How do ambient and structural variables influence the entry into and full passage of drainage culverts by mammals and their ability to act as wildlife passages?

Roads present a significant barrier to wildlife movement for many species. While designated wildlife crossing structures have been heralded as an attractive solution to many of the problems associated with roads, they are often prohibitively expensive. Autoroute 10 in Southern Quebec is one of many highways in Canada that would benefit from such structures, but currently has none in place. However, the highway has a series of periodically placed drainage culverts designed to allow water to cross underneath the road surface. Through monitoring trail camera footage inside of 13 drainage culverts, and animal track stations along a 20 kilometre stretch of highway A10, this project aims to (1) determine what factors influence the number of full passages of drainage culverts by mammals, and (2) parse the effects that these factors have on the entry into and subsequent full passage of drainage culverts by individual animals. Overall, 20 species were observed outside of the drainage culverts in this study, but only animals highly tolerant to water, including raccoons and American mink, were observed fully crossing the structures with regularity. Water level and polyethylene as a construction material were the strongest deterrents for both the number of full passages, as well as entry into the culverts. Additionally, we found that many factors influenced an individual entering a culvert, while no variables impacted its full passage once it had entered. Moving forward, this data will be invaluable in determining where best to focus future habitat fragmentation mitigation efforts along highway 10. In this study we introduced zero-inflated negative binomial generalized linear mixed models as a statistical method in a road ecology study for analyzing the effects that variables have on excess zeros in the data, as well as the value of combining trail camera data inside of drainage culverts with track data in the adjacent habitat. We conclude that drainage culverts are ultimately not suitable substitutes for designated crossing structures for mammals, and recommend that where it is not feasible to install designated wildlife crossing structures, dry ledges be installed in existing drainage culverts to better allow small- and medium-sized mammals to safely cross under the road surface while avoiding the water inside of them. Future road ecology studies are needed along all major highways, both with and without mitigation measures already in place, to better understand the effects that roads are having on wildlife

Raising the Bar: The Modern Community College Presidency

One of the largest challenges facing community colleges in the new millennium is identifying leaders who possess the necessary skills and competencies to successfully navigate the modern presidency. Facing a dynamic shift in the fiscal landscape, community college presidents are tasked with filling the gap between institutional needs and existing forms of financial support. The purpose of this study was to examine community college presidents with former fundraising backgrounds and to explore the impact of prior fundraising experience on their current roles. Because the president plays a pivotal role in the acquisition of alternative funding sources, the effectiveness of this leader is critical to the overall mission of the institution; therefore, it is necessary to understand how their prior experiences in fundraising may impact the ease with which they develop and engage in external relationships with key constituents. Employing purposive sampling methods, three current community college presidents serving public, single-campus two-year colleges with institutionally affiliated foundations were selected as case study participants. The qualitative research design engaged various methods of data collection with face-to-face semi-structured interviews serving as the primary data source, accompanied by document collection, observational field notes, and reflexive journal entries. In this inquiry, the research questions spanned three broad categories, which served as the framework for coding and analyzing the data. The categories included: (a) impact of full-time fundraising experience; (b) fundraising skills and competencies perceived as valuable to the community college presidency; and (c) advice for aspiring college presidents. The findings suggested that advancement professionals are well suited for the presidency based on the heightened expectation of fundraising as a means of achieving financial stability and the increasingly external nature of the presidency. The valuable fundraising skills and competencies recommended for today\u27s leaders included personalized communication and the ability to build lasting relationships with a variety of constituents. The study\u27s participants offered advice for future leaders related to organizational leadership and professional preparation based upon their own personal journey to the presidency. The highly transferable skills that presidents with prior fundraising experience bring to the position establish them as qualified and effective candidates for the modern presidency

Direct and Catalytic C-Glycosylation of Arenes: Expeditious Synthesis of the Remdesivir Nucleoside

Since early 2020, scientists have strived to find an effective solution to fight SARS-CoV-2, especially by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stage of the infection. However, the current synthetic routes rely on the use of protecting groups, air-sensitive reagents, and cryogenic conditions, impeding the cost-efficient supply to patients. We therefore focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium-catalyzed and completely stereoselective C -glycosylation that initially yields the open-chain polyols, which can be selectively cyclized to provide either the kinetic α-furanose or the thermodynamically favored β-anomer. The method significantly expedites the synthesis of Remdesivir precursor GS-441524 after subsequent Mn-catalyzed C–H oxidation and deoxycyanation

Intrinsic resistance to PIM kinase inhibition in AML through p38α-mediated feedback activation of mTOR signaling

Although conventional therapies for acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) are effective in inducing remission, many patients relapse upon treatment. Hence, there is an urgent need for novel therapies. PIM kinases are often overexpressed in AML and DLBCL and are therefore an attractive therapeutic target. However, in vitro experiments have demonstrated that intrinsic resistance to PIM inhibition is common. It is therefore likely that only a minority of patients will benefit from single agent PIM inhibitor treatment. In this study, we performed an shRNA-based genetic screen to identify kinases whose suppression is synergistic with PIM inhibition. Here, we report that suppression of p38α (MAPK14) is synthetic lethal with the PIM kinase inhibitor AZD1208. PIM inhibition elevates reactive oxygen species (ROS) levels, which subsequently activates p38α and downstream AKT/mTOR signaling. We found that p38α inhibitors sensitize hematological tumor cell lines to AZD1208 treatment in vitro and in vivo. These results were validated in ex vivo patient-derived AML cells. Our findings provide mechanistic and translational evidence supporting the rationale to test a combination of p38α and PIM inhibitors in clinical trials for AML and DLBCL

