestinal injury exist. In this study, we show a previously unknown mechanism for the development of intestinal injury equivalent to that seen in human NEC and that is not dependent on TLR4 pathways. These data are congruent with the new hypothesis that NEC may be the consequence of several disease processes ending in a final common inflammatory pathway.
Journal Article
Corticosterone as a Potential Confounding Factor in Delineating Mechanisms Underlying Ketamine’s Rapid Antidepressant Actions
Recent research into the rapid antidepressant effect of subanesthetic doses of ketamine have identified a series of relevant protein cascades activated within hours of administration. Prior to, or concurrent with, these activation cascades, ketamine treatment generates dissociative and psychotomimetic side effects along with an increase in circulating glucocorticoids. In rats, we observed an over 3-fold increase in corticosterone levels in both serum and brain tissue, within an hour of administration of low dose ketamine (10 mg/kg), but not with (2R, 6R)-hydroxynorketamine (HNK) (10 mg/kg), a ketamine metabolite shown to produce antidepressant-like action in rodents without inducing immediate side-effects. Hippocampal tissue from ketamine, but not HNK, injected animals displayed a significant increase in the expression of sgk1 , a downstream effector of glucocorticoid receptor signaling. To examine the role conscious sensation of ketamine’s side effects plays in the release of corticosterone, we assessed serum corticosterone levels after ketamine administration while under isoflurane anesthesia. Under anesthesia, ketamine failed to increase circulating corticosterone levels relative to saline controls. Concurrent with its antidepressant effects, ketamine generates a release of glucocorticoids potentially linked to disturbing cognitive side effects and the activation of distinct molecular pathways which should be considered when attempting to delineate the molecular mechanisms of its antidepressant function.
Journal Article
Tumor Necrosis Factor Induces Developmental Stage-Dependent Structural Changes in the Immature Small Intestine
Background. Premature infants are commonly subject to intestinal inflammation. Since the human small intestine does not reach maturity until term gestation, premature infants have a unique challenge, as either acute or chronic inflammation may alter the normal development of the intestinal tract. Tumor necrosis factor (TNF) has been shown to acutely alter goblet cell numbers and villus length in adult mice. In this study we tested the effects of TNF on villus architecture and epithelial cells at different stages of development of the immature small intestine. Methods. To examine the effects of TNF-induced inflammation, we injected acute, brief, or chronic exposures of TNF in neonatal and juvenile mice. Results. TNF induced significant villus blunting through a TNF receptor-1 (TNFR1) mediated mechanism, leading to loss of villus area. This response to TNFR1 signaling was altered during intestinal development, despite constant TNFR1 protein expression. Acute TNF-mediated signaling also significantly decreased Paneth cells. Conclusions. Taken together, the morphologic changes caused by TNF provide insight as to the effects of inflammation on the developing intestinal tract. Additionally, they suggest a mechanism which, coupled with an immature immune system, may help to explain the unique susceptibility of the immature intestine to inflammatory diseases such as NEC.
Journal Article
Southern Comfort
A user's guide to the Pawleys Island Hammock and the place whence it comes
Magazine Article
The Swordsman
Peter Westbrook, the greatest saber fencer in the US, is profiled. Half black and half Japanese, he has dominated the traditionally Caucasian sport.
Magazine Article
