Estimating the Economic Impacts of Gull Lake View Golf Club and Resort

Gull Lake View Golf Club and Resort, located in Augusta, Michigan, operates several golf courses in the greater Kalamazoo region. A significant portion of its clients is not only from outside the region, but also outside the state of Michigan. Along with golf operations, Gull Lake View offers lodging, spa services, eating and drinking establishments, and meetings, weddings, and other events. The Resort wanted to better understand from where outside the region its patrons come and the economic impact resulting from the activities generated by these patrons

Assessing Community Needs: City of Toledo and Lucas County, Ohio

At the core of issues in Lucas County and, in particular, the City of Toledo is poverty. While this does not necessarily provide an “Aha!” moment, current conditions that contribute to being economically disadvantaged in many areas of the city and county affect not only current residents but will also affect future residents—without meaningful and targeted interventions. It is beyond the scope of the Toledo Community Foundation, or any single institution for that matter, to unilaterally address the range of issues presented in this study. Remedying these issues must be accomplished through the coordination and leveraging of resources, including public, private, personal, and not-for-profit resources

The Nlrp3 inflammasome regulates acute graft-versus-host disease

The success of allogeneic hematopoietic cell transplantation is limited by acute graft-versus-host disease (GvHD), a severe complication accompanied by high mortality rates. Yet, the molecular mechanisms initiating this disease remain poorly defined. In this study, we show that, after conditioning therapy, intestinal commensal bacteria and the damage-associated molecular pattern uric acid contribute to Nlrp3 inflammasome-mediated IL-1β production and that gastrointestinal decontamination and uric acid depletion reduced GvHD severity. Early blockade of IL-1β or genetic deficiency of the IL-1 receptor in dendritic cells (DCs) and T cells improved survival. The Nlrp3 inflammasome components Nlrp3 and Asc, which are required for pro-IL-1β cleavage, were critical for the full manifestation of GvHD. In transplanted mice, IL-1β originated from multiple intestinal cell compartments and exerted its effects on DCs and T cells, the latter being preferentially skewed toward Th17. Compatible with these mouse data, increased levels of active caspase-1 and IL-1β were found in circulating leukocytes and intestinal GvHD lesions of patients. Thus, the identification of a crucial role for the Nlrp3 inflammasome sheds new light on the pathogenesis of GvHD and opens a potential new avenue for the targeted therapy of this severe complication

The Necrotic Signal Induced by Mycophenolic Acid Overcomes Apoptosis-Resistance in Tumor Cells

The amount of inosine monophosphate dehydrogenase (IMPDH), a pivotal enzyme for the biosynthesis of the guanosine tri-phosphate (GTP), is frequently increased in tumor cells. The anti-viral agent ribavirin and the immunosuppressant mycophenolic acid (MPA) are potent inhibitors of IMPDH. We recently showed that IMPDH inhibition led to a necrotic signal requiring the activation of Cdc42.Herein, we strengthened the essential role played by this small GTPase in the necrotic signal by silencing Cdc42 and by the ectopic expression of a constitutive active mutant of Cdc42. Since resistance to apoptosis is an essential step for the tumorigenesis process, we next examined the effect of the MPA–mediated necrotic signal on different tumor cells demonstrating various mechanisms of resistance to apoptosis (Bcl2-, HSP70-, Lyn-, BCR-ABL–overexpressing cells). All tested cells remained sensitive to MPA–mediated necrotic signal. Furthermore, inhibition of IMPDH activity in Chronic Lymphocytic Leukemia cells was significantly more efficient at eliminating malignant cells than apoptotic inducers.These findings indicate that necrosis and apoptosis are split signals that share few if any common hub of signaling. In addition, the necrotic signaling pathway induced by depletion of the cellular amount of GTP/GDP would be of great interest to eliminate apoptotic-resistant tumor cells

Recovery of cortical effective connectivity and recovery of consciousness in vegetative patients

Patients surviving severe brain injury may regain consciousness without recovering their ability to understand, move and communicate. Recently, electrophysiological and neuroimaging approaches, employing simple sensory stimulations or verbal commands, have proven useful in detecting higher order processing and, in some cases, in establishing some degree of communication in brain-injured subjects with severe impairment of motor function. To complement these approaches, it would be useful to develop methods to detect recovery of consciousness in ways that do not depend on the integrity of sensory pathways or on the subject's ability to comprehend or carry out instructions. As suggested by theoretical and experimental work, a key requirement for consciousness is that multiple, specialized cortical areas can engage in rapid causal interactions (effective connectivity). Here, we employ transcranial magnetic stimulation together with high-density electroencephalography to evaluate effective connectivity at the bedside of severely brain injured, non-communicating subjects. In patients in a vegetative state, who were open-eyed, behaviourally awake but unresponsive, transcranial magnetic stimulation triggered a simple, local response indicating a breakdown of effective connectivity, similar to the one previously observed in unconscious sleeping or anaesthetized subjects. In contrast, in minimally conscious patients, who showed fluctuating signs of non-reflexive behaviour, transcranial magnetic stimulation invariably triggered complex activations that sequentially involved distant cortical areas ipsi- and contralateral to the site of stimulation, similar to activations we recorded in locked-in, conscious patients. Longitudinal measurements performed in patients who gradually recovered consciousness revealed that this clear-cut change in effective connectivity could occur at an early stage, before reliable communication was established with the subject and before the spontaneous electroencephalogram showed significant modifications. Measurements of effective connectivity by means of transcranial magnetic stimulation combined with electroencephalography can be performed at the bedside while by-passing subcortical afferent and efferent pathways, and without requiring active participation of subjects or language comprehension; hence, they offer an effective way to detect and track recovery of consciousness in brain-injured patients who are unable to exchange information with the external environment