Modulation of the <i>Neisseria gonorrhoeae </i>drug efflux conduit MtrE

We acknowledge funding through the Wellcome Trust Interdisciplinary Research Funds (grant WT097818MF), the Scottish Universities’ Physics Alliance (SUPA), Tenovus Tayside (grant T16/30) and the Tayside Charitable Trust. O.N.V. has been funded through a BBSRC CASE award (BB/J013072/1).Widespread antibiotic resistance, especially of Gram-negative bacteria, has become a severe concern for human health. Tripartite efflux pumps are one of the major contributors to resistance in Gram-negative pathogens, by efficiently expelling a broad spectrum of antibiotics from the organism. In Neisseria gonorrhoeae, one of the first bacteria for which pan-resistance has been reported, the most expressed efflux complex is MtrCDE. Here we present the electrophysiological characterisation of the outer membrane component MtrE and the membrane fusion protein MtrC, obtained by a combination of planar lipid bilayer recordings and in silico techniques. Our in vitro results show that MtrE can be regulated by periplasmic binding events and that the interaction between MtrE and MtrC is sufficient to stabilize this complex in an open state. In contrast to other efflux conduits, the open complex only displays a slight preference for cations. The maximum conductance we obtain in the in vitro recordings is comparable to that seen in our computational electrophysiology simulations conducted on the MtrE crystal structure, indicating that this state may reflect a physiologically relevant open conformation of MtrE. Our results suggest that the MtrC/E binding interface is an important modulator of MtrE function, which could potentially be targeted by new efflux inhibitors.Publisher PDFPeer reviewe

A83-01 inhibits TGF-β-induced upregulation of Wnt3 and epithelial to mesenchymal transition in HER2-overexpressing breast cancer cells

PurposeThe aim of this study is to investigate the mechanisms of interactions between TGF-β and Wnt/β-catenin pathways that induce and regulate EMT and promote breast cancer cells to become resistant to treatment.MethodsThe effect of TGF-β on Wnt/β-catenin signaling pathway was examined by using a human Wnt/β-catenin-regulated cDNA plate array and western blot analysis. The interaction of Twist at promoter of Wnt3 was examined by chromatin immunoprecipitation (ChIP) assay. Secreted Wnt3 level was determined by ELISA assay.ResultsHER2-overexpressing breast cancer cells treated with TGF-β have a reduced response to trastuzumab and exhibited EMT-like phenotype. The TGF-β-induced EMT in HER2-cells was concordant with upregulation of Wnt3 and β-catenin pathways. The TGF-β-induced induction of Wnt3 during EMT was found to be Smad3-dependent. ChIP analysis identified occupancy of Twist at promoter region of Wnt3. Knock-down of Twist by shRNA confirmed the significance of Twist in response to TGF-β regulating Wnt3 during EMT. Subsequently, TGF-β-induced matrix metalloproteinases, MMP1, MMP7, MMP9, MMP26, Vascular endothelial growth factors (VEGF), and activation of Wnt/β-catenin signaling were repressed by the shRNA treatment. TGF-βR1 ALK5 kinase inhibitor, A83-01 can effectively prevent the TGF-β-induced Twist and Wnt3. Co-treating A83-01 and trastuzumab inhibited TGF-β-induced cell invasion significantly in both trastuzumab responsive and resistant cells.ConclusionsOur data demonstrated an important interdependence between TGF-β and Wnt/β-catenin pathways inducing EMT in HER2-overexpressing breast cancer cells. Twist served as a linkage between the two pathways during TGF-β-induced EMT. A83-01 could inhibit the TGF-β-initiated pathway interactions and enhance HER2-cells response to trastuzumab treatment

Essays on Investor Preferences

Investor preferences have been relocating, bringing portfolio risk further to the fore and sustainability newly supervening the risk-return trade-off postulated by standard portfolio theory. This cumulative thesis comprises three essays dealing with these investor preferences. The first and second paper of this thesis attempt to provide a better understanding of the motives of sustainable retail investors. The first paper studies whether engagement in sustainable consumer behavior spills over to or substitutes sustainable investments. I observe inconsistent behavior, as investors' sustainability-conscious consumer habits negatively relate to their likelihood to invest in sustainable funds. This is in line with the theory of moral licensing according to which sustainable consumers are relieved from a guilty conscience about putting their investments' financial returns in the first place, whereas the remaining consumers seek moral balance through sustainable investments. The second paper uses a quasi-experimental design together with a survey to determine the relation between individuals' sustainability awareness in non-investment-related decision making and sustainable investment preferences. We find that awareness for sustainability that is detached from investment decisions positively relates to sustainable investment choices among the clients of robo advisors. The papers provide advice to practitioners that facilitates the development of sound marketing strategies for sustainable financial products, to help unlock more of the hidden retail investor potential for sustainable investments. The third paper in this thesis addresses the risk preferences of institutional private equity investors. It assesses whether the models commonly used in practice are adequate to capture private equity portfolio risk, as they assume well-diversified portfolios. A random portfolio selection procedure shows that the idiosyncratic portfolio risk in private equity is underestimated, even in large limited partner portfolios. Moreover, the results of a mixed-effects model indicate that limited partners differ regarding their ability to diversify their portfolio. Our results serve practitioners as they indicate that limited partners should include idiosyncratic portfolio risk to their reporting

Hans Malmede: Jugendkriminalität und Zwangserziehung im deutschen Kaiserreich bis 1914. Ein Beitrag zur Historischen Jugendforschung. Baltmannsweiler: Schneider Verlag Hohengehren 2002 (250 S.) [Rezension]

Rezension von. Hans Malmede: Jugendkriminalität und Zwangserziehung im deutschen Kaiserreich bis 1914. Ein Beitrag zur Historischen Jugendforschung. Baltmannsweiler: Schneider Verlag Hohengehren 2002 (250 S.; ISBN 3-89676-598-1; 19,80 EUR)