Pilot Project Funding Opportunities

Learn about funding opportunities offered through the UMCCTS in the 2012-2013 academic year. Bill Thomas and Greg Babcock describe the resources available at MassBiologics and the new Next Hundred Million Pilot Program funding opportunity

mTORC1 contributes to ER stress induced cell death

Indiana University-Purdue University Indianapolis (IUPUI)Patients with the genetic disorder tuberous sclerosis complex (TSC) suffer from neoplastic growths in multiple organ systems. These growths are the result of inactivating mutations in either the TSC1 or TSC2 tumor suppressor genes, which negatively regulate the activity of mammalian target of rapamycin complex 1(mTORC1). There is currently no cure for this disease; however, my research has found that cells harboring TSC2-inactivating mutations derived from a rat model of TSC are sensitive to apoptosis induced by the clinically approved proteasome inhibitor, bortezomib, in a manner dependent on their high levels of mTORC1 activation. We see that bortezomib induces the unfolded protein response (UPR) in our cell model of TSC, resulting in cell death via apoptosis. The UPR is induced by accumulation of unfolded protein in the endoplasmic reticulum (ER) which activates the three branches of this pathway: Activating transcription factor 6 (ATF6) cleavage, phosphorylation of eukaryotic initiation factor 2α (eIF2α), and the splicing of X-box binding protein1 (XBP1) mRNA. Phosphorylation of eIF2α leads to global inhibition of protein synthesis, preventing more unfolded protein from accumulating in the ER. This phosphorylation also induces the transcription and translation of ATF4 and CCAAT-enhancer binding protein homologous protein (CHOP). Blocking mTORC1 activity in these cells using the mTORC1 inhibitor, rapamycin, prevented the expression of ATF4 and CHOP at both the mRNA and protein level during bortezomib treatment. Rapamycin treatment also reduced apoptosis induced by bortezomib; however, it did not affect bortezomib-induced eIF2α phosphorylation or ATF6 cleavage. These data indicate that rapamycin can repress the induction of UPR-dependent apoptosis by suppressing the transcription of ATF4 and CHOP mRNAs. In addition to these findings, we find that a TSC2-null angiomyolipoma cell line forms vacuoles when treated with the proteasome inhibitor MG-132. We found these vacuoles to be derived from the ER and that rapamycin blocked their formation. Rapamycin also enhanced expansion of the ER during MG-132 stress and restored its degradation by autophagy. Taken together these findings suggest that bortezomib might be used to treat neoplastic growths associated with TSC. However, they also caution against combining specific cell death inducing agents with rapamycin during chemotherapy

Electron Affinity of Chlorine Dioxide

The flowing afterglow technique was used to determine the electron affinity of chlorine dioxide. A value of 2.37 ± 0.10 eV was found by bracketing between the electron affinities of HS° and SF4 as a lower limit and that of NO2 as an upper limit. This value is in excellent agreement with 2.32 eV predicted from a simple thermodynamic cycle involving the reduction potential of the C102/C102- couple and a Gibbs hydration energy identical with that of SO2-

Approaches to healthcare personnel exemption requests from coronavirus disease 2019 (COVID-19) vaccination: Results of a national survey

OBJECTIVE: Although a growing number of healthcare facilities are implementing healthcare personnel (HCP) coronavirus disease 2019 (COVID-19) vaccination requirements, vaccine exemption request management as a part of such programs is not well described. DESIGN: Cross-sectional survey. PARTICIPANTS: Infectious disease (ID) physician members of the Emerging Infections Network with infection prevention or hospital epidemiology responsibilities. METHODS: Eligible persons were sent a web-based survey focused on hospital plans and practices around exemption allowances from HCP COVID-19 vaccine requirements. RESULTS: Of the 695 ID physicians surveyed, 263 (38%) responded. Overall, 160 respondent institutions (92%) allowed medical exemptions, whereas 132 (76%) allowed religious exemptions. In contrast, only 14% (n = 24) allowed deeply held personal belief exemptions. The types of medical exemptions allowed varied considerably across facilities, with allergic reactions to the vaccine or its components accepted by 145 facilities (84%). For selected scenarios commonly used as the basis for religious and deeply held personal belief exemption requests, 144 institutions (83%) would not approve exemptions focused on concerns regarding right of consent or violations of freedom of personal choice, and 140 institutions (81%) would not approve exemptions focused on introducing foreign substances into one\u27s body or the sanctity of the body. Most respondents noted plans for additional infection prevention interventions for HCP who received an exemption for COVID-19 vaccination. CONCLUSIONS: Although many respondent institutions allowed exemptions from HCP COVID-19 vaccination requirements, the types of exemptions allowed and how the exemption programs were structured varied widely

Coronavirus disease 2019 (COVID-19) vaccination preparedness policies in US hospitals

We surveyed infectious disease specialists about early coronavirus disease 2019 (COVID-19) vaccination preparedness. Almost all responding institutions rated their facility\u27s preparedness plan as either excellent or adequate. Vaccine hesitancy and concern about adverse reactions were the most commonly anticipated barriers to COVID-19 vaccination. Only 60% believed that COVID-19 vaccination should be mandatory

Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice

<p>Abstract</p> <p>Background</p> <p>Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are expressed by microglia and infiltrating macrophages following ischemic stroke. Whereas IL-1β is primarily neurotoxic in ischemic stroke, TNF-α may have neurotoxic and/or neuroprotective effects. We investigated whether IL-1β and TNF-α are synthesized by overlapping or segregated populations of cells after ischemic stroke in mice.</p> <p>Methods</p> <p>We used flow cytometry and immunohistochemistry to examine cellular co-expression of IL-1β and TNF-α at 6, 12 and 24 hours after permanent middle cerebral artery occlusion in mice, validating the results by the use of bone marrow chimeric mice.</p> <p>Results</p> <p>We found that IL-1β and TNF-α were expressed in largely segregated populations of CD11b⁺CD45^dimmicroglia and CD11b⁺CD45^highmacrophages, with cells expressing both cytokines only rarely. The number of Gr1⁺granulocytes producing IL-1β or TNF-α was very low, and we observed no IL-1β- or TNF-α-expressing T cells or astrocytes.</p> <p>Conclusion</p> <p>Taken together, the results show that IL-1β and TNF-α are produced by largely segregated populations of microglia and macrophages after ischemic stroke in mice. Our findings provide evidence of a functional diversity among different subsets of microglia and macrophages that is potentially relevant to future design of anti-inflammatory therapies in stroke.</p

Classification and Ranking of Selectd Arkansas Lakes

Trophic-state related problems associated with waters in the United States have generated tremendous public interest and concern, particularly during the past decade. These interests and concerns led to Public Law 92-500, the mandate by Congress known as the Federal Water Pollution Control Act. Various sections of PL 92-500 directly address the need for trophic-state analyses, particularly Section 314 referred to as the Clean Lakes Program which assigns states the responsibility for classifying their lakes according to water quality, identifying methods of pollution control and restoring those lakes which have become degraded

Excavation at Aguas Buenas, Robinson Crusoe Island, Chile, of a gunpowder magazine and the supposed campsite of Alexander Selkirk, together with an account of early navigational dividers

Excavations were undertaken of a ruined building at Aguas Buenas, identified as an 18th-century Spanish gunpowder magazine. Evidence was also found for the campsite of an early European occupant of the island. A case is made that this was Alexander Selkirk, a castaway here from 1704 to 1709. Selkirk was the model for Defoe’s Robinson Crusoe. A detailed discussion is given of a fragment of copper alloy identifi ed as being from a pair of navigational dividers